Category Archive Cancer, Neoplasms and Palliative Care A – Z

What Is Peritoneal Cancer – Causes, Symptoms, Treatment

Peritoneal cancer is the invasion of the serous membrane lining the peritoneal cavity by malignant cells. The malignant cells originate de novo in the mesothelioma or disseminate from other primary tumor sites. It represents an advanced stage of cancer with a poor prognosis. To decrease morbidity and mortality, early diagnosis and prompt management are essential. The article reviews the etiology, epidemiology, and pathogenesis associated with the disease. It also highlights the role of the interprofessional team required in the management of peritoneal cancer.

The invasion of the serous membrane lining the abdominal cavity, viscera, and coelom in amniotes by malignant cells is called peritoneal surface malignancy or peritoneal cancer (PC). It is divided into primary and secondary types. The de novo origin of cancer in the mesothelium of the abdomen causes primary mesothelioma. In contrast, the dissemination of tumor cells in the peritoneal cavity from other sites results in secondary peritoneal cancer. Primary cancer has been classified based on its histology by investigators. Extraovarian primary peritoneal carcinoma (EOPPC), serous surface papillary carcinoma, papillary serous carcinoma of the peritoneum, extra ovarian Mullerian adenocarcinoma, and normal-sized ovarian carcinoma syndrome all are different terms used for the first type.

Other types include malignant mesothelioma (MPM), multicystic mesothelioma, leiomyosarcomas, leiomyomatosis peritoneal disseminate, and desmoplastic small round cells tumor (DSRCT). Swerdlow first reported EOPPC as ‘Mesothelioma of pelvic peritoneum’ in a case report published in 1959. It behaves similarly to serous ovarian cancer with little or no involvement of ovaries. All the types have variable histological features but are alike in their presentation, diagnostic evaluation, and treatment methods. Secondary or metastatic peritoneal carcinomatosis arises commonly from primitive malignancies involving gastrointestinal and gynecological structures. The metastasis occurs via transcoelomic, vascular, or lymphatic routes. It was first described in 1931 as a local spread from ovarian cancer.

Primary cancer is classed as stage III or IV and metastasis as stage IV. The vague clinical presentation is responsible for late diagnosis and an overall decrease in survival. The surgical resection and intraperitoneal chemotherapy form hallmarks for disease eradication. However, a better understanding of peritoneum physiology and tumor seeding pathways combined with advancement in technologies has led to the development of effective treatment therapies. In the absence of extensive systemic disease, locoregional control of the disease can provide a promising role in the management of this late-stage cancer.

Causes of Peritoneal Cancer

Primary peritoneal cancer is idiopathic cancer arising from the peritoneal layers of the abdominal cavity. Its subtype, EOPPC, resembles serous ovarian carcinoma and occurs exclusively in women (mean age, 56-62 years). There are just a few reports of its occurrence in males. It can be caused by germline mutations in the BRCA 1 gene which has been reported in 17.6% of cases. Thus, in any patient with familial breast cancer, serous peritoneal cancer should be excluded. Malignant peritoneal mesothelioma is an aggressive tumor caused by asbestos exposure in 33% to 50% of cases and occurs in older males (60 years and older).

Disseminated peritoneal leiomyomatosis is associated with a high estrogenic state in postmenopausal women. Leiomyosarcoma is a secondary tumor occurring in Li Fraumeni syndrome along with retinoblastoma. Desmoplastic round small cell tumor occurs in adolescents (median age 19 years) and 85% in Caucasians.

Secondary peritoneal carcinomatosis is commonly caused by invading malignant cells from tumors involving the stomach, colon, pancreas, gall bladder, appendix, breast, uterus, ovary, and lungs. The peritoneal involvement in appendiceal cancer is called pseudomyxoma peritonei (PMP). It is successfully managed and results in a lifetime without relapse. The metastasis from ovarian, gastric, and colorectal malignancies is associated with increased chances of recurrence and fatality, and they are also the three most common etiologies of metastatic spread in the peritoneum.

The peritoneum is the serous membrane lining the abdomen, which supports the abdominal viscera and provides a conduit for blood, lymph, and nerve conduction. It consists of two layers; the parietal peritoneum, attached with the abdominal wall, and the visceral peritoneum surrounding the organs. The space between the bilaminar layers is the abdominal cavity or coelom and contains the peritoneal fluid, which encloses abdominal organs and provides lubrication for peristaltic movements. Its volume is around 100ml.

The peritoneum is the largest dynamic membrane that can adapt according to different pathologies. Histologically, it consists of mesothelium and submesothelial connective tissue, separated by a thin basement membrane called basal lamina comprising of collagen IV and laminin. The elastic matrix is made of collagen I, III, and cells such as fibroblasts, adipocytes, and macrophages. It also hosts lymphatics and blood vessels. The mesodermal layer is derived from mesoderm and has both the characteristics of epithelial and mesenchymal cells. It acts as the first line of defense due to the tight junctions among the cells and also expresses cytokeratin, fibronectin, and other markers. It binds tumor cells with the peritoneum. The peritoneal deposits occur at sites of immune cell aggregates, ‘milky spots’ named by Ranvier, and contain mesothelial cells and blood vessels. The submesothelial stroma causes adhesion to cancer cells via integrins and hence, penetration into the peritoneum.

The carcinogenesis of peritoneal cancers can be explained by ‘seed and soil theory’ given by Stephen Paget. It describes how a malignant tumor gives up cells (seeds) that travel in all directions but can only survive and multiply at tumor accepting localizations (soil). It explains the predilection of colorectal, ovarian, and gastric tumor cells for the peritoneum. Organ-specific metastasis is due to molecular interaction and compatibility between receptors on malignant cells and ligands on host cells. This was explained by Sugarbaker in 1979.

The primary spread from the tumor is due to the extensive intramural growth beyond the serosal layers. The secondary seeding occurs in surgical tumor resections that result in the spillage of malignant cells. The first step is the detachment of cancer cells from the primary due to the down-regulation of intracellular adhesion molecules called E- Cadherin. Then, tumors cells enter the bloodstream, lymphatics, or intracoelomic route to be carried to distant specific sites, and vascular factors present in the peritoneal fluid promote their growth during transport. The process of metastasis, including adhesion, degradation, migration, angiogenesis, and immune evasion, follows.

The adhesion molecules on mesothelial cells like intercellular adhesion molecule 1 (ICAM-1), and vascular adhesion molecule 1 (VCAM-1) interact with tumor cells’ receptors like CD44 and cytokines such as tumor necrosis alpha (TNFa), interleukin- 1beta, and interleukin-1gamma are released. Hence, the basement membrane is exposed. CD44 has a role in metastasis of colorectal and ovarian cancer. In trans-lymphatic metastasis, cells enter the lymph capillaries at milky spots or lymphatic stomata. It is seen in PMP. The cells then invade the submesothelial stroma, where the hepatocyte growth factor (HPF) binds to its tyrosine kinase receptor and start the growth of the tumor. This is mediated by the c-MET protoncogene. The fibroblasts and macrophages present within the matrix secrete metalloproteinases (MTP) and degrade the peritoneal-blood border in the stroma. This results in the progression of metastasis. Finally, the growth of tumors takes place by the production of growth factors like IGF-1 and EGFR. To sustain this exponential production of cells, newer blood vessels are formed through the production of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor 1 (HIF-1).

EOPPC pathogenesis can be explained by the theory of retention of ‘differentiating potential’ by mesothelial cells of the peritoneum. The cells undergo a malignant transformation called ‘Mullerian metaplasia’. The same embryonal mesoderm forms the germinal epithelium of ovaries and mesothelial cells of the peritoneum, which explains the resemblance of the two tumors. The oncogenic stimulus is the loss of heterozygosity at p53 or BRCA-1 loci or the overexpression of Her-2/neu. Its pathogenesis is also explained with the multifocal origin of the tumor. The process of nonrandom X chromosome inactivation follows a consistent pattern, that indicates the unifocal origin of tumors. However, different patterns of inactivation result in tumors that have independent sites of development. Gu et al. did a study regarding the clonality of peritoneal and ovarian cancer. 54% of patients showed nonrandom inactivation, and most had different patterns.

Histologically, psammoma bodies are characteristic of this tumor.

Asbestos exposure is linked to the development of MPM. Other risk factors are talc, mica, erionite, volcanic ash, radiation, and chronic peritonitis. Asbestos inhalation is responsible for causing cellular damage, which leads to carcinogenesis. The following essential processes explain it:

  • Asbestos in the body produces reactive oxygen species damaging DNA.
  • Asbestos fibers either physically disrupt the cell cycle genes by entering mesothelial cells or induce inflammation and tumorigenesis by releasing cytokines and growth factors from macrophages and mesothelial cells. Epigenetic modifiers like BRCA-1 associated protein-1 (BAP-1) and cyclin-dependent kinase inhibitor 2A/ alternative reading frame (CDKN2A/ARF) genes are specific for mesothelial cell transformation in MPM. High-mobility group box 1(HMGB1) produced by mesothelial cells causes necrosis, inflammation, and carcinogenesis. TNFa released by macrophages causes activation of nuclear factor-kb and promotes cell survival.
  • Lastly, the large surface area of asbestos renders it to absorb more carcinogens, thus promoting malignancy.

Histologically, they are divided into epithelial, sarcomatous, and bimorphic types.

Leiomyosarcomas show variable smooth muscle actin and eosinophilic spindle cells. It is caused by a deletion in retinoblastoma gene1 (RB1) 10q and PTEN 13q. The mutations at TP53 also add to the risk.

Desmoplastic small round cell tumor, a small round blue cell tumor, is associated with Ewing tumor family chromosomal translocation t(11;22)(p13;q12), causing the formation of EWSR1-WT1 fusion oncogene that result in tumor development.

Complications related to peritoneal metastases:

  • Ascites: Peritoneal metastases tend to produce fluid in the abdomen, known as ascites, which causes abdominal distension (Figure 2).
  • Intestinal obstruction: Peritoneal metastases may cause blockage of the intestines.
  • Hydronephrosis: The kidney ureters may be blocked by peritoneal metastases. This may affect kidney function.
  • Bloating
  • Abdominal pain
  • Nausea and vomiting
  • Constipation
  • Loss of appetite
  • Weight loss

Diagnosis of Peritoneal Cancer

Clinical presentation in peritoneal cancer is variable depending on the extent of involvement. It is usually diagnosed in late stages due to the vague symptomatology. EOPPC has an indistinguishable presentation from epithelial ovarian cancer. The Gynecologic Oncology Group has defined the following criterion for EOPPC diagnosis:

  • Both ovaries should be of normal size, and the enlargement is benign.
  • The surface area of malignant involvement of extra-ovarian sites should be larger than either of the ovaries.
  • There should be no malignancy in either ovaries or the tumor in serosa, and cortex of size less than 5X5 mm can be present.
  • The tumor in the extra-ovarian site should be serosal both histologically and cytologically.

All the peritoneal carcinomas present with non-specific symptoms like abdominal bloating, distension, nausea, indigestion, anorexia, weight loss, fatigue, constipation, abdominal or back pain. The most common symptoms for presentation are abdominal distension and pain, while usual signs are palpable abdominal mass and ascites. Non-specific abdominal symptoms and ascites occur in 85% of the patients. Tumor-associated lymphadenopathy causes local mass effects and can even lead to obstruction of superior vena cava. This has been seen primarily in peritoneal malignant mesothelioma. Patients with DSRCT can also present with hematemesis in some cases. The mesothelium involvement in the absence of primary is occasionally seen as an incidental finding in laparotomy or autopsy.

Peritoneal carcinomatosis has characteristic symptoms of the primary tumor itself and non-specific symptoms. The secondary metastatic deposits may range from microscopic involvement to nodules to bulky disease, and this extent of involvement and location determines the symptoms.

The growth in both primary and secondary tumors causes pressure effects resulting in mechanical intestinal obstruction. Such patients present in an emergency with an ‘acute abdomen.’  Bowel obstructions are seen mainly in colorectal cancers in about 20% of cases. In the same study, ascites were reported in 43% of cases of pancreatic cancer.

Lab Test and Imaging

The ‘hidden’ existence of a malignant tumor in the peritoneum is responsible for increased fatality in patients of PC. Therefore, practical methods for early and timely diagnosis are required to prevent surgeries of unresectable tumors and harm from unnecessary chemotherapy drugs.

Techniques for diagnosing PC are crucial as most tumors are often discovered incidentally during the surgeries. It includes:

CT Scan

CT scan is the foremost modality used in patients presenting with abdominal pain and distension. In some cases, a preliminary test like Ultrasound (USG) is done. The USG is, however, unable to detect malignant granulations less than 2 cm in size. In PC, ultrasonographic features include ascites which is echo-free or have low-level echoes, and hyperechogenic nodules representing cell deposition in the peritoneum. Adhesion of bowel loops, omental matting, and lymphadenopathy can also be seen.

CT scans can detect granulations of size as small as 5mm. In PC, it has a sensitivity of 70% if the lesion is 2 cm, which is further reduced to 28% in the case of tumor size of 5 mm. The CT scan findings are non-specific and similar in both neoplastic and non-neoplastic conditions. Ascites is the most common finding together with contrast-enhanced diffuse or nodular thickening of the peritoneum. Oral and intravenous contrast material is administered, particularly for viewing small peritoneal deposits. It is true for cystic lesions but limits the identification of calcified lesions. In addition, omental cakes, defined as increased density of large cell masses between the bowel and anterior abdominal wall, are also seen.

The CT scan findings in EOPPC are similar together with normal ovaries and the absence of the primary tumor. Chiou et al. reported that common CT scan findings in primary PC are ascites (82%), peritoneal nodules (73%), omental caking (64%), and pelvic mass (36%).

In MPM, the CT scan identifies a solid, heterogeneous mass with irregular margins. It shows ascites in 60-100% of cases. The MPM usually lacks lymph nodes and distant metastasis.

The leiomyosarcomas show a contrast-enhanced heterogeneous solid and cystic mass with septations, necrosis, and calcifications.

The scan in the DSCRT demonstrates a well enhanced lobulated mass comprising of necrosis, hemorrhage, and fibrous components, usually in retrovesical or rectouterine space.

Hence, the CT scan is the primary diagnostic modality and also helps in guiding the interventional radiologists for conducting biopsies and surgeons for performing cytoreductive surgeries.

MRI Scan

Gadolinium (Gd)-enhanced MRI is better than the helical CT scan for visualization of small peritoneal carcinomatosis. The detection sensitivity of MRI is 84% for tumors of all sizes as compared to 54% for CT scans. The sensitivity is further increased for tumors with dimensions less than 1 cm (85-90%). For peritoneal tumors, T1 shows an intermediate signal, T2 high signal, and C+ (Gd) enhancement. The use of MRI in PC has increased over time and is now the imaging modality of choice for diagnosing and staging subcentimeter lesions due to its higher contrast resolution. The histological type is differentiated on biopsy due to resemblance in radiological appearances. Therefore, imaging techniques in PC are used for identification of the following aspects:

  • The primary site of metastasis.
  • The morphology of the main tumor as solid, cystic, or mixed.
  • The quantity of ascites.
  • The presence/absence of peritoneal dissemination.
  • Diffuse or nodular spread.
  • The lymphadenopathy and lymph nodes involved.
  • Distant sites of metastasis if present or not.

PET Scan

The mainstay of imaging modalities for PC is CT scans and MRIs. However, small peritoneal implants are not visible by them. In such cases, FDG PET-CT scan (2-[Fluorine 18] fluoro-2-deoxy-D-glucose positron emission tomography) has the potential to improve the detection. It identifies malignant cells due to their increased glucose metabolism. This method helps in early detection, staging, monitoring treatment response, and long-term follow up. The sensitivity of fused PET-CT scans (unenhanced) and PET-MDCT scans (multidetector) ranges between 58% to 100%. In the FDG PET-CT scan, false-negative results occur due to certain tumor cells that do not take up ‘F’ such as mucinous tumors of ovaries or signet ring gastric cancer. In contrast, false-positive results are seen in benign and inflammatory conditions where cells take up ‘F.’ The diffuse or nodular uptake of ‘F’ by cells in the peritoneum can result in detecting certain occult malignancies or metastasis and significantly impact the management of PC.

Invasive Techniques

The resemblance in radiological appearances of neoplastic and non-neoplastic lesions is responsible for establishing the requirement of invasive techniques. For example, the histological type and subtypes of the tumor can only be differentiated on biopsy. In PC, invasive procedures include:

  • 1. Abdominal percutaneous paracentesis.
  • 2. Diagnostic laparoscopy.

1. Paracentesis

Ascitic fluid analysis

In PC, ascites is exudative with high protein (2.5 mg/dl), elevated LDH (400 SU), and low glucose (40 mg/dl). The frank bloody ascites are seen in peritoneal carcinomatosis in only 10% cases, and blood-tinged (RBC >10,000 mm) ascites are seen in 8.3% of cases. Furthermore, increased levels of a vascular endothelial factor (VEGF), and some other tumor markers are also found in increased amounts.

Tumor Markers

To assess the effectiveness of tumor markers in diagnosing the malignancy, a study to determine the correlation of tumor markers in serum and ascites was done. Tumor markers such as carcinoembryonic antigen (CEA), CA 19-9, CA-125, CYFRA (cytokeratin fragments) were studied and reported to be highly correlated in both ascites and serum. Also, CA-125, CEA, and CYFRA are produced by normal epithelial cells and thus can be found in certain benign conditions. CYFRA was the only tumor marker found in higher quantities in malignant conditions. Still, no benefit of measuring the tumor markers in ascites than in serum was found for diagnosis. However, another study later reported that the use of tumor markers along with cytology in ascites increases the diagnostic yield by 37%. The combination of 3 tumor markers (CA 19-9, CA 15-3, CEA) was reported to have a sensitivity (86%) and specificity (97%) in cases of negative cytology. Regarding the significance of tumor marker measurement in ascites, different studies (using different cutoff levels of tumor markers) have rendered varying results. Hence, it is considered an unproven and unhelpful test due to its low sensitivity.

Cytology

Cytology is positive in first specimens in 83% of cases of malignant-related ascites, and yield increases to 93% and 97% if two and three samples are sent respectively. It provides beneficial results except in malignant mesothelioma. The sensitivity of peritoneal cytology for detecting malignancy is 50% to 70%. However, subtyping the tumor from cytology alone is difficult, and immunohistochemical (IHC) staining is required. It is essential to use the specific IHC stains for the correct tumor differentiation, grading, and providing appropriate treatment. The most commonly used stains in PC includes calretinin, cytokeratin, and BerEP4. The calretinin is a mesothelial marker and indicates the presence of both normal and malignant mesothelial cells. Calretinin and BerEP4 positive cells indicate their epithelial origin and are used for the diagnosis of EOPPC. The malignant mesothelioma stains negative for BerEP4 and positive for cytokeratin CK5/6, calretinin, and podoplanin. The DSRCT cells stains for cytokeratin, desmin, neuron-specific enolase, and WT1. The metastatic adenocarcinomas show no nuclear staining for calretinin and cytokeratins. The tumors from the upper gastrointestinal tract (GIT) are positive for CK-7 and show variable results for CDX2/CK20. In contrast, tumors from lower GIT are negative for CK-7 and positive for CDX2/CK20. This increases the chances of detection of malignancy and its pathological subtype from ascites, especially in ambiguous cases. However, a definite role remains unclear, and therefore it is just used as an adjunct.

2. Laparoscopy

Laparoscopy is a minimally invasive procedure that provides direct visualization for a directed peritoneal lavage and tumor identification with a sensitivity of 100%. Biopsies of suspected lesions are taken during laparoscopy, and histological diagnosis is made. It is a useful tool for staging the tumor. It also prevents extensive procedures like open laparotomies by differentiating an unresectable tumor from operatable ones. It is done by calculating PCI (peritoneal carcinomatosis index), which assesses the spread of tumors in thirteen abdominal regions and each of which gets a score of 3. The total score ranges from 0-39. The higher the PCI score, the worse the prognosis. It also predicts the response of surgery in PC patients. As compared to laparoscopy, abdominal exploration is also done by open laparotomy, which contributes to the detection of even 1-2 mm lesions.

Treatment of Peritoneal Cancer

The best therapeutic approach is adopting multimodal therapy for peritoneal cancer. A combination of surgery, chemotherapy and targeted therapy is the mainstay of treatment. Chemotherapy includes systemic and peritoneal chemotherapy. The foundation for implementing this treatment strategy was laid by Dr. Sugarbaker. Multiple clinical trials and systematic reviews have been done over time, which emphasizes the survival benefits of multimodal therapy over the traditional palliative approach (60 months vs. 4 to 12 months).

EOPPC is managed the same way as the serous ovarian carcinomas. Hysterectomy with bilateral salpingo-oophorectomy and omentectomy is done in all cases. It is followed by chemotherapy and targeted therapy with poly (ADP-ribose) polymerase (PARP) inhibitors that block DNA repair. It includes olaparib, rucaparib, niraparib, or veliparib. Platinum-based chemotherapy is favorable and used for the neo-adjuvant treatment strategy. However, many platinum-resistant tumors have proven unresponsive, and multimodal therapy is advantageous in such cases. A phase III clinical trial has indicated the superiority of intraperitoneal chemotherapy over intravenous in terms of overall survival (60 months Vs. 50 months, p=0.03). Moreover, debulking surgery, defined as wide excision of the tumor with <2 cm residual nodules, also called cytoreductive surgery (CRS), is performed with chemotherapy producing optimal results in 33% to 69% of patients. In contrast, salvage chemotherapy is employed in tumor recurrence and incorporates doxorubicin, methotrexate, paclitaxel, and 5-fluorouracil.

In MPM, cytoreductive surgery and intraperitoneal chemotherapy (IPC) are considered the first line. In intraperitoneal chemotherapy, heated (HIPEC), or early postoperative (EPIC), data collected favors the HIPEC. Drugs used are cisplatin along with mitomycin C, melphalan, ifosfamide. Systemic chemotherapy is considered in high surgical risk and recurrent tumors. Recent advances in immunotherapy with checkpoint inhibitors have shown activity in MPM.

In DSRCT, neo-adjuvant chemotherapy is the primary approach for management. Systemic chemotherapy comprising cyclophosphamide, ifosfamide, vincristine, etoposide, doxorubicin, and mesna (P6 protocol) is done, followed by aggressive surgical excision. However, the studies on using HIPEC as an adjunct therapy are still going on. Consolidative whole abdominal radiotherapy in the pediatric population in particular, and in adults generally is essential to improve the outcome.

Primary Leiomyosarcomas of the peritoneal cavity is an aggressive tumor that is managed with extensive wide margin surgeries in resectable tumors and systemic chemotherapy for metastatic disease. Pre and postoperative radiotherapy are of paramount importance.

The CRS and HIPEC have yielded tremendous evidence-based significance in this challenging metastatic disease of the peritoneum. Bypassing the hepatic metabolism and first-pass effect, intraperitoneal chemotherapy provides improved therapeutic ratio for drugs and overall better clinical outcomes.

Cytoreductive Surgery (CRS)

It is the procedure of surgically removing all the tumors from the parietal and visceral peritoneal layers, and incorporates both en-bloc resections of affected organs or tissues and peritonectomy. No tumor nodule greater than 2.5 mm is left. Electrosurgery is employed for visceral implants where surgical excision remains difficult and to limit bleeding from the visceral peritoneum.  Hence, the goal is the eradication of the macroscopically visible disease. However, due to associated enhanced morbidity, patient selection for this procedure is deemed essential. The PCI (peritoneal carcinomatosis index), a measure to quantify the extent of peritoneal involvement, and the histological tumor grade are used. Good performance status of the patient is also required. The PCI score > 17 in colorectal associated PC and PCI> 12 in gastric cancer are contraindications for the surgery. The tumor involvement of crucial anatomic sites of the abdomen and multiple extra-abdominal metastatic lesions also precludes the CRS. Moreover, the procedure requires technical skills and conduction of excellent hemostasis. The response of surgery is recorded by a ‘completeness of cytoreduction score (CCR). CCR 0 is no residual disease, CCR 1 is the minimal disease of <2.5 mm, CCR 2 is 2.5 mm-2.5 cm of the tumor, and CCR 3 is >2.5 cm of residual disease. The postoperative complications are responsible for long-term morbidity and include veno-thrombotic events, operative site abscess, anastomotic leaks, fistula, and long-term intensive care stay.

Hypothermic Intraperitoneal Chemotherapy (HIPEC)

It is the process of pumping powerful chemotherapy drugs at a temperature higher than average body temperature (usually 108F/41-43C) into the peritoneal cavity for 2 hours immediately following the surgery. Hyperthermia impairs DNA repair in cells, induces apoptosis, inhibits angiogenesis, and promotes denaturation of proteins. This cytotoxic effect causes cancer cells to die at 104F while the healthy cells survive the temperature till 111F. The surgery improves the absorption ability of drugs, while the loco-regional action of chemotherapy drugs results in homogenous drug distribution and causes minimal exposure to the rest of the body. The goal of this chemotherapy peritoneal dwelling is to remove the microscopic residual disease efficiently. The agents preferred in HIPEC are mitomycin C, Oxaliplatin, cisplatin, and doxorubicin. The procedure lasts for 60-100 mins.

Moreover, instead of CRS, the laparoscopic approach can also be utilized for the administration of HIPEC. Laparoscopic HIPEC was found effective in 95% of cases of refractory malignant ascites in a related systematic review of the literature. It has a role in adjuvant, neoadjuvant, or palliative therapy; palliation being the major indication. The laparoscopic process produces increased intra-abdominal pressure, which can enhance the penetration ability of chemotherapy drugs. Another advantage is significantly lower morbidity and mortality, and the disadvantage is the higher recurrence rates. The side effects of HIPEC are neutropenia, spontaneous bowel perforations, electrolyte imbalance, acute renal failure, and bleeding diathesis.

Early Postoperative Intraperitoneal Chemotherapy (EPIC)

It is another regimen of intraperitoneal delivery of chemotherapy drugs. It is started on postoperative day one and continued for 5-7 days. The solution containing chemotherapy drugs bathes the mesothelium for 4 to 24 hours, then is drained over 1 hour and, finally, re-administered. Prior to starting the therapy, it is pertinent to look for the stable status of patients after surgery, such as normal white blood cell count and the ability to tolerate the treatment. This can delay the starting to 2nd postoperative day as well. A catheter is secured with sutures for delivery, and multiple closed suction drains are placed for drainage. The drugs introduced are cell-specific types as compared to cell cycle nonspecific drugs used in HIPEC. 5-fluorouracil, taxanes, and leucovorin are usually employed.

EPIC VS. HIPS

EPIC has the advantage over HIPEC that increased lingering and longer contact time between drugs, and the peritoneal surface is allowed, resulting in more uniform drug distribution and enhanced cytotoxic effects. The instilled solution of chemotherapy drugs covers only 30 to 40% of the peritoneal surface if allowed for a short period. Moreover, the adhesions following surgery are formed without any delay in chemotherapy induction, which renders the cancer cells entrapped in the fibrin deposits. However, the cells are still susceptible to the actions of chemotherapy drugs over five days allowed in EPIC. Further advantages are that the closed abdominal technique in EPIC is easier, and drugs do not need to be heated. Therefore, the studies in mice indicated the superiority of EPIC over HIPEC in terms of overall survival. However, clinical studies for comparison of the two types of intraperitoneal regimens did not regard the same. The EPIC group showed higher incidence of digestive fistulas (26% in EPIC vs 0% in HIPEC, p=0.02) and peritoneal carcinomatosis recurrence (57% vs. 26%, p=0.03). Overall survival was statistically insignificant. Another study on adjunctive use of EPIC after HIPEC and CRS reported that patients who receive EPIC had increased morbidity (postoperative complications 58% in CRS+HIPEC+EPIC vs. 25% in CRS+HIPEC, p=0.048) and longer hospitalization (16 days vs. 13 days, p=0.019) with no overall change in survival.

Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC)

It is a novel approach to administering intraperitoneal drugs in a minimally invasive manner. It is used as a laparoscopic palliative approach in patients in whom CRS +HIPEC is not an indication, has a considerable tumor load, or large quantities of persistent ascites. The goal is to alleviate symptoms and improve quality of life (QoL). The procedure involves connecting a device called Capnopen with an injector and inserting it into the peritoneum through a trocar. There is a nebulizer technology that pressurizes the chemotherapy drugs into aerosols. The process takes 1 hour, and drugs like cisplatin and doxorubicin are used. The drugs are removed after 30 mins by a closed suction system. Through PIPAC, drug delivery is done in a repeated, safe way without adverse systemic effects. This pressurized delivery results in the requirement of smaller doses with resulting higher drug concentration, deeper penetration, and an effective uniform drug distribution. The chemical bowel perforations are decreased as compared to HIPEC. The renal and hepatic toxicity post-PIPAC is minimal to zero. However, it cannot be performed in cases of biliary or small bowel obstructions and extra-abdominal metastasis.

The studies on the use of PIPAC in PC from intestinal, appendiceal, gastric, and ovarian cancers have emphasized its safety, better tolerability, and control on ascites production. The median survival after PIPAC is 15.7 months. However, the disadvantages are that the aerosols cannot access some anatomic locations in the peritoneal cavity, and the adhesions secondary to surgery create obstacles to aerosol diffusion. Thus, it is not a good option in patients in the early course of the disease or recurrence after CRS. Moreover, tumor response following PIPAC alone is insufficient, and the addition of systemic chemotherapy can improve clinical response and QoL. This rational approach is referred to as bidirectional treatment and results in PCI improvement from 50% to 88%. Hence, more clinical trials are required to test for its efficacy and usage.

 

Peritoneal Cancer – Causes, Symptoms, Treatment

Peritoneal Cancer/Peritoneal carcinomatosis (PC) generally refers to the metastatic involvement of the peritoneum. The name was first coined in 1931 by Sampson for the thorough description of metastatic involvement of the peritoneal stromal surface by ovarian cancer cells. Since then, it refers to almost any peritoneal metastatic deposits, metastatic cancer to the peritoneum is more common than a primary peritoneal malignancy. It often occurs with gastrointestinal or gynecological malignancies of advanced stages with locoregional involvement. This activity articulates how to evaluate for this condition properly, and highlights the role of the interprofessional team in caring for patients with this condition.

The peritoneum is a continuous membrane that covers the abdominal and pelvic cavities. Anatomically it has two layers that are, in and of themselves, continuous. One is the parietal peritoneum, which covers the inner surfaces of the abdominal and pelvic wall, and the other layer is the visceral peritoneum, which covers the abdominal organs and their suspending structures in the abdominopelvic cavity.[rx] The greater omentum, a prominent peritoneal fold, also referred to as the gastrocolic ligament,  has been referred to as a policeman of the abdomen, recognizing its role in containing inflammation and minimizing the spread of infection or local disease in the abdominopelvic cavity.  This unique nature of the omentum puts it at risk of involvement with any abdominal malignancies through the local disease spread.

The term peritoneal carcinomatosis (PC) generally refers to the metastatic involvement of the peritoneum. The name was first coined in 1931 by Sampson for the thorough description of metastatic involvement of the peritoneal stromal surface by ovarian cancer cells.[rx] Since then, it refers to almost any peritoneal metastatic deposits, metastatic cancer to the peritoneum is more common than a primary peritoneal malignancy. It often occurs with gastrointestinal or gynecological malignancies of advanced stages with locoregional involvement. Historically, the presence of metastatic deposits in the peritoneal cavity implied an incurable, fatal disease where curative surgical therapy was no longer a reasonable option. Newer surgical techniques and innovations in medical management strategies have dramatically changed the course of the disease over the past years. Effective treatment approaches have evolved, allowing for improvements in disease-free and overall survival.[rx]

Causes of Peritoneal Cancer

Peritoneal involvement is most common with cancers of the gastrointestinal (GI), reproductive, and genitourinary tracts. Ovarian, colon, and gastric cancers are by far the most common conditions presenting in advanced stages with peritoneal metastasis. Cancers involving other organs such as the pancreas, appendix, small intestine, endometrium, and prostate can also cause peritoneal metastasis, but such occur less frequently. While peritoneal carcinomatosis can arise from extra-abdominal primary malignancies, such cases are uncommon; and they account for approximately 10% of diagnosed cases of peritoneal metastasis.[rx] Examples include breast cancer, lung cancer, and malignant melanoma. Ovarian cancer is the most common neoplastic disease-causing peritoneal metastasis in 46% of cases owing to the anatomic location of the ovaries and their close contact with the peritoneum as well as the embryological developmental continuity of ovarian epithelial cells with peritoneal mesothelial cells.[rx][rx]

  • Colorectal cancer patients also contribute to a higher number of patients with peritoneal involvement due to the high incidence of these cancers overall. About 7% of cases develop synchronous peritoneal metastasis.[rx]
  • Approximately 9% of non-endocrinal pancreatic cancer cases present with PC.
  • Gastric carcinoma tends to reach an advanced stage at first presentation, and 14% of such cases can have peritoneal metastasis.[rx]
  • A neuroendocrine tumor arising from the gastrointestinal tract (GI-NET) is a slow-growing neoplasm, and it can metastasize to the peritoneum. PC can occur in about 6% of GI-NET patients.[rx] Its frequency increases with age.
  • As described earlier, peritoneal carcinomatosis from extra-abdominal malignancy presents in only 10% of cases where metastatic breast cancer (41%), lung cancer (21%), and malignant melanoma (9%) account for the majority of the cases.[rx]
  • Lung cancer is the primary cause of newly diagnosed cancers worldwide, accounting for over a million new cases per year. However, peritoneal carcinomatosis in lung cancer is rare and occurs in about 2.5 to 16% of autopsy results. Considering the scale of lung cancer rates globally, it could be the reason for a higher number of peritoneal carcinomatosis cases worldwide.[rx]
  • Sometimes it is difficult to find the primary tumor site. In such cases, we have peritoneal carcinomatosis with an unknown primary (UP). About 3 to 5% of cases of peritoneal carcinomatosis are of unknown origin.[rx]

Cancer cell metastasis is a complex phenomenon involving a multistage process and multidirectional spread. Dissemination, adhesion, invasion, and proliferation are the significant steps for the development of peritoneal metastasis from any primary. Primary malignant cells can spread through local invasion, lymphatics, or blood to distal sites. In the case of peritoneal metastasis, malignant cells originating from primary abdominal organs usually spread through a transcoelomic mechanism. Peritoneal fluid cycles through the peritoneal cavity in a specific direction, and this could spread the cancer cells in a particular manner. Currently, extensive research has given more detailed knowledge about the pathophysiology of peritoneal metastasis. This complex process involves multilevel reactions among molecular and cellular components of the primary tumor site as well as the peritoneum. Peritoneal mesothelial cells provide adhesion to the invading cancer cells and stromal components, and endothelial cells help in proliferation.[rx] Paget’s original theory of “seed and soil” very well describes the pattern of peritoneal metastasis in cancers such as ovarian, colorectal, stomach, etc. It proposed that the organ-preference patterns of cancer metastasis are the product of favorable interactions between metastatic tumor cells (the “seed”) and their organ microenvironment (the “soil”), which several research studies have extensively demonstrated.[rx]

One theory describes that peritoneal carcinomatosis from gastrointestinal cancers can occur in two different ways: 1) Via transversal growth and 2) via the intraperitoneal spread. Transversal growth means tumor cells can exfoliate from the primary tumor into the peritoneal cavity, also known as synchronous peritoneal carcinomatosis. This variant usually occurs preoperatively. Intraperitoneal spread implies spread due to surgical trauma, where tumor cells get released unintentionally from transected lymph node or blood vessel or upon manipulation of the primary tumor during handling, referred to as metachronous peritoneal carcinomatosis. The most common dissemination of malignant cells in the peritoneum are with spontaneous exfoliation. Leucocyte-associated adhesional molecules like CD44, selectins, and/or integrin have been identified for cancer cell adhesion. Peritoneal stroma is the rich source for all the necessary factors required for proliferation.[rx]

Hematogenous spread involving the peritoneal cavity can occur in patients with malignant melanoma, lung, and breast cancer. In such cases, the embolic metastatic focus begins as a small nodule with eventual progression. The lymphatic spread usually revolves around the ligaments and mesentery, and such dissemination can occur in non-Hodgkin lymphoma or neuroendocrine tumor (NET).

Biological research describes three types of peritoneal cancer spread, which is helpful to understand to guide surgical management:

  • Random Proximal Distribution (RPD): Typically occurs in moderate and high-grade cancers in their early implantation due to the adherence molecules on the cancer cells near the tumor area. Examples include adenocarcinoma and carcinoid of an appendix, non-mucinous colorectal cancer, gastric cancer, and serous ovarian cancer.
  • Complete Redistribution (CRD): Here, there is no adhesion with the peritoneum near the primary tumor due to the low biological activity of the cancer cells. Examples are pseudomyxoma peritonei, diffuse malignant mesothelioma.
  • Widespread Cancer Distribution (WCD): The presence of adherence molecules on the cancer cells, along with mucus production, leads to the aggressive and widespread dissemination of cancer. Examples in this category include mucinous colorectal cancer, mucinous ovarian cancer, cystadenocarcinoma of the appendix.

This understanding of the pattern of spread helps in determining the best surgical approach: RPD treatment is best via selective peritonectomy of macroscopically involved regions. While CRD and WCD treatment should be with complete peritonectomy and extensive cytoreduction therapy.[rx]

Complications related to peritoneal metastases:

  • Ascites: Peritoneal metastases tend to produce fluid in the abdomen, known as ascites, which causes abdominal distension (Figure 2).
  • Intestinal obstruction: Peritoneal metastases may cause blockage of the intestines.
  • Hydronephrosis: The kidney ureters may be blocked by peritoneal metastases. This may affect kidney function.
  • Bloating
  • Abdominal pain
  • Nausea and vomiting
  • Constipation
  • Loss of appetite
  • Weight loss

Diagnosis of Peritoneal Cancer

Patients with peritoneal metastasis usually present in a late stage of the disease. They typically present with symptoms and signs associated with their advanced primary cancer, or often peritoneal carcinomatosis is an accidental finding during surgical exploration for primary tumor resection or during other elective procedures. The two most important clinical findings related to peritoneal carcinomatosis have been ascites and bowel obstruction. However, they are found clinically in less than 50% of patients.[rx][rx] Similar to any other cancer, patients may complain of loss of appetite, organ-specific symptoms such as abdominal pain, nausea, vomiting, constipation, abdominal distension, weight loss, etc. Two main clinical features that could raise the suspicion for peritoneal metastasis include 1) the presence of malignant cells in ascitic fluid (28% to 30% of colorectal peritoneal metastasis patients), and 2) bowel obstruction (8% to 20% of patients with colorectal peritoneal metastasis.[rx]

Given the non-specific clinical picture associated with patients with peritoneal metastasis, it is highly unpredictable and difficult to diagnose this condition just based on clinical presentation. However, whenever there is a finding suggesting the possibility of abdominal cancer, clinicians should keep a low threshold for considering the presence of advanced-stage disease, as evidenced by the presence of peritoneal metastasis, even when imaging does not show readily show this. The peritoneum and any ascitic fluid can undergo an examination at the time of surgical exploration during a planned or emergent procedure.

Lab Test and Imaging

Metastatic cancer of the peritoneum is often an incidental finding detected during surgical exploration or on diagnostic imaging with modalities like CT scan or MRI performed for other indications. Biopsy of detected tumors or lesions is a confirmatory test to identify the type of cancer cells and to differentiate it from primary peritoneal cancer.

 The primary objectives of the work-up and investigation modalities employed in cases of suspected peritoneal metastasis are the following:

  • Early detection of possible peritoneal metastasis in a patient with recently diagnosed abdominal or pelvic malignancy and to rule out the presence of distant metastases in extra-abdominal areas, which becomes an absolute contraindication for surgery with curative intent.
  • To determine the extent, size, and major organ involvement by metastatic cancer to decide proper patient selection for cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC).
  • Early staging of the PC to help ascertain valuable information about potential outcomes and predict prognosis after treatment.

Cancerous lesions involving the peritoneum are sometimes visible with CT Scan, MRI, and 18F-fluorodeoxyglucose (FDG) positron emission tomography PET/CT. Each modality has its importance depending on the type of cancer and area of involvement. Presently the peritoneal carcinomatosis index (PCI) scoring system proposed by Dr. Sugarbacker provides a useful tool for better patient selection for surgery and a better understanding of prognosis and outcome (described in the management and staging section below). So most of the imaging studies are employed for their diagnostic parameters based on how accurately they can contribute to the PCI score preoperatively.[rx]

  • Ultrasound – Malignant ascites may be anechoic or have low-level echoes, and aids in the identification of deposits . Nodules are of intermediate echogenicity, hypoechoic compared to the peritoneum, whereas infiltration of the omentum results in hyperechogenicity.
  • CT Scan – It can provide appropriate site-specific cancer involvement in the abdominal cavity. The crucial findings for peritoneal metastasis are focal or diffuse thickening of peritoneal folds, which could appear as sclerotic, nodular, reticular, reticulonodular, or large plaque-like structures. Sometimes a large, thick layer of inhomogeneous density would be visible between the abdominal wall and bowel loops, which is sometimes called an “omental cake.” It is a neoplastic tissue layer. CT will also detect micronodules and micronodules if they are lying at the surface of the liver or spleen. Ascites can also be detected if it is over 50 ml.[rx] The sensitivity of computed tomography scan of the abdomen and pelvis for the diagnosis of colorectal cancer-related PM is 90% for cancer nodules larger than 5 cm but drops to less than 25% for lesions smaller than 5 cm.[rx] CT scan used for the detection of peritoneal tumors for future management decisions was also found to have inter-observer differences among radiologists and is not considered as the most reliable tool for the same.[rx] Additionally, CT is inefficient in assessing small bowel lesions, which could underestimate the PCI score preoperatively. However, it is still a valid tool to achieve optimal cytoreduction in cases of ovarian metastasis with moderate accuracy.[rx] Currently, abdominopelvic CT scanning is the first line of investigation for the detection of peritoneal metastasis in the presence of any abdominal primary.
    Peritoneal metastases can range in appearance from invisible to multiple large masses, and historically CT can only detect 60-80% of peritoneal metastases later shown to be present at surgery, although more recent studies reported detection rates of 85-93% 1,3. Appearances include 1:

    • thickening and enhancement of peritoneal reflections (especially if nodular)
    • soft tissue nodulesstranding and thickening of the omentum (omental cake)
    • stranding and distortion of the small bowel mesentery
    • ascites, especially if loculated
    • calcifications 2 (particularly in cystadenocarcinoma of the ovary)
      • nodular with the non-calcified component are typical
      • nodal calcification

    Intraperitoneal contrast has been investigated as a way of improving sensitivity to the presence of small deposits, and may improve detection but has not been widely adopted 3.

  • MRI – It is also one of the diagnostic tools for detecting peritoneal metastasis. However, it has not shown any significant superiority over CT scanning. One study did demonstrate an advantage of MR over single-helical CT for the detection of metastasis over peritoneum, omentum, and bowel.[rx] The combined use of MRI and CT has improved the preoperative estimation of PCI compared to only CT-determined PCI.[rx] Diffuse weighted MRI is used more for its diagnostic parameters, and one recently published study showed significant results. Whole-body diffuse weighted imagine-MRI (WB-DWI/MRI) was significantly better in the prediction of inoperability for peritoneal carcinomatosis than CT with sensitivity 90.6%, specificity 100%, PPV 100%, and NPV 90.3%. For CT alone these values were 25.0, 92.9, 80.0 and 52.0%, respectively.[rx]
  • PET Scan – The use of a PET-CT scan is more useful than just a PET scan, as the addition of CT allows for better anatomic visualization. 18F-fluorodeoxyglucose (FDG) positron emission tomography PET/CT is the preferred imaging that can detect the presence of cancer lesions based on the glucose uptake of the cells. It can be falsely negative when cells do not show good glucose uptake. Thus in cases where it is used for postoperative imaging, it would be better to document preoperative results for comparison to avoid false-negative results.[rx] To identify the exact localization and area of the peritoneal metastasis, PET-CT provides better accuracy and especially better NPV than MRI.[rx] PET-CT adds good value to conventional imaging mainly for monitoring response to the therapy, especially on long-term follow-up.[rx]
  • Diagnostic Laparoscopy – Surgeons recommend preoperative use of diagnostic laparoscopy for the assessment of the resectability of peritoneal tumor nodules before undergoing cytoreductive surgery (CRS). This approach is useful in patients for whom the previous imagining studies are insufficient in providing adequate information about the extent of disease involvement. However, it is sometimes not favored due to the difficulty related to trocar insertion and fear of port-site tumor recurrence. But currently, many surgeons are advocating its important role in affirmative decision making before actually going for laparotomy. In one study, it was found to have a positive predictive value of 83.3%. It also helped to avoid unnecessary laparotomy in 45% of the cases with no port-site recurrences or morbidity after 18 months.[rx] Similarly, another study suggested detailed technical aspects of the diagnostic laparoscopy, with over 94% of confirmative findings with the use of only two trocars and 99% for all cases.[rx] Extensive studies would be needed to get more evidence for its routine practical use.

New Proposed Diagnostic Methods

Different surgeon groups have proposed new diagnostic techniques for the optimum detection of peritoneal carcinomatosis and a more accurate understanding of its extent and size before considering surgical exploration:

  • Detection of ascitic CEA (carcinoma embryonic antigen) is a useful measure for diagnosing colorectal cancer (CRC) with PM.[rx]
  • Extensive involvement of small bowel by peritoneal carcinomatosis precludes the use of cytoreductive surgery. CT lacks sufficient accuracy in preoperative detection of disease in the small intestine that may subsequently impact the decision to offer CRS. One group of researchers demonstrated that CT-enteroclysis (CTE) is very useful in detecting cancerous implants in small bowel/mesentery. It showed 92% sensitivity, 96% specificity, 97% PPV and 91% NPV.[rx]
  • Another group of investigators explored the use of single-incision flexible endoscopy (SIFE) for diagnostic staging before surgery, and they compared it to rigid endoscopy (SIRE). The major objective was to avoid trocar site metastasis by reducing the need for extra trocar usage. The study showed feasibility in 94% of cases with SIFE and demonstrated superiority to SIRE in terms of technical exploration and outcomes. Future studies are needed to compare this with conventional laparoscopy.[rx]

Treatment of Peritoneal Cancer

Recent advancements in surgical techniques and favorable outcomes related to targeted chemotherapy have encouraged the aggressive treatment of PC whenever it is feasible and accessible. Complete cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) and systemic chemotherapy has become the mainstay treatment for peritoneal carcinomatosis (PC) originating from most gastrointestinal and genitourinary tracts carcinomas. The efficacy of this treatment was validated in 2003 by a randomized clinical trial that compared CRS combined with HIPEC versus systemic chemotherapy alone (median survival: 22.3 vs. 12.6 months, P = 0.032).[rx] Macroscopically complete CRS (CRS-R0) is a major prognostic factor, with 5-year survival rates as high as 45% compared to less than 10% when CRS is incomplete.[rx] Dr. Sugarbaker changed the perception relating to peritoneal carcinomatosis from being terminal cancer to being a loco-regional disease and recommended an aggressive surgical approach with CRS, given the positive survival benefits.

The first step in the management centers is the appropriate patient selection for surgery.

Patient selection

  • Patient characteristics: age, comorbidities, general condition, and functional status. The objective is to determine the fitness of the patient for the anticipated trauma of surgery and its perioperative impact.
  • Exclude generalized metastatic disease: As pointed in the diagnostic section, CT and/or MRI or sometimes PET/CT can be used to investigate potential distal metastases depending on the type of cancer. Possible sites to look for are thorax, spine bones, brain, etc.
  • The extent of the peritoneal disease:

CT/MRI is the primary investigation tool to determine the size, extent, and type of peritoneal lesions. PCI scoring system described in figure 1 is routinely used to determine the surgical resectability and possibly favorable prognosis. Diagnostic laparoscopy provides very accurate estimates for PCI along with probable completeness of the cytoreduction (CC) index and outcome assessment in terms of disease-free survival, overall survival, and quality of life. The involvement of the small bowel impacts the PCI score and can suggest a bad prognosis. The following are the usual surgical sites used for preoperative determination of the extent of the disease for exclusion from CRS. [rx]

  • Massive mesenteric root infiltration not amenable to complete cytoreduction
  • Significant pancreatic capsule infiltration or pancreatic involvement requiring major resection not feasibly or amenable to complete surgical cytoreduction
  • More than one-third of small bowel length involvement requiring resection
  • Extensive hepatic metastasis

Some surgeons advocate the use of peritoneal surface disease severity score (PSDSS) for the early preoperative assessment of the prognosis based on the symptoms, PCI index, and primary tumor histology. However, extensive study results are needed to implement it in regular practice.[rx]

Cytoreductive Surgery (CRS) and Hyperthermic Intraperitoneal Chemotherapy

Upon the determination of patient fitness for surgery with selection driven by feasibility criteria, CRS is performed commonly through an open abdominal wall incision approach along with perioperative intraperitoneal chemotherapy. This novel treatment option became a reality for surgeons through the extensive work of Dr. Sugarbacker[rx] and his suggested surgical techniques. Cytoreductive surgery includes peritonectomy and individualized manual resection of the tumor lesions from different areas of the abdominal wall and mesentery. Peritonectomy now classifies as a curative treatment method for patients with peritoneal carcinomatosis, with the latter viewed as the locoregional spread instead of systemic disease. The usual surgical intention for any cancer treatment is the removal of all cancer cells through en-block resections with clear margins. However, for peritoneal carcinomatosis, it is highly difficult to achieve the complete removal of malignant cells. The idea behind cytoreduction is to reach complete removal of any macroscopic lesions, and the simultaneous use of HIPEC would potentially remove microscopic cancer lesions.[rx][rx] This technical approach has shown tremendous survival benefits along with disease-free survival and improved quality of life in patients. Currently, CRS combined with HIPEC is a first-line treatment for appendiceal and colorectal cancer-related PM.[rx][rx] It has also shown a promising role in ovarian, gastric, and neuroendocrine tumors.[rx][rx][rx] 

Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC)

This newer innovative therapeutic intervention has potential use in patients with extensive peritoneal carcinomatosis who may be deemed unresectable or unfit for surgery. The basis for aerosol chemotherapy is the premise that the intraabdominal application of chemotherapeutic drugs under pressure could potentially enhance tissue penetration and increases distribution.[rx] It has also been found to have superior benefits of drug delivery to tumor tissue with a significant effect on tumor regression than conventional intraperitoneal chemotherapy or systemic chemotherapy.[rx] This treatment option is beneficial in patients with extraperitoneal metastases in which this method could work as an effective palliative treatment option. Further ongoing prospective trials will decide on its future role and regular use.

​Peritoneal metastasis is difficult to treat and is best managed by a multi-disciplinary team that includes surgeons and medical oncologists.

  • Systemic chemotherapy: Chemotherapy drugs given intravenously or sometimes in combination with oral tablets circulate through the whole body. This type of treatment is suitable for cancers that have metastasized to multiple parts of the body.
  • Cytoreductive Surgery (CRS) with Hyperthermic intraperitoneal Chemotherapy (HIPEC):
    CRS is an extensive surgery that removes all visible cancers within the abdominal cavity. At the end of CRS, a heated chemotherapy solution is applied to the peritoneal cavity to destroy the remaining cancer cells that cannot be seen with the naked eye.
  • Intra-peritoneal (IP) chemotherapy: IP chemotherapy (Figure 3) is injected into the peritoneal cavity via an intraperitoneal port that is inserted via keyhole surgery. The port is buried under the skin and connected to a catheter that enters the peritoneal space.
  • Pressurized Intra-Peritoneal Aerosol Chemotherapy (PIPAC): PIPAC (Figure 4) is a novel method of delivering chemotherapy directly into the peritoneal cavity in an aerosol form. It utilizes the physical properties of pressurized gas to distribute the drug evenly and deeply. This allows greater penetration of the drug into the cancer cells, with reduced systemic side effects of the chemotherapy agent. PIPAC is performed as a short and simple laparoscopic (keyhole) surgery. Under general anesthesia, small instruments will be placed into the abdomen. A micro-pump will deliver the chemotherapy drug into the peritoneal cavity as an aerosol. At the end of the procedure, any residual gas within the peritoneal cavity will be removed.

Currently, PIPAC is a minimally invasive palliative procedure that aims to prolong survival and preserve the quality of life. Due to the low dosage applied, PIPAC can be combined with systemic palliative chemotherapy and has minimal organ toxicity. This procedure can be repeated at intervals of 6 weeks to 3 months.

PIPAC GIF (Infinity Loop).gif

Figure 4: Set-up of Pressurised Intra-Peritoneal Aerosol Chemotherapy (PIPAC)

Video Demonstration of PIPAC treatment

 

Peritoneal Metastases – Causes, Symptoms, Treatment

Peritoneal Metastases/Peritoneal carcinomatosis (PC) generally refers to the metastatic involvement of the peritoneum. The name was first coined in 1931 by Sampson for the thorough description of metastatic involvement of the peritoneal stromal surface by ovarian cancer cells. Since then, it refers to almost any peritoneal metastatic deposits, metastatic cancer to the peritoneum is more common than a primary peritoneal malignancy. It often occurs with gastrointestinal or gynecological malignancies of advanced stages with locoregional involvement. This activity articulates how to evaluate for this condition properly, and highlights the role of the interprofessional team in caring for patients with this condition.

The peritoneum is a continuous membrane that covers the abdominal and pelvic cavities. Anatomically it has two layers that are, in and of themselves, continuous. One is the parietal peritoneum, which covers the inner surfaces of the abdominal and pelvic wall, and the other layer is the visceral peritoneum, which covers the abdominal organs and their suspending structures in the abdominopelvic cavity.[rx] The greater omentum, a prominent peritoneal fold, also referred to as the gastrocolic ligament,  has been referred to as a policeman of the abdomen, recognizing its role in containing inflammation and minimizing the spread of infection or local disease in the abdominopelvic cavity.  This unique nature of the omentum puts it at risk of involvement with any abdominal malignancies through the local disease spread.

The term peritoneal carcinomatosis (PC) generally refers to the metastatic involvement of the peritoneum. The name was first coined in 1931 by Sampson for the thorough description of metastatic involvement of the peritoneal stromal surface by ovarian cancer cells.[rx] Since then, it refers to almost any peritoneal metastatic deposits, metastatic cancer to the peritoneum is more common than a primary peritoneal malignancy. It often occurs with gastrointestinal or gynecological malignancies of advanced stages with locoregional involvement. Historically, the presence of metastatic deposits in the peritoneal cavity implied an incurable, fatal disease where curative surgical therapy was no longer a reasonable option. Newer surgical techniques and innovations in medical management strategies have dramatically changed the course of the disease over the past years. Effective treatment approaches have evolved, allowing for improvements in disease-free and overall survival.[rx]

Causes of Colorectal Peritoneal Metastases

Peritoneal involvement is most common with cancers of the gastrointestinal (GI), reproductive, and genitourinary tracts. Ovarian, colon, and gastric cancers are by far the most common conditions presenting in advanced stages with peritoneal metastasis. Cancers involving other organs such as the pancreas, appendix, small intestine, endometrium, and prostate can also cause peritoneal metastasis, but such occur less frequently. While peritoneal carcinomatosis can arise from extra-abdominal primary malignancies, such cases are uncommon; and they account for approximately 10% of diagnosed cases of peritoneal metastasis.[rx] Examples include breast cancer, lung cancer, and malignant melanoma. Ovarian cancer is the most common neoplastic disease-causing peritoneal metastasis in 46% of cases owing to the anatomic location of the ovaries and their close contact with the peritoneum as well as the embryological developmental continuity of ovarian epithelial cells with peritoneal mesothelial cells.[rx][rx]

  • Colorectal cancer patients also contribute to a higher number of patients with peritoneal involvement due to the high incidence of these cancers overall. About 7% of cases develop synchronous peritoneal metastasis.[rx]
  • Approximately 9% of non-endocrinal pancreatic cancer cases present with PC.
  • Gastric carcinoma tends to reach an advanced stage at first presentation, and 14% of such cases can have peritoneal metastasis.[rx]
  • A neuroendocrine tumor arising from the gastrointestinal tract (GI-NET) is a slow-growing neoplasm, and it can metastasize to the peritoneum. PC can occur in about 6% of GI-NET patients.[rx] Its frequency increases with age.
  • As described earlier, peritoneal carcinomatosis from extra-abdominal malignancy presents in only 10% of cases where metastatic breast cancer (41%), lung cancer (21%), and malignant melanoma (9%) account for the majority of the cases.[rx]
  • Lung cancer is the primary cause of newly diagnosed cancers worldwide, accounting for over a million new cases per year. However, peritoneal carcinomatosis in lung cancer is rare and occurs in about 2.5 to 16% of autopsy results. Considering the scale of lung cancer rates globally, it could be the reason for a higher number of peritoneal carcinomatosis cases worldwide.[rx]
  • Sometimes it is difficult to find the primary tumor site. In such cases, we have peritoneal carcinomatosis with an unknown primary (UP). About 3 to 5% of cases of peritoneal carcinomatosis are of unknown origin.[rx]

Cancer cell metastasis is a complex phenomenon involving a multistage process and multidirectional spread. Dissemination, adhesion, invasion, and proliferation are the significant steps for the development of peritoneal metastasis from any primary. Primary malignant cells can spread through local invasion, lymphatics, or blood to distal sites. In the case of peritoneal metastasis, malignant cells originating from primary abdominal organs usually spread through a transcoelomic mechanism. Peritoneal fluid cycles through the peritoneal cavity in a specific direction, and this could spread the cancer cells in a particular manner. Currently, extensive research has given more detailed knowledge about the pathophysiology of peritoneal metastasis. This complex process involves multilevel reactions among molecular and cellular components of the primary tumor site as well as the peritoneum. Peritoneal mesothelial cells provide adhesion to the invading cancer cells and stromal components, and endothelial cells help in proliferation.[rx] Paget’s original theory of “seed and soil” very well describes the pattern of peritoneal metastasis in cancers such as ovarian, colorectal, stomach, etc. It proposed that the organ-preference patterns of cancer metastasis are the product of favorable interactions between metastatic tumor cells (the “seed”) and their organ microenvironment (the “soil”), which several research studies have extensively demonstrated.[rx]

One theory describes that peritoneal carcinomatosis from gastrointestinal cancers can occur in two different ways: 1) Via transversal growth and 2) via the intraperitoneal spread. Transversal growth means tumor cells can exfoliate from the primary tumor into the peritoneal cavity, also known as synchronous peritoneal carcinomatosis. This variant usually occurs preoperatively. Intraperitoneal spread implies spread due to surgical trauma, where tumor cells get released unintentionally from transected lymph node or blood vessel or upon manipulation of the primary tumor during handling, referred to as metachronous peritoneal carcinomatosis. The most common dissemination of malignant cells in the peritoneum are with spontaneous exfoliation. Leucocyte-associated adhesional molecules like CD44, selectins, and/or integrin have been identified for cancer cell adhesion. Peritoneal stroma is the rich source for all the necessary factors required for proliferation.[rx]

Hematogenous spread involving the peritoneal cavity can occur in patients with malignant melanoma, lung, and breast cancer. In such cases, the embolic metastatic focus begins as a small nodule with eventual progression. The lymphatic spread usually revolves around the ligaments and mesentery, and such dissemination can occur in non-Hodgkin lymphoma or neuroendocrine tumor (NET).

Biological research describes three types of peritoneal cancer spread, which is helpful to understand to guide surgical management:

  • Random Proximal Distribution (RPD): Typically occurs in moderate and high-grade cancers in their early implantation due to the adherence molecules on the cancer cells near the tumor area. Examples include adenocarcinoma and carcinoid of an appendix, non-mucinous colorectal cancer, gastric cancer, and serous ovarian cancer.
  • Complete Redistribution (CRD): Here, there is no adhesion with the peritoneum near the primary tumor due to the low biological activity of the cancer cells. Examples are pseudomyxoma peritonei, diffuse malignant mesothelioma.
  • Widespread Cancer Distribution (WCD): The presence of adherence molecules on the cancer cells, along with mucus production, leads to the aggressive and widespread dissemination of cancer. Examples in this category include mucinous colorectal cancer, mucinous ovarian cancer, cystadenocarcinoma of the appendix.

This understanding of the pattern of spread helps in determining the best surgical approach: RPD treatment is best via selective peritonectomy of macroscopically involved regions. While CRD and WCD treatment should be with complete peritonectomy and extensive cytoreduction therapy.[rx]

Complications related to peritoneal metastases:

  • Ascites: Peritoneal metastases tend to produce fluid in the abdomen, known as ascites, which causes abdominal distension (Figure 2).
  • Intestinal obstruction: Peritoneal metastases may cause blockage of the intestines.
  • Hydronephrosis: The kidney ureters may be blocked by peritoneal metastases. This may affect kidney function.
  • Bloating
  • Abdominal pain
  • Nausea and vomiting
  • Constipation
  • Loss of appetite
  • Weight loss

Diagnosis of Colorectal Peritoneal Metastases

Patients with peritoneal metastasis usually present in a late stage of the disease. They typically present with symptoms and signs associated with their advanced primary cancer, or often peritoneal carcinomatosis is an accidental finding during surgical exploration for primary tumor resection or during other elective procedures. The two most important clinical findings related to peritoneal carcinomatosis have been ascites and bowel obstruction. However, they are found clinically in less than 50% of patients.[rx][rx] Similar to any other cancer, patients may complain of loss of appetite, organ-specific symptoms such as abdominal pain, nausea, vomiting, constipation, abdominal distension, weight loss, etc. Two main clinical features that could raise the suspicion for peritoneal metastasis include 1) the presence of malignant cells in ascitic fluid (28% to 30% of colorectal peritoneal metastasis patients), and 2) bowel obstruction (8% to 20% of patients with colorectal peritoneal metastasis.[rx]

Given the non-specific clinical picture associated with patients with peritoneal metastasis, it is highly unpredictable and difficult to diagnose this condition just based on clinical presentation. However, whenever there is a finding suggesting the possibility of abdominal cancer, clinicians should keep a low threshold for considering the presence of advanced-stage disease, as evidenced by the presence of peritoneal metastasis, even when imaging does not show readily show this. The peritoneum and any ascitic fluid can undergo an examination at the time of surgical exploration during a planned or emergent procedure.

Lab Test and Imaging

Metastatic cancer of the peritoneum is often an incidental finding detected during surgical exploration or on diagnostic imaging with modalities like CT scan or MRI performed for other indications. Biopsy of detected tumors or lesions is a confirmatory test to identify the type of cancer cells and to differentiate it from primary peritoneal cancer.

 The primary objectives of the work-up and investigation modalities employed in cases of suspected peritoneal metastasis are the following:

  • Early detection of possible peritoneal metastasis in a patient with recently diagnosed abdominal or pelvic malignancy and to rule out the presence of distant metastases in extra-abdominal areas, which becomes an absolute contraindication for surgery with curative intent.
  • To determine the extent, size, and major organ involvement by metastatic cancer to decide proper patient selection for cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC).
  • Early staging of the PC to help ascertain valuable information about potential outcomes and predict prognosis after treatment.

Cancerous lesions involving the peritoneum are sometimes visible with CT Scan, MRI, and 18F-fluorodeoxyglucose (FDG) positron emission tomography PET/CT. Each modality has its importance depending on the type of cancer and area of involvement. Presently the peritoneal carcinomatosis index (PCI) scoring system proposed by Dr. Sugarbacker provides a useful tool for better patient selection for surgery and a better understanding of prognosis and outcome (described in the management and staging section below). So most of the imaging studies are employed for their diagnostic parameters based on how accurately they can contribute to the PCI score preoperatively.[rx]

  • Ultrasound – Malignant ascites may be anechoic or have low-level echoes, and aids in the identification of deposits . Nodules are of intermediate echogenicity, hypoechoic compared to the peritoneum, whereas infiltration of the omentum results in hyperechogenicity.
  • CT Scan – It can provide appropriate site-specific cancer involvement in the abdominal cavity. The crucial findings for peritoneal metastasis are focal or diffuse thickening of peritoneal folds, which could appear as sclerotic, nodular, reticular, reticulonodular, or large plaque-like structures. Sometimes a large, thick layer of inhomogeneous density would be visible between the abdominal wall and bowel loops, which is sometimes called an “omental cake.” It is a neoplastic tissue layer. CT will also detect micronodules and micronodules if they are lying at the surface of the liver or spleen. Ascites can also be detected if it is over 50 ml.[rx] The sensitivity of computed tomography scan of the abdomen and pelvis for the diagnosis of colorectal cancer-related PM is 90% for cancer nodules larger than 5 cm but drops to less than 25% for lesions smaller than 5 cm.[rx] CT scan used for the detection of peritoneal tumors for future management decisions was also found to have inter-observer differences among radiologists and is not considered as the most reliable tool for the same.[rx] Additionally, CT is inefficient in assessing small bowel lesions, which could underestimate the PCI score preoperatively. However, it is still a valid tool to achieve optimal cytoreduction in cases of ovarian metastasis with moderate accuracy.[rx] Currently, abdominopelvic CT scanning is the first line of investigation for the detection of peritoneal metastasis in the presence of any abdominal primary.
    Peritoneal metastases can range in appearance from invisible to multiple large masses, and historically CT can only detect 60-80% of peritoneal metastases later shown to be present at surgery, although more recent studies reported detection rates of 85-93% 1,3. Appearances include 1:

    • thickening and enhancement of peritoneal reflections (especially if nodular)
    • soft tissue nodulesstranding and thickening of the omentum (omental cake)
    • stranding and distortion of the small bowel mesentery
    • ascites, especially if loculated
    • calcifications 2 (particularly in cystadenocarcinoma of the ovary)
      • nodular with the non-calcified component are typical
      • nodal calcification

    Intraperitoneal contrast has been investigated as a way of improving sensitivity to the presence of small deposits, and may improve detection but has not been widely adopted 3.

  • MRI – It is also one of the diagnostic tools for detecting peritoneal metastasis. However, it has not shown any significant superiority over CT scanning. One study did demonstrate an advantage of MR over single-helical CT for the detection of metastasis over peritoneum, omentum, and bowel.[rx] The combined use of MRI and CT has improved the preoperative estimation of PCI compared to only CT-determined PCI.[rx] Diffuse weighted MRI is used more for its diagnostic parameters, and one recently published study showed significant results. Whole-body diffuse weighted imagine-MRI (WB-DWI/MRI) was significantly better in the prediction of inoperability for peritoneal carcinomatosis than CT with sensitivity 90.6%, specificity 100%, PPV 100%, and NPV 90.3%. For CT alone these values were 25.0, 92.9, 80.0 and 52.0%, respectively.[rx]
  • PET Scan – The use of a PET-CT scan is more useful than just a PET scan, as the addition of CT allows for better anatomic visualization. 18F-fluorodeoxyglucose (FDG) positron emission tomography PET/CT is the preferred imaging that can detect the presence of cancer lesions based on the glucose uptake of the cells. It can be falsely negative when cells do not show good glucose uptake. Thus in cases where it is used for postoperative imaging, it would be better to document preoperative results for comparison to avoid false-negative results.[rx] To identify the exact localization and area of the peritoneal metastasis, PET-CT provides better accuracy and especially better NPV than MRI.[rx] PET-CT adds good value to conventional imaging mainly for monitoring response to the therapy, especially on long-term follow-up.[rx]
  • Diagnostic Laparoscopy – Surgeons recommend preoperative use of diagnostic laparoscopy for the assessment of the resectability of peritoneal tumor nodules before undergoing cytoreductive surgery (CRS). This approach is useful in patients for whom the previous imagining studies are insufficient in providing adequate information about the extent of disease involvement. However, it is sometimes not favored due to the difficulty related to trocar insertion and fear of port-site tumor recurrence. But currently, many surgeons are advocating its important role in affirmative decision making before actually going for laparotomy. In one study, it was found to have a positive predictive value of 83.3%. It also helped to avoid unnecessary laparotomy in 45% of the cases with no port-site recurrences or morbidity after 18 months.[rx] Similarly, another study suggested detailed technical aspects of the diagnostic laparoscopy, with over 94% of confirmative findings with the use of only two trocars and 99% for all cases.[rx] Extensive studies would be needed to get more evidence for its routine practical use.

New Proposed Diagnostic Methods

Different surgeon groups have proposed new diagnostic techniques for the optimum detection of peritoneal carcinomatosis and a more accurate understanding of its extent and size before considering surgical exploration:

  • Detection of ascitic CEA (carcinoma embryonic antigen) is a useful measure for diagnosing colorectal cancer (CRC) with PM.[rx]
  • Extensive involvement of small bowel by peritoneal carcinomatosis precludes the use of cytoreductive surgery. CT lacks sufficient accuracy in preoperative detection of disease in the small intestine that may subsequently impact the decision to offer CRS. One group of researchers demonstrated that CT-enteroclysis (CTE) is very useful in detecting cancerous implants in small bowel/mesentery. It showed 92% sensitivity, 96% specificity, 97% PPV and 91% NPV.[rx]
  • Another group of investigators explored the use of single-incision flexible endoscopy (SIFE) for diagnostic staging before surgery, and they compared it to rigid endoscopy (SIRE). The major objective was to avoid trocar site metastasis by reducing the need for extra trocar usage. The study showed feasibility in 94% of cases with SIFE and demonstrated superiority to SIRE in terms of technical exploration and outcomes. Future studies are needed to compare this with conventional laparoscopy.[rx]

Treatment of Colorectal Peritoneal Metastases

Recent advancements in surgical techniques and favorable outcomes related to targeted chemotherapy have encouraged the aggressive treatment of PC whenever it is feasible and accessible. Complete cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) and systemic chemotherapy has become the mainstay treatment for peritoneal carcinomatosis (PC) originating from most gastrointestinal and genitourinary tracts carcinomas. The efficacy of this treatment was validated in 2003 by a randomized clinical trial that compared CRS combined with HIPEC versus systemic chemotherapy alone (median survival: 22.3 vs. 12.6 months, P = 0.032).[rx] Macroscopically complete CRS (CRS-R0) is a major prognostic factor, with 5-year survival rates as high as 45% compared to less than 10% when CRS is incomplete.[rx] Dr. Sugarbaker changed the perception relating to peritoneal carcinomatosis from being terminal cancer to being a loco-regional disease and recommended an aggressive surgical approach with CRS, given the positive survival benefits.

The first step in the management centers is the appropriate patient selection for surgery.

Patient selection

  • Patient characteristics: age, comorbidities, general condition, and functional status. The objective is to determine the fitness of the patient for the anticipated trauma of surgery and its perioperative impact.
  • Exclude generalized metastatic disease: As pointed in the diagnostic section, CT and/or MRI or sometimes PET/CT can be used to investigate potential distal metastases depending on the type of cancer. Possible sites to look for are thorax, spine bones, brain, etc.
  • The extent of the peritoneal disease:

CT/MRI is the primary investigation tool to determine the size, extent, and type of peritoneal lesions. PCI scoring system described in figure 1 is routinely used to determine the surgical resectability and possibly favorable prognosis. Diagnostic laparoscopy provides very accurate estimates for PCI along with probable completeness of the cytoreduction (CC) index and outcome assessment in terms of disease-free survival, overall survival, and quality of life. The involvement of the small bowel impacts the PCI score and can suggest a bad prognosis. The following are the usual surgical sites used for preoperative determination of the extent of the disease for exclusion from CRS. [rx]

  • Massive mesenteric root infiltration not amenable to complete cytoreduction
  • Significant pancreatic capsule infiltration or pancreatic involvement requiring major resection not feasibly or amenable to complete surgical cytoreduction
  • More than one-third of small bowel length involvement requiring resection
  • Extensive hepatic metastasis

Some surgeons advocate the use of peritoneal surface disease severity score (PSDSS) for the early preoperative assessment of the prognosis based on the symptoms, PCI index, and primary tumor histology. However, extensive study results are needed to implement it in regular practice.[rx]

Cytoreductive Surgery (CRS) and Hyperthermic Intraperitoneal Chemotherapy

Upon the determination of patient fitness for surgery with selection driven by feasibility criteria, CRS is performed commonly through an open abdominal wall incision approach along with perioperative intraperitoneal chemotherapy. This novel treatment option became a reality for surgeons through the extensive work of Dr. Sugarbacker[rx] and his suggested surgical techniques. Cytoreductive surgery includes peritonectomy and individualized manual resection of the tumor lesions from different areas of the abdominal wall and mesentery. Peritonectomy now classifies as a curative treatment method for patients with peritoneal carcinomatosis, with the latter viewed as the locoregional spread instead of systemic disease. The usual surgical intention for any cancer treatment is the removal of all cancer cells through en-block resections with clear margins. However, for peritoneal carcinomatosis, it is highly difficult to achieve the complete removal of malignant cells. The idea behind cytoreduction is to reach complete removal of any macroscopic lesions, and the simultaneous use of HIPEC would potentially remove microscopic cancer lesions.[rx][rx] This technical approach has shown tremendous survival benefits along with disease-free survival and improved quality of life in patients. Currently, CRS combined with HIPEC is a first-line treatment for appendiceal and colorectal cancer-related PM.[rx][rx] It has also shown a promising role in ovarian, gastric, and neuroendocrine tumors.[rx][rx][rx] 

Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC)

This newer innovative therapeutic intervention has potential use in patients with extensive peritoneal carcinomatosis who may be deemed unresectable or unfit for surgery. The basis for aerosol chemotherapy is the premise that the intraabdominal application of chemotherapeutic drugs under pressure could potentially enhance tissue penetration and increases distribution.[rx] It has also been found to have superior benefits of drug delivery to tumor tissue with a significant effect on tumor regression than conventional intraperitoneal chemotherapy or systemic chemotherapy.[rx] This treatment option is beneficial in patients with extraperitoneal metastases in which this method could work as an effective palliative treatment option. Further ongoing prospective trials will decide on its future role and regular use.

​Peritoneal metastasis is difficult to treat and is best managed by a multi-disciplinary team that includes surgeons and medical oncologists.

  • Systemic chemotherapy: Chemotherapy drugs given intravenously or sometimes in combination with oral tablets circulate through the whole body. This type of treatment is suitable for cancers that have metastasized to multiple parts of the body.
  • Cytoreductive Surgery (CRS) with Hyperthermic intraperitoneal Chemotherapy (HIPEC):
    CRS is an extensive surgery that removes all visible cancers within the abdominal cavity. At the end of CRS, a heated chemotherapy solution is applied to the peritoneal cavity to destroy the remaining cancer cells that cannot be seen with the naked eye.
  • Intra-peritoneal (IP) chemotherapy: IP chemotherapy (Figure 3) is injected into the peritoneal cavity via an intraperitoneal port that is inserted via keyhole surgery. The port is buried under the skin and connected to a catheter that enters the peritoneal space.
  • Pressurized Intra-Peritoneal Aerosol Chemotherapy (PIPAC): PIPAC (Figure 4) is a novel method of delivering chemotherapy directly into the peritoneal cavity in an aerosol form. It utilizes the physical properties of pressurized gas to distribute the drug evenly and deeply. This allows greater penetration of the drug into the cancer cells, with reduced systemic side effects of the chemotherapy agent. PIPAC is performed as a short and simple laparoscopic (keyhole) surgery. Under general anesthesia, small instruments will be placed into the abdomen. A micro-pump will deliver the chemotherapy drug into the peritoneal cavity as an aerosol. At the end of the procedure, any residual gas within the peritoneal cavity will be removed.

Currently, PIPAC is a minimally invasive palliative procedure that aims to prolong survival and preserve the quality of life. Due to the low dosage applied, PIPAC can be combined with systemic palliative chemotherapy and has minimal organ toxicity. This procedure can be repeated at intervals of 6 weeks to 3 months.

PIPAC GIF (Infinity Loop).gif

Figure 4: Set-up of Pressurised Intra-Peritoneal Aerosol Chemotherapy (PIPAC)

Video Demonstration of PIPAC treatment

 

Colorectal Peritoneal Metastases – Symptoms, Treatment

Peritoneal carcinomatosis (PC) generally refers to the metastatic involvement of the peritoneum. The name was first coined in 1931 by Sampson for the thorough description of metastatic involvement of the peritoneal stromal surface by ovarian cancer cells. Since then, it refers to almost any peritoneal metastatic deposits, metastatic cancer to the peritoneum is more common than a primary peritoneal malignancy. It often occurs with gastrointestinal or gynecological malignancies of advanced stages with locoregional involvement. This activity articulates how to evaluate for this condition properly, and highlights the role of the interprofessional team in caring for patients with this condition.

The peritoneum is a continuous membrane that covers the abdominal and pelvic cavities. Anatomically it has two layers that are, in and of themselves, continuous. One is the parietal peritoneum, which covers the inner surfaces of the abdominal and pelvic wall, and the other layer is the visceral peritoneum, which covers the abdominal organs and their suspending structures in the abdominopelvic cavity.[rx] The greater omentum, a prominent peritoneal fold, also referred to as the gastrocolic ligament,  has been referred to as a policeman of the abdomen, recognizing its role in containing inflammation and minimizing the spread of infection or local disease in the abdominopelvic cavity.  This unique nature of the omentum puts it at risk of involvement with any abdominal malignancies through the local disease spread.

The term peritoneal carcinomatosis (PC) generally refers to the metastatic involvement of the peritoneum. The name was first coined in 1931 by Sampson for the thorough description of metastatic involvement of the peritoneal stromal surface by ovarian cancer cells.[rx] Since then, it refers to almost any peritoneal metastatic deposits, metastatic cancer to the peritoneum is more common than a primary peritoneal malignancy. It often occurs with gastrointestinal or gynecological malignancies of advanced stages with locoregional involvement. Historically, the presence of metastatic deposits in the peritoneal cavity implied an incurable, fatal disease where curative surgical therapy was no longer a reasonable option. Newer surgical techniques and innovations in medical management strategies have dramatically changed the course of the disease over the past years. Effective treatment approaches have evolved, allowing for improvements in disease-free and overall survival.[rx]

Causes of Colorectal Peritoneal Metastases

Peritoneal involvement is most common with cancers of the gastrointestinal (GI), reproductive, and genitourinary tracts. Ovarian, colon, and gastric cancers are by far the most common conditions presenting in advanced stages with peritoneal metastasis. Cancers involving other organs such as the pancreas, appendix, small intestine, endometrium, and prostate can also cause peritoneal metastasis, but such occur less frequently. While peritoneal carcinomatosis can arise from extra-abdominal primary malignancies, such cases are uncommon; and they account for approximately 10% of diagnosed cases of peritoneal metastasis.[rx] Examples include breast cancer, lung cancer, and malignant melanoma. Ovarian cancer is the most common neoplastic disease-causing peritoneal metastasis in 46% of cases owing to the anatomic location of the ovaries and their close contact with the peritoneum as well as the embryological developmental continuity of ovarian epithelial cells with peritoneal mesothelial cells.[rx][rx]

  • Colorectal cancer patients also contribute to a higher number of patients with peritoneal involvement due to the high incidence of these cancers overall. About 7% of cases develop synchronous peritoneal metastasis.[rx]
  • Approximately 9% of non-endocrinal pancreatic cancer cases present with PC.
  • Gastric carcinoma tends to reach an advanced stage at first presentation, and 14% of such cases can have peritoneal metastasis.[rx]
  • A neuroendocrine tumor arising from the gastrointestinal tract (GI-NET) is a slow-growing neoplasm, and it can metastasize to the peritoneum. PC can occur in about 6% of GI-NET patients.[rx] Its frequency increases with age.
  • As described earlier, peritoneal carcinomatosis from extra-abdominal malignancy presents in only 10% of cases where metastatic breast cancer (41%), lung cancer (21%), and malignant melanoma (9%) account for the majority of the cases.[rx]
  • Lung cancer is the primary cause of newly diagnosed cancers worldwide, accounting for over a million new cases per year. However, peritoneal carcinomatosis in lung cancer is rare and occurs in about 2.5 to 16% of autopsy results. Considering the scale of lung cancer rates globally, it could be the reason for a higher number of peritoneal carcinomatosis cases worldwide.[rx]
  • Sometimes it is difficult to find the primary tumor site. In such cases, we have peritoneal carcinomatosis with an unknown primary (UP). About 3 to 5% of cases of peritoneal carcinomatosis are of unknown origin.[rx]

Cancer cell metastasis is a complex phenomenon involving a multistage process and multidirectional spread. Dissemination, adhesion, invasion, and proliferation are the significant steps for the development of peritoneal metastasis from any primary. Primary malignant cells can spread through local invasion, lymphatics, or blood to distal sites. In the case of peritoneal metastasis, malignant cells originating from primary abdominal organs usually spread through a transcoelomic mechanism. Peritoneal fluid cycles through the peritoneal cavity in a specific direction, and this could spread the cancer cells in a particular manner. Currently, extensive research has given more detailed knowledge about the pathophysiology of peritoneal metastasis. This complex process involves multilevel reactions among molecular and cellular components of the primary tumor site as well as the peritoneum. Peritoneal mesothelial cells provide adhesion to the invading cancer cells and stromal components, and endothelial cells help in proliferation.[rx] Paget’s original theory of “seed and soil” very well describes the pattern of peritoneal metastasis in cancers such as ovarian, colorectal, stomach, etc. It proposed that the organ-preference patterns of cancer metastasis are the product of favorable interactions between metastatic tumor cells (the “seed”) and their organ microenvironment (the “soil”), which several research studies have extensively demonstrated.[rx]

One theory describes that peritoneal carcinomatosis from gastrointestinal cancers can occur in two different ways: 1) Via transversal growth and 2) via the intraperitoneal spread. Transversal growth means tumor cells can exfoliate from the primary tumor into the peritoneal cavity, also known as synchronous peritoneal carcinomatosis. This variant usually occurs preoperatively. Intraperitoneal spread implies spread due to surgical trauma, where tumor cells get released unintentionally from transected lymph node or blood vessel or upon manipulation of the primary tumor during handling, referred to as metachronous peritoneal carcinomatosis. The most common dissemination of malignant cells in the peritoneum are with spontaneous exfoliation. Leucocyte-associated adhesional molecules like CD44, selectins, and/or integrin have been identified for cancer cell adhesion. Peritoneal stroma is the rich source for all the necessary factors required for proliferation.[rx]

Hematogenous spread involving the peritoneal cavity can occur in patients with malignant melanoma, lung, and breast cancer. In such cases, the embolic metastatic focus begins as a small nodule with eventual progression. The lymphatic spread usually revolves around the ligaments and mesentery, and such dissemination can occur in non-Hodgkin lymphoma or neuroendocrine tumor (NET).

Biological research describes three types of peritoneal cancer spread, which is helpful to understand to guide surgical management:

  • Random Proximal Distribution (RPD): Typically occurs in moderate and high-grade cancers in their early implantation due to the adherence molecules on the cancer cells near the tumor area. Examples include adenocarcinoma and carcinoid of an appendix, non-mucinous colorectal cancer, gastric cancer, and serous ovarian cancer.
  • Complete Redistribution (CRD): Here, there is no adhesion with the peritoneum near the primary tumor due to the low biological activity of the cancer cells. Examples are pseudomyxoma peritonei, diffuse malignant mesothelioma.
  • Widespread Cancer Distribution (WCD): The presence of adherence molecules on the cancer cells, along with mucus production, leads to the aggressive and widespread dissemination of cancer. Examples in this category include mucinous colorectal cancer, mucinous ovarian cancer, cystadenocarcinoma of the appendix.

This understanding of the pattern of spread helps in determining the best surgical approach: RPD treatment is best via selective peritonectomy of macroscopically involved regions. While CRD and WCD treatment should be with complete peritonectomy and extensive cytoreduction therapy.[rx]

Complications related to peritoneal metastases:

  • Ascites: Peritoneal metastases tend to produce fluid in the abdomen, known as ascites, which causes abdominal distension (Figure 2).
  • Intestinal obstruction: Peritoneal metastases may cause blockage of the intestines.
  • Hydronephrosis: The kidney ureters may be blocked by peritoneal metastases. This may affect kidney function.
  • Bloating
  • Abdominal pain
  • Nausea and vomiting
  • Constipation
  • Loss of appetite
  • Weight loss

Diagnosis of Colorectal Peritoneal Metastases

Patients with peritoneal metastasis usually present in a late stage of the disease. They typically present with symptoms and signs associated with their advanced primary cancer, or often peritoneal carcinomatosis is an accidental finding during surgical exploration for primary tumor resection or during other elective procedures. The two most important clinical findings related to peritoneal carcinomatosis have been ascites and bowel obstruction. However, they are found clinically in less than 50% of patients.[rx][rx] Similar to any other cancer, patients may complain of loss of appetite, organ-specific symptoms such as abdominal pain, nausea, vomiting, constipation, abdominal distension, weight loss, etc. Two main clinical features that could raise the suspicion for peritoneal metastasis include 1) the presence of malignant cells in ascitic fluid (28% to 30% of colorectal peritoneal metastasis patients), and 2) bowel obstruction (8% to 20% of patients with colorectal peritoneal metastasis.[rx]

Given the non-specific clinical picture associated with patients with peritoneal metastasis, it is highly unpredictable and difficult to diagnose this condition just based on clinical presentation. However, whenever there is a finding suggesting the possibility of abdominal cancer, clinicians should keep a low threshold for considering the presence of advanced-stage disease, as evidenced by the presence of peritoneal metastasis, even when imaging does not show readily show this. The peritoneum and any ascitic fluid can undergo an examination at the time of surgical exploration during a planned or emergent procedure.

Lab Test and Imaging

Metastatic cancer of the peritoneum is often an incidental finding detected during surgical exploration or on diagnostic imaging with modalities like CT scan or MRI performed for other indications. Biopsy of detected tumors or lesions is a confirmatory test to identify the type of cancer cells and to differentiate it from primary peritoneal cancer.

 The primary objectives of the work-up and investigation modalities employed in cases of suspected peritoneal metastasis are the following:

  • Early detection of possible peritoneal metastasis in a patient with recently diagnosed abdominal or pelvic malignancy and to rule out the presence of distant metastases in extra-abdominal areas, which becomes an absolute contraindication for surgery with curative intent.
  • To determine the extent, size, and major organ involvement by metastatic cancer to decide proper patient selection for cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC).
  • Early staging of the PC to help ascertain valuable information about potential outcomes and predict prognosis after treatment.

Cancerous lesions involving the peritoneum are sometimes visible with CT Scan, MRI, and 18F-fluorodeoxyglucose (FDG) positron emission tomography PET/CT. Each modality has its importance depending on the type of cancer and area of involvement. Presently the peritoneal carcinomatosis index (PCI) scoring system proposed by Dr. Sugarbacker provides a useful tool for better patient selection for surgery and a better understanding of prognosis and outcome (described in the management and staging section below). So most of the imaging studies are employed for their diagnostic parameters based on how accurately they can contribute to the PCI score preoperatively.[rx]

  • Ultrasound – Malignant ascites may be anechoic or have low-level echoes, and aids in the identification of deposits . Nodules are of intermediate echogenicity, hypoechoic compared to the peritoneum, whereas infiltration of the omentum results in hyperechogenicity.
  • CT Scan – It can provide appropriate site-specific cancer involvement in the abdominal cavity. The crucial findings for peritoneal metastasis are focal or diffuse thickening of peritoneal folds, which could appear as sclerotic, nodular, reticular, reticulonodular, or large plaque-like structures. Sometimes a large, thick layer of inhomogeneous density would be visible between the abdominal wall and bowel loops, which is sometimes called an “omental cake.” It is a neoplastic tissue layer. CT will also detect micronodules and micronodules if they are lying at the surface of the liver or spleen. Ascites can also be detected if it is over 50 ml.[rx] The sensitivity of computed tomography scan of the abdomen and pelvis for the diagnosis of colorectal cancer-related PM is 90% for cancer nodules larger than 5 cm but drops to less than 25% for lesions smaller than 5 cm.[rx] CT scan used for the detection of peritoneal tumors for future management decisions was also found to have inter-observer differences among radiologists and is not considered as the most reliable tool for the same.[rx] Additionally, CT is inefficient in assessing small bowel lesions, which could underestimate the PCI score preoperatively. However, it is still a valid tool to achieve optimal cytoreduction in cases of ovarian metastasis with moderate accuracy.[rx] Currently, abdominopelvic CT scanning is the first line of investigation for the detection of peritoneal metastasis in the presence of any abdominal primary.
    Peritoneal metastases can range in appearance from invisible to multiple large masses, and historically CT can only detect 60-80% of peritoneal metastases later shown to be present at surgery, although more recent studies reported detection rates of 85-93% 1,3. Appearances include 1:

    • thickening and enhancement of peritoneal reflections (especially if nodular)
    • soft tissue nodulesstranding and thickening of the omentum (omental cake)
    • stranding and distortion of the small bowel mesentery
    • ascites, especially if loculated
    • calcifications 2 (particularly in cystadenocarcinoma of the ovary)
      • nodular with the non-calcified component are typical
      • nodal calcification

    Intraperitoneal contrast has been investigated as a way of improving sensitivity to the presence of small deposits, and may improve detection but has not been widely adopted 3.

  • MRI – It is also one of the diagnostic tools for detecting peritoneal metastasis. However, it has not shown any significant superiority over CT scanning. One study did demonstrate an advantage of MR over single-helical CT for the detection of metastasis over peritoneum, omentum, and bowel.[rx] The combined use of MRI and CT has improved the preoperative estimation of PCI compared to only CT-determined PCI.[rx] Diffuse weighted MRI is used more for its diagnostic parameters, and one recently published study showed significant results. Whole-body diffuse weighted imagine-MRI (WB-DWI/MRI) was significantly better in the prediction of inoperability for peritoneal carcinomatosis than CT with sensitivity 90.6%, specificity 100%, PPV 100%, and NPV 90.3%. For CT alone these values were 25.0, 92.9, 80.0 and 52.0%, respectively.[rx]
  • PET Scan – The use of a PET-CT scan is more useful than just a PET scan, as the addition of CT allows for better anatomic visualization. 18F-fluorodeoxyglucose (FDG) positron emission tomography PET/CT is the preferred imaging that can detect the presence of cancer lesions based on the glucose uptake of the cells. It can be falsely negative when cells do not show good glucose uptake. Thus in cases where it is used for postoperative imaging, it would be better to document preoperative results for comparison to avoid false-negative results.[rx] To identify the exact localization and area of the peritoneal metastasis, PET-CT provides better accuracy and especially better NPV than MRI.[rx] PET-CT adds good value to conventional imaging mainly for monitoring response to the therapy, especially on long-term follow-up.[rx]
  • Diagnostic Laparoscopy – Surgeons recommend preoperative use of diagnostic laparoscopy for the assessment of the resectability of peritoneal tumor nodules before undergoing cytoreductive surgery (CRS). This approach is useful in patients for whom the previous imagining studies are insufficient in providing adequate information about the extent of disease involvement. However, it is sometimes not favored due to the difficulty related to trocar insertion and fear of port-site tumor recurrence. But currently, many surgeons are advocating its important role in affirmative decision making before actually going for laparotomy. In one study, it was found to have a positive predictive value of 83.3%. It also helped to avoid unnecessary laparotomy in 45% of the cases with no port-site recurrences or morbidity after 18 months.[rx] Similarly, another study suggested detailed technical aspects of the diagnostic laparoscopy, with over 94% of confirmative findings with the use of only two trocars and 99% for all cases.[rx] Extensive studies would be needed to get more evidence for its routine practical use.

New Proposed Diagnostic Methods

Different surgeon groups have proposed new diagnostic techniques for the optimum detection of peritoneal carcinomatosis and a more accurate understanding of its extent and size before considering surgical exploration:

  • Detection of ascitic CEA (carcinoma embryonic antigen) is a useful measure for diagnosing colorectal cancer (CRC) with PM.[rx]
  • Extensive involvement of small bowel by peritoneal carcinomatosis precludes the use of cytoreductive surgery. CT lacks sufficient accuracy in preoperative detection of disease in the small intestine that may subsequently impact the decision to offer CRS. One group of researchers demonstrated that CT-enteroclysis (CTE) is very useful in detecting cancerous implants in small bowel/mesentery. It showed 92% sensitivity, 96% specificity, 97% PPV and 91% NPV.[rx]
  • Another group of investigators explored the use of single-incision flexible endoscopy (SIFE) for diagnostic staging before surgery, and they compared it to rigid endoscopy (SIRE). The major objective was to avoid trocar site metastasis by reducing the need for extra trocar usage. The study showed feasibility in 94% of cases with SIFE and demonstrated superiority to SIRE in terms of technical exploration and outcomes. Future studies are needed to compare this with conventional laparoscopy.[rx]

Treatment of Colorectal Peritoneal Metastases

Recent advancements in surgical techniques and favorable outcomes related to targeted chemotherapy have encouraged the aggressive treatment of PC whenever it is feasible and accessible. Complete cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) and systemic chemotherapy has become the mainstay treatment for peritoneal carcinomatosis (PC) originating from most gastrointestinal and genitourinary tracts carcinomas. The efficacy of this treatment was validated in 2003 by a randomized clinical trial that compared CRS combined with HIPEC versus systemic chemotherapy alone (median survival: 22.3 vs. 12.6 months, P = 0.032).[rx] Macroscopically complete CRS (CRS-R0) is a major prognostic factor, with 5-year survival rates as high as 45% compared to less than 10% when CRS is incomplete.[rx] Dr. Sugarbaker changed the perception relating to peritoneal carcinomatosis from being terminal cancer to being a loco-regional disease and recommended an aggressive surgical approach with CRS, given the positive survival benefits.

The first step in the management centers is the appropriate patient selection for surgery.

Patient selection

  • Patient characteristics: age, comorbidities, general condition, and functional status. The objective is to determine the fitness of the patient for the anticipated trauma of surgery and its perioperative impact.
  • Exclude generalized metastatic disease: As pointed in the diagnostic section, CT and/or MRI or sometimes PET/CT can be used to investigate potential distal metastases depending on the type of cancer. Possible sites to look for are thorax, spine bones, brain, etc.
  • The extent of the peritoneal disease:

CT/MRI is the primary investigation tool to determine the size, extent, and type of peritoneal lesions. PCI scoring system described in figure 1 is routinely used to determine the surgical resectability and possibly favorable prognosis. Diagnostic laparoscopy provides very accurate estimates for PCI along with probable completeness of the cytoreduction (CC) index and outcome assessment in terms of disease-free survival, overall survival, and quality of life. The involvement of the small bowel impacts the PCI score and can suggest a bad prognosis. The following are the usual surgical sites used for preoperative determination of the extent of the disease for exclusion from CRS. [rx]

  • Massive mesenteric root infiltration not amenable to complete cytoreduction
  • Significant pancreatic capsule infiltration or pancreatic involvement requiring major resection not feasibly or amenable to complete surgical cytoreduction
  • More than one-third of small bowel length involvement requiring resection
  • Extensive hepatic metastasis

Some surgeons advocate the use of peritoneal surface disease severity score (PSDSS) for the early preoperative assessment of the prognosis based on the symptoms, PCI index, and primary tumor histology. However, extensive study results are needed to implement it in regular practice.[rx]

Cytoreductive Surgery (CRS) and Hyperthermic Intraperitoneal Chemotherapy

Upon the determination of patient fitness for surgery with selection driven by feasibility criteria, CRS is performed commonly through an open abdominal wall incision approach along with perioperative intraperitoneal chemotherapy. This novel treatment option became a reality for surgeons through the extensive work of Dr. Sugarbacker[rx] and his suggested surgical techniques. Cytoreductive surgery includes peritonectomy and individualized manual resection of the tumor lesions from different areas of the abdominal wall and mesentery. Peritonectomy now classifies as a curative treatment method for patients with peritoneal carcinomatosis, with the latter viewed as the locoregional spread instead of systemic disease. The usual surgical intention for any cancer treatment is the removal of all cancer cells through en-block resections with clear margins. However, for peritoneal carcinomatosis, it is highly difficult to achieve the complete removal of malignant cells. The idea behind cytoreduction is to reach complete removal of any macroscopic lesions, and the simultaneous use of HIPEC would potentially remove microscopic cancer lesions.[rx][rx] This technical approach has shown tremendous survival benefits along with disease-free survival and improved quality of life in patients. Currently, CRS combined with HIPEC is a first-line treatment for appendiceal and colorectal cancer-related PM.[rx][rx] It has also shown a promising role in ovarian, gastric, and neuroendocrine tumors.[rx][rx][rx] 

Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC)

This newer innovative therapeutic intervention has potential use in patients with extensive peritoneal carcinomatosis who may be deemed unresectable or unfit for surgery. The basis for aerosol chemotherapy is the premise that the intraabdominal application of chemotherapeutic drugs under pressure could potentially enhance tissue penetration and increases distribution.[rx] It has also been found to have superior benefits of drug delivery to tumor tissue with a significant effect on tumor regression than conventional intraperitoneal chemotherapy or systemic chemotherapy.[rx] This treatment option is beneficial in patients with extraperitoneal metastases in which this method could work as an effective palliative treatment option. Further ongoing prospective trials will decide on its future role and regular use.

​Peritoneal metastasis is difficult to treat and is best managed by a multi-disciplinary team that includes surgeons and medical oncologists.

  • Systemic chemotherapy: Chemotherapy drugs given intravenously or sometimes in combination with oral tablets circulate through the whole body. This type of treatment is suitable for cancers that have metastasized to multiple parts of the body.
  • Cytoreductive Surgery (CRS) with Hyperthermic intraperitoneal Chemotherapy (HIPEC):
    CRS is an extensive surgery that removes all visible cancers within the abdominal cavity. At the end of CRS, a heated chemotherapy solution is applied to the peritoneal cavity to destroy the remaining cancer cells that cannot be seen with the naked eye.
  • Intra-peritoneal (IP) chemotherapy: IP chemotherapy (Figure 3) is injected into the peritoneal cavity via an intraperitoneal port that is inserted via keyhole surgery. The port is buried under the skin and connected to a catheter that enters the peritoneal space.
  • Pressurized Intra-Peritoneal Aerosol Chemotherapy (PIPAC): PIPAC (Figure 4) is a novel method of delivering chemotherapy directly into the peritoneal cavity in an aerosol form. It utilizes the physical properties of pressurized gas to distribute the drug evenly and deeply. This allows greater penetration of the drug into the cancer cells, with reduced systemic side effects of the chemotherapy agent. PIPAC is performed as a short and simple laparoscopic (keyhole) surgery. Under general anesthesia, small instruments will be placed into the abdomen. A micro-pump will deliver the chemotherapy drug into the peritoneal cavity as an aerosol. At the end of the procedure, any residual gas within the peritoneal cavity will be removed.

Currently, PIPAC is a minimally invasive palliative procedure that aims to prolong survival and preserve the quality of life. Due to the low dosage applied, PIPAC can be combined with systemic palliative chemotherapy and has minimal organ toxicity. This procedure can be repeated at intervals of 6 weeks to 3 months.

PIPAC GIF (Infinity Loop).gif

Figure 4: Set-up of Pressurised Intra-Peritoneal Aerosol Chemotherapy (PIPAC)

Video Demonstration of PIPAC treatment

 

Peritoneal Carcinomatosis – Causes, Symptoms, Treatment

Peritoneal carcinomatosis (PC) generally refers to the metastatic involvement of the peritoneum. The name was first coined in 1931 by Sampson for the thorough description of metastatic involvement of the peritoneal stromal surface by ovarian cancer cells. Since then, it refers to almost any peritoneal metastatic deposits, metastatic cancer to the peritoneum is more common than a primary peritoneal malignancy. It often occurs with gastrointestinal or gynecological malignancies of advanced stages with locoregional involvement. This activity articulates how to evaluate for this condition properly, and highlights the role of the interprofessional team in caring for patients with this condition.

The peritoneum is a continuous membrane that covers the abdominal and pelvic cavities. Anatomically it has two layers that are, in and of themselves, continuous. One is the parietal peritoneum, which covers the inner surfaces of the abdominal and pelvic wall, and the other layer is the visceral peritoneum, which covers the abdominal organs and their suspending structures in the abdominopelvic cavity.[rx] The greater omentum, a prominent peritoneal fold, also referred to as the gastrocolic ligament,  has been referred to as a policeman of the abdomen, recognizing its role in containing inflammation and minimizing the spread of infection or local disease in the abdominopelvic cavity.  This unique nature of the omentum puts it at risk of involvement with any abdominal malignancies through the local disease spread.

The term peritoneal carcinomatosis (PC) generally refers to the metastatic involvement of the peritoneum. The name was first coined in 1931 by Sampson for the thorough description of metastatic involvement of the peritoneal stromal surface by ovarian cancer cells.[rx] Since then, it refers to almost any peritoneal metastatic deposits, metastatic cancer to the peritoneum is more common than a primary peritoneal malignancy. It often occurs with gastrointestinal or gynecological malignancies of advanced stages with locoregional involvement. Historically, the presence of metastatic deposits in the peritoneal cavity implied an incurable, fatal disease where curative surgical therapy was no longer a reasonable option. Newer surgical techniques and innovations in medical management strategies have dramatically changed the course of the disease over the past years. Effective treatment approaches have evolved, allowing for improvements in disease-free and overall survival.[rx]

Causes of Peritoneal Carcinomatosis

Peritoneal involvement is most common with cancers of the gastrointestinal (GI), reproductive, and genitourinary tracts. Ovarian, colon, and gastric cancers are by far the most common conditions presenting in advanced stages with peritoneal metastasis. Cancers involving other organs such as the pancreas, appendix, small intestine, endometrium, and prostate can also cause peritoneal metastasis, but such occur less frequently. While peritoneal carcinomatosis can arise from extra-abdominal primary malignancies, such cases are uncommon; and they account for approximately 10% of diagnosed cases of peritoneal metastasis.[rx] Examples include breast cancer, lung cancer, and malignant melanoma. Ovarian cancer is the most common neoplastic disease-causing peritoneal metastasis in 46% of cases owing to the anatomic location of the ovaries and their close contact with the peritoneum as well as the embryological developmental continuity of ovarian epithelial cells with peritoneal mesothelial cells.[rx][rx]

  • Colorectal cancer patients also contribute to a higher number of patients with peritoneal involvement due to the high incidence of these cancers overall. About 7% of cases develop synchronous peritoneal metastasis.[rx]
  • Approximately 9% of non-endocrinal pancreatic cancer cases present with PC.
  • Gastric carcinoma tends to reach an advanced stage at first presentation, and 14% of such cases can have peritoneal metastasis.[rx]
  • A neuroendocrine tumor arising from the gastrointestinal tract (GI-NET) is a slow-growing neoplasm, and it can metastasize to the peritoneum. PC can occur in about 6% of GI-NET patients.[rx] Its frequency increases with age.
  • As described earlier, peritoneal carcinomatosis from extra-abdominal malignancy presents in only 10% of cases where metastatic breast cancer (41%), lung cancer (21%), and malignant melanoma (9%) account for the majority of the cases.[rx]
  • Lung cancer is the primary cause of newly diagnosed cancers worldwide, accounting for over a million new cases per year. However, peritoneal carcinomatosis in lung cancer is rare and occurs in about 2.5 to 16% of autopsy results. Considering the scale of lung cancer rates globally, it could be the reason for a higher number of peritoneal carcinomatosis cases worldwide.[rx]
  • Sometimes it is difficult to find the primary tumor site. In such cases, we have peritoneal carcinomatosis with an unknown primary (UP). About 3 to 5% of cases of peritoneal carcinomatosis are of unknown origin.[rx]

Cancer cell metastasis is a complex phenomenon involving a multistage process and multidirectional spread. Dissemination, adhesion, invasion, and proliferation are the significant steps for the development of peritoneal metastasis from any primary. Primary malignant cells can spread through local invasion, lymphatics, or blood to distal sites. In the case of peritoneal metastasis, malignant cells originating from primary abdominal organs usually spread through a transcoelomic mechanism. Peritoneal fluid cycles through the peritoneal cavity in a specific direction, and this could spread the cancer cells in a particular manner. Currently, extensive research has given more detailed knowledge about the pathophysiology of peritoneal metastasis. This complex process involves multilevel reactions among molecular and cellular components of the primary tumor site as well as the peritoneum. Peritoneal mesothelial cells provide adhesion to the invading cancer cells and stromal components, and endothelial cells help in proliferation.[rx] Paget’s original theory of “seed and soil” very well describes the pattern of peritoneal metastasis in cancers such as ovarian, colorectal, stomach, etc. It proposed that the organ-preference patterns of cancer metastasis are the product of favorable interactions between metastatic tumor cells (the “seed”) and their organ microenvironment (the “soil”), which several research studies have extensively demonstrated.[rx]

One theory describes that peritoneal carcinomatosis from gastrointestinal cancers can occur in two different ways: 1) Via transversal growth and 2) via the intraperitoneal spread. Transversal growth means tumor cells can exfoliate from the primary tumor into the peritoneal cavity, also known as synchronous peritoneal carcinomatosis. This variant usually occurs preoperatively. Intraperitoneal spread implies spread due to surgical trauma, where tumor cells get released unintentionally from transected lymph node or blood vessel or upon manipulation of the primary tumor during handling, referred to as metachronous peritoneal carcinomatosis. The most common dissemination of malignant cells in the peritoneum are with spontaneous exfoliation. Leucocyte-associated adhesional molecules like CD44, selectins, and/or integrin have been identified for cancer cell adhesion. Peritoneal stroma is the rich source for all the necessary factors required for proliferation.[rx]

Hematogenous spread involving the peritoneal cavity can occur in patients with malignant melanoma, lung, and breast cancer. In such cases, the embolic metastatic focus begins as a small nodule with eventual progression. The lymphatic spread usually revolves around the ligaments and mesentery, and such dissemination can occur in non-Hodgkin lymphoma or neuroendocrine tumor (NET).

Biological research describes three types of peritoneal cancer spread, which is helpful to understand to guide surgical management:

  • Random Proximal Distribution (RPD): Typically occurs in moderate and high-grade cancers in their early implantation due to the adherence molecules on the cancer cells near the tumor area. Examples include adenocarcinoma and carcinoid of an appendix, non-mucinous colorectal cancer, gastric cancer, and serous ovarian cancer.
  • Complete Redistribution (CRD): Here, there is no adhesion with the peritoneum near the primary tumor due to the low biological activity of the cancer cells. Examples are pseudomyxoma peritonei, diffuse malignant mesothelioma.
  • Widespread Cancer Distribution (WCD): The presence of adherence molecules on the cancer cells, along with mucus production, leads to the aggressive and widespread dissemination of cancer. Examples in this category include mucinous colorectal cancer, mucinous ovarian cancer, cystadenocarcinoma of the appendix.

This understanding of the pattern of spread helps in determining the best surgical approach: RPD treatment is best via selective peritonectomy of macroscopically involved regions. While CRD and WCD treatment should be with complete peritonectomy and extensive cytoreduction therapy.[rx]

Complications related to peritoneal metastases:

  • Ascites: Peritoneal metastases tend to produce fluid in the abdomen, known as ascites, which causes abdominal distension (Figure 2).
  • Intestinal obstruction: Peritoneal metastases may cause blockage of the intestines.
  • Hydronephrosis: The kidney ureters may be blocked by peritoneal metastases. This may affect kidney function.
  • Bloating
  • Abdominal pain
  • Nausea and vomiting
  • Constipation
  • Loss of appetite
  • Weight loss

Diagnosis of Peritoneal Carcinomatosis

Patients with peritoneal metastasis usually present in a late stage of the disease. They typically present with symptoms and signs associated with their advanced primary cancer, or often peritoneal carcinomatosis is an accidental finding during surgical exploration for primary tumor resection or during other elective procedures. The two most important clinical findings related to peritoneal carcinomatosis have been ascites and bowel obstruction. However, they are found clinically in less than 50% of patients.[rx][rx] Similar to any other cancer, patients may complain of loss of appetite, organ-specific symptoms such as abdominal pain, nausea, vomiting, constipation, abdominal distension, weight loss, etc. Two main clinical features that could raise the suspicion for peritoneal metastasis include 1) the presence of malignant cells in ascitic fluid (28% to 30% of colorectal peritoneal metastasis patients), and 2) bowel obstruction (8% to 20% of patients with colorectal peritoneal metastasis.[rx]

Given the non-specific clinical picture associated with patients with peritoneal metastasis, it is highly unpredictable and difficult to diagnose this condition just based on clinical presentation. However, whenever there is a finding suggesting the possibility of abdominal cancer, clinicians should keep a low threshold for considering the presence of advanced-stage disease, as evidenced by the presence of peritoneal metastasis, even when imaging does not show readily show this. The peritoneum and any ascitic fluid can undergo an examination at the time of surgical exploration during a planned or emergent procedure.

Lab Test and Imaging

Metastatic cancer of the peritoneum is often an incidental finding detected during surgical exploration or on diagnostic imaging with modalities like CT scan or MRI performed for other indications. Biopsy of detected tumors or lesions is a confirmatory test to identify the type of cancer cells and to differentiate it from primary peritoneal cancer.

 The primary objectives of the work-up and investigation modalities employed in cases of suspected peritoneal metastasis are the following:

  • Early detection of possible peritoneal metastasis in a patient with recently diagnosed abdominal or pelvic malignancy and to rule out the presence of distant metastases in extra-abdominal areas, which becomes an absolute contraindication for surgery with curative intent.
  • To determine the extent, size, and major organ involvement by metastatic cancer to decide proper patient selection for cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC).
  • Early staging of the PC to help ascertain valuable information about potential outcomes and predict prognosis after treatment.

Cancerous lesions involving the peritoneum are sometimes visible with CT Scan, MRI, and 18F-fluorodeoxyglucose (FDG) positron emission tomography PET/CT. Each modality has its importance depending on the type of cancer and area of involvement. Presently the peritoneal carcinomatosis index (PCI) scoring system proposed by Dr. Sugarbacker provides a useful tool for better patient selection for surgery and a better understanding of prognosis and outcome (described in the management and staging section below). So most of the imaging studies are employed for their diagnostic parameters based on how accurately they can contribute to the PCI score preoperatively.[rx]

  • Ultrasound – Malignant ascites may be anechoic or have low-level echoes, and aids in the identification of deposits . Nodules are of intermediate echogenicity, hypoechoic compared to the peritoneum, whereas infiltration of the omentum results in hyperechogenicity.
  • CT Scan – It can provide appropriate site-specific cancer involvement in the abdominal cavity. The crucial findings for peritoneal metastasis are focal or diffuse thickening of peritoneal folds, which could appear as sclerotic, nodular, reticular, reticulonodular, or large plaque-like structures. Sometimes a large, thick layer of inhomogeneous density would be visible between the abdominal wall and bowel loops, which is sometimes called an “omental cake.” It is a neoplastic tissue layer. CT will also detect micronodules and micronodules if they are lying at the surface of the liver or spleen. Ascites can also be detected if it is over 50 ml.[rx] The sensitivity of computed tomography scan of the abdomen and pelvis for the diagnosis of colorectal cancer-related PM is 90% for cancer nodules larger than 5 cm but drops to less than 25% for lesions smaller than 5 cm.[rx] CT scan used for the detection of peritoneal tumors for future management decisions was also found to have inter-observer differences among radiologists and is not considered as the most reliable tool for the same.[rx] Additionally, CT is inefficient in assessing small bowel lesions, which could underestimate the PCI score preoperatively. However, it is still a valid tool to achieve optimal cytoreduction in cases of ovarian metastasis with moderate accuracy.[rx] Currently, abdominopelvic CT scanning is the first line of investigation for the detection of peritoneal metastasis in the presence of any abdominal primary.
    Peritoneal metastases can range in appearance from invisible to multiple large masses, and historically CT can only detect 60-80% of peritoneal metastases later shown to be present at surgery, although more recent studies reported detection rates of 85-93% 1,3. Appearances include 1:

    • thickening and enhancement of peritoneal reflections (especially if nodular)
    • soft tissue nodulesstranding and thickening of the omentum (omental cake)
    • stranding and distortion of the small bowel mesentery
    • ascites, especially if loculated
    • calcifications 2 (particularly in cystadenocarcinoma of the ovary)
      • nodular with the non-calcified component are typical
      • nodal calcification

    Intraperitoneal contrast has been investigated as a way of improving sensitivity to the presence of small deposits, and may improve detection but has not been widely adopted 3.

  • MRI – It is also one of the diagnostic tools for detecting peritoneal metastasis. However, it has not shown any significant superiority over CT scanning. One study did demonstrate an advantage of MR over single-helical CT for the detection of metastasis over peritoneum, omentum, and bowel.[rx] The combined use of MRI and CT has improved the preoperative estimation of PCI compared to only CT-determined PCI.[rx] Diffuse weighted MRI is used more for its diagnostic parameters, and one recently published study showed significant results. Whole-body diffuse weighted imagine-MRI (WB-DWI/MRI) was significantly better in the prediction of inoperability for peritoneal carcinomatosis than CT with sensitivity 90.6%, specificity 100%, PPV 100%, and NPV 90.3%. For CT alone these values were 25.0, 92.9, 80.0 and 52.0%, respectively.[rx]
  • PET Scan – The use of a PET-CT scan is more useful than just a PET scan, as the addition of CT allows for better anatomic visualization. 18F-fluorodeoxyglucose (FDG) positron emission tomography PET/CT is the preferred imaging that can detect the presence of cancer lesions based on the glucose uptake of the cells. It can be falsely negative when cells do not show good glucose uptake. Thus in cases where it is used for postoperative imaging, it would be better to document preoperative results for comparison to avoid false-negative results.[rx] To identify the exact localization and area of the peritoneal metastasis, PET-CT provides better accuracy and especially better NPV than MRI.[rx] PET-CT adds good value to conventional imaging mainly for monitoring response to the therapy, especially on long-term follow-up.[rx]
  • Diagnostic Laparoscopy – Surgeons recommend preoperative use of diagnostic laparoscopy for the assessment of the resectability of peritoneal tumor nodules before undergoing cytoreductive surgery (CRS). This approach is useful in patients for whom the previous imagining studies are insufficient in providing adequate information about the extent of disease involvement. However, it is sometimes not favored due to the difficulty related to trocar insertion and fear of port-site tumor recurrence. But currently, many surgeons are advocating its important role in affirmative decision making before actually going for laparotomy. In one study, it was found to have a positive predictive value of 83.3%. It also helped to avoid unnecessary laparotomy in 45% of the cases with no port-site recurrences or morbidity after 18 months.[rx] Similarly, another study suggested detailed technical aspects of the diagnostic laparoscopy, with over 94% of confirmative findings with the use of only two trocars and 99% for all cases.[rx] Extensive studies would be needed to get more evidence for its routine practical use.

New Proposed Diagnostic Methods

Different surgeon groups have proposed new diagnostic techniques for the optimum detection of peritoneal carcinomatosis and a more accurate understanding of its extent and size before considering surgical exploration:

  • Detection of ascitic CEA (carcinoma embryonic antigen) is a useful measure for diagnosing colorectal cancer (CRC) with PM.[rx]
  • Extensive involvement of small bowel by peritoneal carcinomatosis precludes the use of cytoreductive surgery. CT lacks sufficient accuracy in preoperative detection of disease in the small intestine that may subsequently impact the decision to offer CRS. One group of researchers demonstrated that CT-enteroclysis (CTE) is very useful in detecting cancerous implants in small bowel/mesentery. It showed 92% sensitivity, 96% specificity, 97% PPV and 91% NPV.[rx]
  • Another group of investigators explored the use of single-incision flexible endoscopy (SIFE) for diagnostic staging before surgery, and they compared it to rigid endoscopy (SIRE). The major objective was to avoid trocar site metastasis by reducing the need for extra trocar usage. The study showed feasibility in 94% of cases with SIFE and demonstrated superiority to SIRE in terms of technical exploration and outcomes. Future studies are needed to compare this with conventional laparoscopy.[rx]

Treatment of Peritoneal Carcinomatosis

Recent advancements in surgical techniques and favorable outcomes related to targeted chemotherapy have encouraged the aggressive treatment of PC whenever it is feasible and accessible. Complete cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) and systemic chemotherapy has become the mainstay treatment for peritoneal carcinomatosis (PC) originating from most gastrointestinal and genitourinary tracts carcinomas. The efficacy of this treatment was validated in 2003 by a randomized clinical trial that compared CRS combined with HIPEC versus systemic chemotherapy alone (median survival: 22.3 vs. 12.6 months, P = 0.032).[rx] Macroscopically complete CRS (CRS-R0) is a major prognostic factor, with 5-year survival rates as high as 45% compared to less than 10% when CRS is incomplete.[rx] Dr. Sugarbaker changed the perception relating to peritoneal carcinomatosis from being terminal cancer to being a loco-regional disease and recommended an aggressive surgical approach with CRS, given the positive survival benefits.

The first step in the management centers is the appropriate patient selection for surgery.

Patient selection

  • Patient characteristics: age, comorbidities, general condition, and functional status. The objective is to determine the fitness of the patient for the anticipated trauma of surgery and its perioperative impact.
  • Exclude generalized metastatic disease: As pointed in the diagnostic section, CT and/or MRI or sometimes PET/CT can be used to investigate potential distal metastases depending on the type of cancer. Possible sites to look for are thorax, spine bones, brain, etc.
  • The extent of the peritoneal disease:

CT/MRI is the primary investigation tool to determine the size, extent, and type of peritoneal lesions. PCI scoring system described in figure 1 is routinely used to determine the surgical resectability and possibly favorable prognosis. Diagnostic laparoscopy provides very accurate estimates for PCI along with probable completeness of the cytoreduction (CC) index and outcome assessment in terms of disease-free survival, overall survival, and quality of life. The involvement of the small bowel impacts the PCI score and can suggest a bad prognosis. The following are the usual surgical sites used for preoperative determination of the extent of the disease for exclusion from CRS. [rx]

  • Massive mesenteric root infiltration not amenable to complete cytoreduction
  • Significant pancreatic capsule infiltration or pancreatic involvement requiring major resection not feasibly or amenable to complete surgical cytoreduction
  • More than one-third of small bowel length involvement requiring resection
  • Extensive hepatic metastasis

Some surgeons advocate the use of peritoneal surface disease severity score (PSDSS) for the early preoperative assessment of the prognosis based on the symptoms, PCI index, and primary tumor histology. However, extensive study results are needed to implement it in regular practice.[rx]

Cytoreductive Surgery (CRS) and Hyperthermic Intraperitoneal Chemotherapy

Upon the determination of patient fitness for surgery with selection driven by feasibility criteria, CRS is performed commonly through an open abdominal wall incision approach along with perioperative intraperitoneal chemotherapy. This novel treatment option became a reality for surgeons through the extensive work of Dr. Sugarbacker[rx] and his suggested surgical techniques. Cytoreductive surgery includes peritonectomy and individualized manual resection of the tumor lesions from different areas of the abdominal wall and mesentery. Peritonectomy now classifies as a curative treatment method for patients with peritoneal carcinomatosis, with the latter viewed as the locoregional spread instead of systemic disease. The usual surgical intention for any cancer treatment is the removal of all cancer cells through en-block resections with clear margins. However, for peritoneal carcinomatosis, it is highly difficult to achieve the complete removal of malignant cells. The idea behind cytoreduction is to reach complete removal of any macroscopic lesions, and the simultaneous use of HIPEC would potentially remove microscopic cancer lesions.[rx][rx] This technical approach has shown tremendous survival benefits along with disease-free survival and improved quality of life in patients. Currently, CRS combined with HIPEC is a first-line treatment for appendiceal and colorectal cancer-related PM.[rx][rx] It has also shown a promising role in ovarian, gastric, and neuroendocrine tumors.[rx][rx][rx] 

Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC)

This newer innovative therapeutic intervention has potential use in patients with extensive peritoneal carcinomatosis who may be deemed unresectable or unfit for surgery. The basis for aerosol chemotherapy is the premise that the intraabdominal application of chemotherapeutic drugs under pressure could potentially enhance tissue penetration and increases distribution.[rx] It has also been found to have superior benefits of drug delivery to tumor tissue with a significant effect on tumor regression than conventional intraperitoneal chemotherapy or systemic chemotherapy.[rx] This treatment option is beneficial in patients with extraperitoneal metastases in which this method could work as an effective palliative treatment option. Further ongoing prospective trials will decide on its future role and regular use.

​Peritoneal metastasis is difficult to treat and is best managed by a multi-disciplinary team that includes surgeons and medical oncologists.

  • Systemic chemotherapy: Chemotherapy drugs given intravenously or sometimes in combination with oral tablets circulate through the whole body. This type of treatment is suitable for cancers that have metastasized to multiple parts of the body.
  • Cytoreductive Surgery (CRS) with Hyperthermic intraperitoneal Chemotherapy (HIPEC):
    CRS is an extensive surgery that removes all visible cancers within the abdominal cavity. At the end of CRS, a heated chemotherapy solution is applied to the peritoneal cavity to destroy the remaining cancer cells that cannot be seen with the naked eye.
  • Intra-peritoneal (IP) chemotherapy: IP chemotherapy (Figure 3) is injected into the peritoneal cavity via an intraperitoneal port that is inserted via keyhole surgery. The port is buried under the skin and connected to a catheter that enters the peritoneal space.
  • Pressurized Intra-Peritoneal Aerosol Chemotherapy (PIPAC): PIPAC (Figure 4) is a novel method of delivering chemotherapy directly into the peritoneal cavity in an aerosol form. It utilizes the physical properties of pressurized gas to distribute the drug evenly and deeply. This allows greater penetration of the drug into the cancer cells, with reduced systemic side effects of the chemotherapy agent. PIPAC is performed as a short and simple laparoscopic (keyhole) surgery. Under general anesthesia, small instruments will be placed into the abdomen. A micro-pump will deliver the chemotherapy drug into the peritoneal cavity as an aerosol. At the end of the procedure, any residual gas within the peritoneal cavity will be removed.

Currently, PIPAC is a minimally invasive palliative procedure that aims to prolong survival and preserve the quality of life. Due to the low dosage applied, PIPAC can be combined with systemic palliative chemotherapy and has minimal organ toxicity. This procedure can be repeated at intervals of 6 weeks to 3 months.

PIPAC GIF (Infinity Loop).gif

Figure 4: Set-up of Pressurised Intra-Peritoneal Aerosol Chemotherapy (PIPAC)

Video Demonstration of PIPAC treatment

 

Thrombocytopenia in Pregnancy – Causes, Symptoms, Treatment

Thrombocytopenia in Pregnancy/Thrombocytopenia, defined as a platelet count of under 150 x 10^9/L, is the second most common hematological abnormality in pregnancy. The International working group (IWG) adopted a lower threshold of platelets, 100 x 10^9/L, to define immune thrombocytopenia, which is observed in less than 1% of all pregnancies. Thrombocytopenia in pregnancy occurs either due to obstetric conditions (like gestational thrombocytopenia, pre-eclampsia/eclampsia) or secondary to systemic disorders (like thrombocytopenic thrombotic purpura, immune thrombocytopenia). For the present discussion, the approach to thrombocytopenia has its basis on the trimester in which the thrombocytopenia develops and the etiology of the thrombocytopenia. This division will help in understanding the workup and guiding management. Even though thrombocytopenia is a common abnormality in pregnancy, it seldom leads to life-threatening complications by itself. The management of thrombocytopenia focuses on the underlying cause. Platelet transfusion is usually not required to achieve a particular goal and is only for bleeding patients. Local hospital policies govern the goal of platelet counts and are quite variable between institutions. Nevertheless, a hematologist must be involved in the management of thrombocytopenia in pregnancy, especially if the platelet count drops below 70 x 10^9/L, or if a coexistent bleeding disorder is either encountered or suspected.

Types of Thrombocytopenia

Although the rare causes of thrombocytopenias do not constitute more than 1% of pregnant patients with low platelet counts, they often designate severe conditions that contribute significantly to maternal morbidity and mortality.

  • Gestation thrombocytopenia: Overall, gestational thrombocytopenia is the reason for low platelets in nearly 75% of pregnancies presenting with thrombocytopenia. It is the most common cause of low platelets in the third trimester of pregnancy.The mechanism behind gestation thrombocytopenia remains anecdotal. Dilution from expanded plasma volume, formation of autoantibody against platelets, pooling or consumption of platelets in the placenta, changes in the activity of von Willebrand factor and ADAMTS-13, increased macrophage colony-stimulating factors from the placenta and inadequate response to thrombopoietin are some of the proposed as the mechanisms leading to gestational thrombocytopenia. In theory, gestational thrombocytopenia is thought to be a continuum of the dilutional changes of pregnancy, where the affected women are simply producing platelets at the lower end of the normal spectrum. However, the fact that it recurs with subsequent pregnancies; tends to develop late in the pregnancy (with increasing gravidity of uterus and changes in placental blood flow), and resolves soon after parturition (which excludes autoimmunity); reflects a mechanism in maternal physiology which is still not completely understood.
  • Immune thrombocytopenia (ITP): ITP is the most common cause of low platelets in the first trimester of pregnancy. Overall it affects 1 to 4% of all pregnancies and affects 1 to 2 per 1000 pregnancies each year. Approximately two-thirds of women have ITP diagnosed before the start of pregnancy. ITP is a heterogeneous disease that can either be diagnosed during pregnancy or may flare up during pregnancy. Up to 60% of patients have an antibody-mediated disease, but in up to 40% of patients, the driver for ITP may be malfunctioning T-cells or antigen-presenting cells. ITP can present in association with a systemic autoimmune disease like systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), scleroderma, anti-phospholipid antibody syndrome (APLS), etc. which can present as a combination of autoimmune-mediated and TMA induced thrombocytopenia.
  • Thrombotic microangiopathy (TMA):

    1. Pregnancy specific TMA

      • Pre-eclampsia (PEC): Throughout the world, PEC affects 2% to 8% of all pregnancies and accounts for 20% of patients developing thrombocytopenia in pregnancy. Thrombocytopenia in a patient with PEC occurs primarily in the second and third trimester of pregnancy and occurs in up to 50% of pre-eclamptic women. Rarely, pre-eclampsia can also occur within the first week post-partum.
      • HELLP (Hemolysis, elevated liver enzymes, low platelets): HELLP syndrome affects 0.2 to 0.8% of all pregnancies. However, it is one of the rare causes of thrombocytopenia in pregnancy. It is associated with pre-eclampsia in up to 70 to 80% of patients. Up to 20% of cases of HELLP are identified 24 to 48 hours postpartum, where thrombocytopenia may persist for up to 4 days after delivery.
      • Acute fatty liver of pregnancy (AFLP): It is a rare cause of thrombocytopenia in pregnancy, which is estimated to affect 1 in 5000 to 20,000 pregnancies.
    2. TMA not specific to pregnancy: These are amongst the rarest causes of thrombocytopenia in pregnancy.

      • Thrombotic thrombocytopenic purpura (TTP): TTP is estimated to affect 1 in 200,000 pregnancies, but 10 to 30% of all adult-related TTP is obstetric. Up to 25% of patients with congenital TTP (also known as Upshaw-Schulman syndrome), characterized by the congenital absence of ADAMTS-13 (A disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13), present for the first time during the first pregnancy or immediately postpartum.
      • Atypical hemolytic-uremic syndrome (HUS): Atypical HUS is seen in up to 1 in 25000 pregnancies and presents with MAHA and renal failure, either at near-term or post-partum.
  • Disseminated Intravascular Coagulation (DIC): DIC occurs in up to 0.35% of all pregnancies. Although DIC can occur in any trimester, it most commonly occurs in the third trimester, either as a direct consequence of an obstetric complication (for eg., PPH, amniotic fluid embolism) or secondary to other pregnancy-related complications (PEC/ HELLP/ AFLP, etc.).
  • Hereditary thrombocytopenia: It is a rare cause of thrombocytopenia in pregnancy that is commonly diagnosed in the first trimester of pregnancy, although it can present during any trimester.
  • Thrombotic microangiopathy (TMA): It is an umbrella of disorders that are united by common clinical and pathological features. The clinical presentation includes microangiopathic hemolytic anemia (MAHA), thrombocytopenia, and organ injury. On a microscopic level, all TMA’s are defined by vascular damage that manifests as arteriolar and capillary thrombosis, which present with characteristic abnormalities in the endothelium and vessel wall.
    • Pregnancy-related TMA occurs secondary to obstetric complications like PEC, HELLP, and AFLP. The pathogenesis of thrombocytopenia in PEC remains unexplained. The belief is that a hypoxic placenta releases antiangiogenic factors that cause endothelial dysfunction, which leads to the clinical manifestations of PEC.
    • The non-pregnancy-related TMA occurs due to absence/inhibition of ADAMTS-13 (leads to TTP) or due to a mutation in the function or expression of proteins controlling the alternative pathway C3 convertase (leads to atypical HUS).
  • Disseminated Intravascular Coagulation (DIC): DIC denotes an imbalance between activated procoagulant pathways and impairment of the internal anticoagulant pathways and fibrinolytic systems. This imbalance in the coagulation system leads to platelet activation and consumption, along with fibrin deposition. It can occur either with a complication of the process of delivery (post-partum hemorrhage (PPH), uterine atony, vaginal lacerations, abruptio placentae, retained dead fetus) or in association with other complications of pregnancy like HELLP, AFLP or other causes of TMA.
  • Others: Bone marrow failure, antiphospholipid antibody syndrome, PNH, autoimmune conditions, and type II VWD are amongst the rare causes of thrombocytopenia in pregnancy. Less than 1% of patients develop thrombocytopenia secondary to ‘other’ causes listed.

Causes of Thrombocytopenia

Thrombocytopenia in pregnancy happens secondary to many etiologies, differing in their pathophysiology and presentation. A summary of possible etiologies is listed here:

  • Gestational thrombocytopenia
  • Immune thrombocytopenia
  • Thrombotic microangiopathy (TMA): TMA in pregnancy divides into pregnancy-specific TMA and non-pregnancy-specific TMA due to differences in management.

    1. Pregnancy specific TMA

      • Pre-eclampsia (PEC):
      • Hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome
      • Acute fatty liver of pregnancy (AFLP)
    2. TMA not specific to pregnancy

      • Thrombotic thrombocytopenic purpura (TTP)
      • Atypical hemolytic-uremic syndrome (HUS)
  • Disseminated intravascular coagulation (DIC)
  • Hereditary thrombocytopenia (HT): Further classify according to the size of the platelet, genetic defect and inheritance pattern (WAS gene, HOXA 11 gene, MYH9 disorders, etc.)
  • Others:

    • Bone marrow failure syndromes

      • Aplastic anemia
      • Myelodysplastic syndrome (MDS),
      • Myeloproliferative neoplasms (MPN),
      • Leukemia/lymphoma
      • Marrow infiltrative disorders
    • Paroxysmal nocturnal hemoglobinuria (PNH),
    • Drug-induced thrombocytopenia,
    • Type IIB von Willebrand disease (VWD).
    • Heparin-induced thrombocytopenia (HIT)

It is also worthwhile to distribute the etiology of thrombocytopenia according to the trimester and the platelet count.

First Trimester

  • Immune thrombocytopenia (ITP) (most common)
  • Hereditary thrombocytopenia (HT)
  • Others (Please see above for a detailed list)
  • Thrombotic microangiopathy (TMA)

Second Trimester

  • Platelet count greater than 100 x 10/L

    • Gestational thrombocytopenia
    • ITP
    • Pre-eclampsia/ HELLP
    • HT/Others/TMA
  • Platelet count under 100 x 10/L

    • ITP (most common)
    • HT
    • Pre-eclampsia/HELLP
    • Others
    • Gestational thrombocytopenia
    • TMA

Third Trimester

  • Platelet count more than 100 x 10/L

    • Gestational Thrombocytopenia (most common)
    • Pre-eclampsia/ HELLP (second most common)
    • Others/TMA/ITP/HT
  • Platelet count less than 50 x 10/L

    • Pre-eclampsia/ HELLP (most common)
    • ITP
    • Others
    • TMA
    • Gestational thrombocytopenia/HT

Symptoms Of Thrombocytopenia

  • Limb anomalies can affect both upper and lower limbs, although upper limb involvement tends to be more severe than lower limb involvement. Individuals with thrombocytopenia absent radius (TAR) syndrome almost always have a bilateral absence of the radius. The thumbs are always present. The thumbs in individuals with TAR syndrome are of near-normal size but are somewhat wider and flatter than usual. They are also held in flexion against the palm and tend to have limited function, particularly in terms of grasp and pinch activities []. The upper limbs may also have hypoplasia or absence of the ulnae, humeri, and shoulder girdles. Fingers may show syndactyly, and fifth finger clinodactyly is common. Lower limbs are affected in almost half of those with TAR syndrome; hip dislocation, coxa valga, femoral and/or tibial torsion, genu varum, and absence of the patella are common findings. The most severe limb involvement is tetraphocomelia.
  • Thrombocytopenia may be congenital or may develop within the first few weeks to months of life. In one review, it was noted that thrombocytopenia developed during the first week of life in only 59% []. In general, thrombocytopenic episodes decrease with age, with most children with TAR syndrome having normal platelet counts by school age. However, cow’s milk allergy is common and can be associated with the exacerbation of thrombocytopenia.
  • Bleeding, most often from the gums or nose. Women with thrombocytopenia may have heavier or longer periods or breakthrough bleeding. You may also see blood in your pee or poop.
  • Red, flat spots on your skin, about the size of a pinhead. You see these mostly on your legs and feet, and they may appear in clumps. Your doctor may call them petechiae.
  • Blotches and bruises. You might have large areas of bleeding under the skin that don’t turn white when you press on them. You also might see what look like the bruises you get from a bump or being hit. They could be blue or purple and change to yellow or green over time. These are caused from the inside, by the sudden leaking from tiny blood vessels. The medical name for these is purpura.
  • Cardiac anomalies affect 15%-22% [] and usually include septal defects rather than complex cardiac malformations.
  • Gastrointestinal involvement includes cow’s milk allergy and gastroenteritis. Both tend to improve with age.
  • Genitourinary anomalies include renal anomalies (both structural and functional) and rarely, Mayer-Rokitansky-Kuster-Hauser syndrome (agenesis of uterus, cervix, and upper part of the vagina) [].
  • Leukemoid reactions have been reported in some individuals with TAR syndrome, with white blood cell counts exceeding 35,000 cells/mm3. These leukemoid reactions are generally transient [].
  • Cognitive development is usually normal in individuals with TAR syndrome.
  • Growth. Most have height on or below the 50th centile.
  • Other skeletal manifestations, including rib and cervical vertebral anomalies (e.g., cervical rib, fused cervical vertebrae), tend to be relatively rare.

Symptoms: Clues To Thrombocytopenia Causes

  • Abdominal Pain
    • HELLP Syndrome (pregnancy)
    • Hemolytic Uremic Syndrome (HUS)
    • Platelet Sequestration (Splenomegaly)
  • Bloody Diarrhea
    1. Hemolytic Uremic Syndrome (HUS)
  • Fever
    • Viral Infections (e.g. CMV, EBV, VZV, HIV, HCV, Parvovirus B19)
    • Tick-Borne Illness ()
    • Dengue Fever
    • Malaria
    • Rickettsial Disease
    • Hemolytic Uremic Syndrome (HUS)
    • Thrombotic Thrombocytopenic Purpura (TTP)
  • Weight loss or Night Sweats
    • HIV Infection
    • Leukemia
    • Myelodysplastic Syndrome

Diagnosis of Thrombocytopenia

In any patient with thrombocytopenia, a thorough history and physical exam help in establishing the etiology behind the low platelet count. Usually, the signs and symptoms of thrombocytopenia do not occur unless the platelet count drops to a very low level or the patient presents with symptoms of the underlying disorder. A temporal profile of thrombocytopenia or its bleeding manifestations (acute, chronic, or relapsing-remitting) does not help in determining the etiology of thrombocytopenia but helps in determining the clinical phenotype. The past medical history of other diseases such as existing autoimmune disorders (systemic lupus erythematosus, rheumatoid arthritis, etc.), infections (rickettsiosis, malaria, etc.), malignancies, and transplant recipients is essential to establish the diagnosis. Likewise, a history of medications (quinine, antibiotics, heparin, etc.), recent vaccinations, travel history, dietary practices, high-risk behaviors (sexual practices, illicit drug use, smoking, alcohol consumption) also helps in guiding the evaluation of thrombocytopenia. Thorough family history is vital in delineating congenital thrombocytopenia, which can present for the first time well into adulthood.

A physical exam provides clues to determining the etiology of thrombocytopenia. Patients with gestational thrombocytopenia are often healthy, asymptomatic women who are found to have low platelets on lab investigations. On the contrary, a pregnant woman with TMA is usually a gravely ill patient often presenting to the emergency room or admitted to high-risk obstetric units. Patients with low platelet count usually present with mucocutaneous bleeding. However, joint bleed or severe bleeding should prompt a workup towards severe coagulopathies like DIC. Physical exam should also evaluate for hepatomegaly and/or splenomegaly (cirrhosis, lymphoproliferative disorders, etc.), skeletal deformities (like absent radius, humeral abnormality, and sometimes phocomelia seen in thrombocytopenia absent radii syndrome), and skin exam (like petechiae or purpura seen commonly with ITP, or, eczema seen in Wiskott-Aldrich Syndrome).

Specific clues in the history and physical exam can point a clinician towards an underlying etiology.

  • Gestational thrombocytopenia: It is diagnosed based on the following criteria.

    • onset in mid-second to the third trimester
    • no symptoms in the mother and no history of bleeding
    • no effect on the outcome of the pregnancy
    • no thrombocytopenia in the neonate
    • self-limited course and resolution in 4 to 8 weeks
    • A tendency to recur with the same degree in subsequent pregnancies
  • Pre-eclampsia: Patients present with severe hypertension after 20 weeks of gestation (defined as systolic pressure more than 160mmHg and diastolic pressure more than 110 mmHg on two separate occasions, at least 4 hours apart) or with severe persistent right upper quadrant epigastric pain which is unresponsive to medications. Eclampsia can present as a sequel to pre-eclampsia with seizures.
  • HELLP syndrome: It correlates with generalized edema in more than 50% of patients who demonstrate hepatic and renal insufficiency in labs.
  • AFLP: Clinically, it is quite challenging to distinguish between AFLP and HELLP syndrome. However, encephalopathy, hypoglycemia, severe coagulopathy, along TMA-like hemolysis, are more frequently present in patients with AFLP.
  • PNH: Patients usually present with hemolytic anemia, pancytopenia, and thrombosis; however, the characteristic finding of hemoglobinuria is almost never seen. Although thrombosis is a rare presenting feature, it usually occurs in atypical sites, like the portal vein or the cerebral vein.
  • HIT: A history of recent exposure to heparin is quintessential to the diagnosis of HIT. The thrombocytopenia usually develops within 5 to 10 days of exposure to heparin but can occur sooner if the previous exposure was relatively recent. The presence of skin necrosis and/or venous thromboembolism should prompt a workup towards HIT. The clinical 4-T score also aids in the diagnosis of HIT.

Lab Test And Imaging

Laboratory evaluation of thrombocytopenia starts with a review of peripheral smear. Pseudothrombocytopenia, defined as clumping of platelets on peripheral smear, can happen in up to 1% of all pregnancies. This ‘fictitious’ thrombocytopenia occurs due to the collection of blood in ethylenediaminetetraacetic acid (EDTA) anticoagulated tubes. The EDTA-dependent platelet auto-antibodies lead to artifactual clumping on the peripheral smear. It can be corrected by collecting the blood in a heparin tube and then performing a manual count on the peripheral smear. A review of a peripheral blood smear helps to determine the morphology of all three cell lines and the detection of red cell fragments (schistocytes) and atypical white cells like myeloblasts; this is particularly important in a critically ill pregnant patient with thrombocytopenia, where a review of peripheral smear must be done to look for schistocytes and rule out TMA.

A complete blood count with differential helps in realizing the degree of thrombocytopenia and provides a clue about the etiology. Evaluation of thrombocytopenia in pregnancy starts by differentiating between isolated thrombocytopenia and thrombocytopenia, which occurs along with changes in red cell and white cell lines.

  • Thrombocytopenia along with changes in other cell lines

    • Thrombocytopenia, along with hemolytic anemia: TMA should be the first consideration in a pregnant woman presenting with anemia and thrombocytopenia.

      • Hemolysis labs include lactate dehydrogenase, haptoglobin levels, total and direct bilirubin, and reticulocyte count, and the clinician should obtain an index in patients suspected of hemolytic anemia.
      • The diagnosis of TMA usually involves the triad of thrombocytopenia, along with hemolysis and renal failure/injury. The lab evaluation for pregnancy-related TMA and non-pregnancy related TMA is similar; however, certain specific tests are needed to differentiate between PEC/HELLP, TTP, and atypical HUS In patients suspected of TMA, Shiga-toxin must be tested to rule out typical HUS.
      • Specific test to rule out TTP includes testing for ADAMTS-13. A level of ADAMTS-13 above 5 to 10% usually rules out TTP.
      • In patients suspected of atypical HUS, a genetic test must be pursued to identify mutations that prevent the expression or function of proteins involved in the regulation of the alternate C3 pathway.
    • Thrombocytopenia associated with bleeding: A coagulation panel should always be done to identify any coagulopathy which may complicate thrombocytopenia with bleeding. As mentioned above, DIC can occur in association with TMA or secondary to obstetric causes. There is no single test to identify DIC, but a score developed by the international society of thrombosis and hemostasis (ISTH) helps in predicting DIC with a sensitivity of 93% and a specificity of 98%. The components of the ISTH score include fibrinogen level, partial thromboplastin time, platelet count, and fibrin markers (D-dimer is a reasonable marker).
    • Paroxysmal nocturnal hemoglobinuria (PNH): The diagnosis of PNH is via flow cytometric analysis of glycosyl-phosphatidylinositol-anchored proteins (GPI-AP) along with a decreased expression of both CD55 and CD59. CD55 and CD59 are still tested to exclude rare, inherited deficiency of single GPI-AP.
  • Isolated thrombocytopenia:

    • Immune thrombocytopenia: ITP usually presents as isolated thrombocytopenia with petechiae or bleeding manifestations. The workup for ITP follows the American society of hematology guidelines (2011) and the international working group (2010). The mandatory tests include a lab evaluation for hepatitis B and C, human immunodeficiency virus, quantitative immunoglobulins, direct antiglobulin test, and blood group (Rh). Tests that can be of potential utility in such patients include antiphospholipid antibodies, anti-nuclear antibodies, anti-thyroid antibodies along with thyroid function tests, and viral studies for cytomegalovirus. Helicobacter Pylori testing should take place in areas with high prevalence.
    • Heparin-induced thrombocytopenia (HIT): Although rare, HIT can cause thrombocytopenia in pregnancy. HIT is diagnosed based on clinical and pathological features. The 4T score helps in determining the clinical probability of HIT and the anti-platelet Factor-4 (PF-4)/heparin antibodies to help in making a pathological diagnosis. The PF-4 dependent enzyme immunoassays (EIA) have a high sensitivity and specificity for HIT antibodies, especially if the cut-off for optical density is raised (in comparison to serotonin-release assay (SRA)]. However, all positive EIA should be tested with washed platelet assays (like carbon-14-SRA) to confirm the diagnosis.

Gestational thrombocytopenia is a diagnosis of exclusion that is based on a thorough history and physical exam and ruling out of conflicting diagnosis with lab support. With sufficient exclusion of other etiologies, then no further laboratory evaluation is needed to confirm a diagnosis of gestational thrombocytopenia. Rarely, the platelet count drops below 70 x 10^9/L in patients with gestational thrombocytopenia. If the platelet count goes below 70 x 10^9/L, then the patient should be evaluated for a secondary cause like ITP. 

  • Complete Blood Count (CBC)
  • Basic chemistry panel (chem8)
    • Evaluate for associated Renal Failure (e.g. TTP, HUS)
    • Expand to the comprehensive panel in Hemolysis
      1. Indirect Bilirubin increased in Hemolysis
      2. Serum Lactate Dehydrogenase and Haptoglobin increased in HUS and TTP
  • Coagulation tests (INR, PTT, Fibrinogen)
    • Normal in isolated Thrombocytopenia, ITP, TTP, HUS
    • Prolonged in DIC, liver disease, Massive Transfusion and Trauma
    • Fibrinogen is decreased in DIC and Trauma
  • Peripheral Blood Smear
    • See Platelet Morphology
    • See Peripheral Blood Smear
    • Schistocytes are present in DIC and Microangiopathic Hemolytic Anemia (TTP, HUS), but not ITP
    • Consider Parasite stains (Tick-Borne Illness, Malaria)
    • Hemolysis will raise Indirect Bilirubin
  • Platelet Count
    • Rule-out Pseudothrombocytopenia
      • Review Peripheral Smear to evaluate for clumping (Pseudothrombocytopenia)
      • Repeat Platelet Count in non-EDTA Anticoagulant (citrate, blue tube)
    • Repeat Platelet Count timing (adjust based on chronicity, stability and bleeding complications)
      • Repeat immediately for developing bleeding complications
      • Repeat in days to 1 week if Platelet Count <50,000 per uL
      • Repeat in 2 weeks if Platelet Count <100,000 per uL
      • Repeat in 4 weeks if Platelet Count <150,000 per uL

Evaluation of patients with isolated thrombocytopenia includes obtaining a CBC, peripheral blood smear, HIV, and HCV tests.

  • Repeat CBC to confirm that thrombocytopenia is real.
  • Anemia and thrombocytopenia occur with infections, DIC, sepsis, thrombotic microangiopathy, autoimmune disorders like Felty syndrome.
  • Leucocytosis and thrombocytopenia can present in infection, malignancy, chronic inflammatory conditions.
  • Pancytopenia occurs in myelodysplastic syndromes.
  • In patients with symptoms or signs of autoimmune disorders like SLE, antiphospholipid antibody syndrome (APS), obtain anti-nuclear antibodies and antiphospholipid antibodies, respectively.
  • In patients with thrombosis, one should consider heparin-induced thrombocytopenia (obtain platelet factor 4 antibodies), APS (check antiphospholipid antibodies ), DIC and PNH (check PT,aPTT, fibrinogen, LDH)
  • Check liver enzymes and coagulation tests in patients with liver disease.
  • A blood smear is used to check the appearance of your platelets under a microscope. For this test, a small amount of blood is drawn from a blood vessel, usually in your arm.
  • Blood clot test a blood clot test measures the time it takes blood to clot. These tests include partial thromboplastin time (PTT) and prothrombin time (PT).
  • Bone marrow biopsy is indicated in conditions when the cause of thrombocytopenia is unclear, and when a hematologic disorder is suspected.

    • A normal number or rise in megakaryocytes in bone marrow is a presenting feature in conditions with increased platelet destruction.
    • The decrease in megakaryocytes, along with an overall reduction in other cells, is seen in aplastic anemia.
    • In SLE, severe reduction or absence of megakaryocytes is seen due to an autoantibody directed against the thrombopoietin receptor.
    • Megaloblastic changes in RBC and granulocytes occur in vitamin B12, folate, and copper deficiency. In myelodysplasia, cells are dysplastic.
  • Single-gene testing – Gene-targeted deletion/duplication analysis of RBM8A is performed first, followed by sequence analysis of RBM8A if no deletion is found. Although the diagnosis of TAR syndrome can be established by identification of a heterozygous minimally deleted 200-kb region at chromosome band 1q21.1, sequence analysis of RBM8A can be done subsequently in individuals with the deletion to confirm the presence of a second pathogenic variant (hypomorphic allele) and allow family studies. Homozygous RBM8A null alleles (e.g., deletions) are thought to be lethal.
  • More comprehensive genomic testing – (when available) including exome sequencing and genome sequencing may be considered if single-gene testing (and/or use of a multigene panel that includes RBM8A) fails to confirm a diagnosis in an individual with features of TAR syndrome. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation).

Treatment of Thrombocytopenia

In pregnancy, thrombocytopenia usually does not lead to an increased risk of bleeding. Even in patients with ITP, where thrombocytopenia is often quite severe, the risk of bleeding remains low. The obstetric indication decides the mode of delivery. Vaginal delivery is preferable from a hematologic standpoint due to the lower risk of bleeding; however, this is not a deciding factor. Administration of neuraxial anesthesia (epidural anesthesia) is a challenge. The American College of Obstetrics and Gynecology recommend a platelet count of 80 x 10^9/L (level C recommendation) as the goal of administering epidural anesthesia. The platelet goal for delivery is more than 50 x 10^9/L, especially if planning a cesarean section. Here we will briefly discuss the management of pregnant patients with thrombocytopenia according to the etiology of the disease.

  • Gestational Thrombocytopenia: The platelet count rarely goes below 70 x 10^9/L in patients with gestational thrombocytopenia. No intervention is required in such patients as the condition resolves spontaneously 4 to 8 weeks after delivery. In patients whose platelet counts drop below 70 x 10^9/L, a component of ITP merits consideration. The use of steroids and intravenous immunoglobulins does not benefit patients with gestational thrombocytopenia. However, it may help those who have ITP superimposed on gestational thrombocytopenia. The neonatal outcomes are excellent, and neonates of mothers with gestational thrombocytopenia never develop thrombocytopenia.
  • Immune thrombocytopenia (ITP): ITP is a very complex and heterogeneous disease. Although many treatment options exist for adult patients with ITP, pregnancy offers a unique challenge in terms of minimizing the fetal-maternal risk. Usually, an intervention is not necessary unless the platelet counts drop below 20 to 30 x 10^9/L in the first two trimesters or if thrombocytopenia is complicated with bleeding, regardless of the platelet count. Treatment in the third trimester depends on the mode of delivery and candidacy for epidural anesthesia. Corticosteroids are usually the first line of treatment in pregnant patients with a response time of 3 to 7 days. They are associated with minimal risk of fetal orofacial cleft palate if started in the first trimester and may lead to maternal diabetes, weight gain, and hypertension if started in the third trimester. A single dose of intravenous immunoglobulins (IVIG) at 1000mg/kg, can lead to a rapid rise in platelets within 24 hours. However, the response lasts only for 2 to 3 weeks. One more dose can be repeated either alone or in combination with steroids if unable to achieve the desired response. It is associated with a small risk of renal tubular acidosis and thrombosis. Anti-D, rituximab, and thrombopoietin receptor agonists have been classified as category C by the FDA. Rituximab has been used safely during pregnancy, with minimal complications to the mother. There are reports of transient neonatal B-cell lymphopenia with the use of rituximab, which resolves by six months of age. Splenectomy can be done safely via a laparoscopic approach in the second and third trimester of pregnancy. However, it is rarely pursued in the modern era and is reserved for patients refractory to medical management. Other medical options include azathioprine and cyclosporine. The use of chemotherapeutic agents like cyclophosphamide, vincristine, etc is usually discouraged in pregnant patients. Mycophenolate mofetil is contraindicated in pregnancy due to teratogenic effects on the fetus.
  • Thrombotic Microangiopathy: The management of TMA in pregnancy focuses on the antecedent cause. The thrombocytopenia is a consequence of the TMA and hence improves with the resolution of the underlying condition. It is critical to differentiate between the pregnancy-specific TMA (PEC/HELLP/AFLP), and non-pregnancy-specific TMA as the management of the two conditions is very different.
    • PEC/HELLP syndrome/AFLP: The goal of treatment is the delivery of the fetus, with supportive care provided for the management of the underlying condition.
    • TTP: prompt initiation of plasma exchange helps remove the inhibitor to ADAMTS-13 and supply the patients with fresh plasma to restore the function of ADAMTS-13, resolve hemolysis. Eventually, anti-inhibitor therapy is initiated to reduce the inhibitor activity. Up to 25% of patients presenting with TTP in adulthood have congenital absence of ADAMTS-13 (Upshaw-Schulman syndrome). In such patients, anti-inhibitor therapy has no role. Such patients should receive periodic infusions of plasma. Trials regarding a recombinant ADAMTS-13 are underway to circumvent the need for plasma infusions. Caplacizumab (CABLIVI) was approved by the FDA in 2019 for the treatment of adult patients with acquired TTP, in combination with plasma exchange and immunosuppressive therapy. It is a von Willebrand factor (vWF)-directed antibody fragment that targets the A1-domain of vWF, and inhibits the interaction between vWF and platelets, thereby reducing both vWF-mediated platelet adhesion and platelet consumption. Its safety in pregnancy has not been established and increases the risk of hemorrhage in both mother and fetus.
    • Atypical HUS: Plasma exchange is not useful in patients with atypical HUS. The FDA has approved eculizumab for patients diagnosed with atypical HUS. Despite being labeled category C by the FDA, several reports have shown that eculizumab can be safely administered during pregnancy.
  • PNH: Eculizumab is a humanized monoclonal IgG antibody that prevents cleavage of C5 into C5a and C5b, eventually blocking the formation of membrane attack complex. It leads to a reduction in complement-mediated hemolysis and improvement in platelet count. As stated above, several reports demonstrate the safety of eculizumab.
  • Disseminated intravascular coagulation: DIC is a consumptive coagulopathy where the primary goal is to treat the underlying cause. However, patients in severe DIC may require supportive measures. Patients in DIC present either with a bleeding phenotype or overt thromboembolism. In a bleeding patient, the goal for platelet transfusion is 30 to 50 x 10^9/L. Plasma/ cryoprecipitate is given to keep prothrombin time less than 3 seconds prolonged and fibrinogen above 1.5 gm/L. In a patient with overt thromboembolism, the clinician should initiate full-dose anticoagulation.
  • Heparin-induced thrombocytopenia: HIT rarely complicates pregnancy, unless the patient receives heparin products. After confirming the diagnosis via platelet activation assays (serotonin release assay is the most commonly used assay), patients should not receive heparin products anymore. In such patients, direct thrombin inhibitors (argatroban and bivalirudin) serve for immediate management. For the follow-up anticoagulation, fondaparinux is an option for anticoagulation in pregnant patients.

Prognosis

The prognosis depends on the underlying etiology for thrombocytopenia. While thrombocytopenia does not lead to complications in pregnancy, the etiology behind the thrombocytopenia can pose significant challenges. The mode of delivery is chosen based on the obstetric indication.

  • Gestational thrombocytopenia: It is a self-limiting condition that usually resolves within 4 to 8 weeks of delivery of the fetus. Although there is a high risk of recurrence with subsequent pregnancies, it is often a benign condition that seldom causes any complications in the mother.
  • Immune thrombocytopenia: ITP can lead to significant bleeding issues in the mother. ITP in the mother can also affect the neonate and lead to neonatal thrombocytopenia. Despite low platelets, the risk of bleeding is quite low in the mother. In the neonates who have thrombocytopenia secondary to maternal ITP, catastrophic bleeding events (like intracranial hemorrhage) occur in less than 1% of patients.
  • TMA: Both pregnancy-related TMA (PEC/HELLP/AFLP) and TMA not specific to pregnancy (TTP/ATypical HUS) are associated with high rates of maternal and neonatal morbidity and mortality. Thrombocytopenia related to these conditions seldom poses any issues in the mother or the neonate. The goal of treatment is the delivery of the baby. Recovery of platelet count may lag behind the delivery of the fetus but eventually resolves once the underlying condition improves.
  • Clinicians should manage other causes of thrombocytopenia (bone marrow failure syndrome, PNH, etc.) according to primary etiology, and the prognosis depends on the underlying etiology.

Neonatal outcome in women with thrombocytopenia

  • The neonatal outcome is excellent in neonates born to mothers with gestational thrombocytopenia. They never develop thrombocytopenia or are at risk of bleeding.
  • Neonates born to mothers with ITP may develop transient thrombocytopenia. Although the passive transfer of antibodies from the mother causing transient thrombocytopenia in the neonate is the most popular theory behind neonates developing thrombocytopenia, it is not entirely proven. The nadir of platelets appears within 24 to 48 hours. Reports of intracranial hemorrhage appear in less than 1% of neonates who develop thrombocytopenia secondary to maternal ITP.

Other Issues

Thrombocytopenia in pregnancy is a benign condition in the majority of patients. However, it may be associated with more severe etiologies in a few patients. A few noteworthy points are listed here.

  • Less than 1% of patients with thrombocytopenia in pregnancy have a platelet count of less than 100 x 10^9/L.
  • A thorough history and complete physical is the initial step in the evaluation of thrombocytopenia in pregnancy.
  • A review of the peripheral smear is the first step in the lab evaluation of thrombocytopenia. It helps in ruling out pseudo-thrombocytopenia and schistocytes.
  • Gestational thrombocytopenia, which is the most common cause of thrombocytopenia in pregnancy, is a diagnosis of exclusion.
  • Despite being the most common cause of thrombocytopenia in pregnancy, gestational thrombocytopenia does not require any intervention as it resolves spontaneously.
  • ITP is the most frequent cause of thrombocytopenia in the first trimester of pregnancy. However, it is also a diagnosis of exclusion.
  • Corticosteroids and IVIG are the first-line treatment for ITP in pregnancy.
  • Rituximab is safe in pregnancy for the treatment of ITP, although it may cause transient B-cell lymphopenia in the neonate, which resolves spontaneously.
  • Pregnancy-related TMA management is by the delivery of the fetus. Thrombocytopenia and other abnormalities may take longer to recover after the delivery of the fetus.
  • TTP is rare during pregnancy, but 10 to 30% of all patients with TTP are obstetric. Up to 25% of TTP in pregnancy is due to a congenital lack of ADAMTS-13 (Upshaw-Schulman syndrome).
  • Eculizumab is designated category C by the FDA, but several reports show that it is safe for the management of atypical HUS and PNH in pregnancy.

Important points to remember for both physicians and patients

  • The mode of delivery depends on the obstetric indication, rather than the platelet count.
  • A platelet count of more than 50 x 10^9/L is safe for delivery.
  • The goal of platelets for administering neuraxial anesthesia is at 80 x 10^9/L.
  • In a patient with gestational thrombocytopenia, if the platelet count drops below 70 x 10^9/L, then a secondary cause, like ITP, should be considered.
  • Platelet transfusions are not required for low platelet counts unless the patient is bleeding.
  • The neonatal outcome is excellent in neonates born to mothers with gestational thrombocytopenia.
  • Transient thrombocytopenia can present in neonates born to mothers with ITP. In less than 1% of neonates, it can lead to intracranial hemorrhage. A pediatrician consult is necessary for such a scenario.
  • Maternal and neonatal morbidity and mortality are high in patients with TMA. The primary goal of treatment is the delivery of the fetus.

References

Secondary Thrombocytosis – Causes, Symptoms, Treatment

Secondary thrombocytosis, also known as reactive thrombocytosis defined as an abnormally high platelet count due to underlying events, disease, or the use of certain medications. Secondary thrombocytosis is the more common type and is usually identified in routine laboratory results. Among individuals with thrombocytosis, 80% to 90% are known to have secondary thrombocytosis. Reactive causes of thrombocytosis include transient processes such as acute blood loss, acute infection, or sustained forms of reactive thrombocytosis include iron deficiency, asplenia, cancer, chronic inflammatory, or infectious diseases. Secondary thrombocytosis (reactive thrombocytosis) is a laboratory anomaly that resolves when the underlying causative condition is addressed.

Platelets are a component of blood produced in the bone marrow that plays a vital role in the blood clotting process. The normal platelet count in adults and children is 150,000/microL to 450,000/microL (150 to 450 x 10/L), but the normal range may vary in different clinical laboratories. Thrombocytosis is a condition where the platelet count exceeds 450,000/μl. It is also referred to as thrombocythemia. Thrombocytosis can be divided into two groups:  primary thrombocytosis and secondary (or reactive) thrombocytosis.

This distinction between primary and secondary thrombocytosis is important as it carries implications for evaluation, prognosis, and treatment. Primary thrombocytosis is due to the unregulated abnormality of platelet production of bone marrow progenitor cells. They are usually associated with the myeloproliferative neoplasms group. Primary thrombocytosis, especially essential thrombocythemia and polycythemia vera, has an increased risk of thrombosis and bleeding compared to secondary thrombocytosis.

In most cases, the symptoms are due to an underlying disorder and not the thrombocytosis itself. Extreme thrombocytosis may rarely result in thrombotic events such as acute myocardial infarction, mesenteric vein thrombosis, and pulmonary embolism. Even though secondary thrombocytosis is benign, the underlying etiology of thrombocytosis (e.g., malignancy, connective tissue disorders, chronic infections) can be associated with an increased risk of adverse outcomes.

Causes of Secondary Thrombocytosis

Common causes of secondary thrombocytosis

  • Infections (acute bacterial and viral infections/chronic infections like tuberculosis)
  • Inflammation
  • Functional and surgical asplenia
  • Hemorrhage/ iron deficiency
  • Drugs- aztreonam, ceftazidime, ibuprofen, epinephrine, glucocorticoids
  • Rheumatoid arthritis, IBD (Inflammatory bowel disease), sarcoidosis
  • Hemolysis
  • Metastatic cancer/lymphoma
  • Allergic reactions
  • Exercise

Symptoms Of Secondary Thrombocytosis

  • Limb anomalies can affect both upper and lower limbs, although upper limb involvement tends to be more severe than lower limb involvement. Individuals with thrombocytopenia absent radius (TAR) syndrome almost always have a bilateral absence of the radius. The thumbs are always present. The thumbs in individuals with TAR syndrome are of near-normal size but are somewhat wider and flatter than usual. They are also held in flexion against the palm and tend to have limited function, particularly in terms of grasp and pinch activities []. The upper limbs may also have hypoplasia or absence of the ulnae, humeri, and shoulder girdles. Fingers may show syndactyly, and fifth finger clinodactyly is common. Lower limbs are affected in almost half of those with TAR syndrome; hip dislocation, coxa valga, femoral and/or tibial torsion, genu varum, and absence of the patella are common findings. The most severe limb involvement is tetraphocomelia.
  • Thrombocytopenia may be congenital or may develop within the first few weeks to months of life. In one review, it was noted that thrombocytopenia developed during the first week of life in only 59% []. In general, thrombocytopenic episodes decrease with age, with most children with TAR syndrome having normal platelet counts by school age. However, cow’s milk allergy is common and can be associated with the exacerbation of thrombocytopenia.
  • Bleeding, most often from the gums or nose. Women with thrombocytopenia may have heavier or longer periods or breakthrough bleeding. You may also see blood in your pee or poop.
  • Red, flat spots on your skin, about the size of a pinhead. You see these mostly on your legs and feet, and they may appear in clumps. Your doctor may call them petechiae.
  • Blotches and bruises. You might have large areas of bleeding under the skin that don’t turn white when you press on them. You also might see what look like the bruises you get from a bump or being hit. They could be blue or purple and change to yellow or green over time. These are caused from the inside, by the sudden leaking from tiny blood vessels. The medical name for these is purpura.
  • Cardiac anomalies affect 15%-22% [] and usually include septal defects rather than complex cardiac malformations.
  • Gastrointestinal involvement includes cow’s milk allergy and gastroenteritis. Both tend to improve with age.
  • Genitourinary anomalies include renal anomalies (both structural and functional) and rarely, Mayer-Rokitansky-Kuster-Hauser syndrome (agenesis of uterus, cervix, and upper part of the vagina) [].
  • Leukemoid reactions have been reported in some individuals with TAR syndrome, with white blood cell counts exceeding 35,000 cells/mm3. These leukemoid reactions are generally transient [].
  • Cognitive development is usually normal in individuals with TAR syndrome.
  • Growth. Most have height on or below the 50th centile.
  • Other skeletal manifestations, including rib and cervical vertebral anomalies (e.g., cervical rib, fused cervical vertebrae), tend to be relatively rare.

Symptoms: Clues To Thrombocytopenia Causes

  • Abdominal Pain
    • HELLP Syndrome (pregnancy)
    • Hemolytic Uremic Syndrome (HUS)
    • Platelet Sequestration (Splenomegaly)
  • Bloody Diarrhea
    1. Hemolytic Uremic Syndrome (HUS)
  • Fever
    • Viral Infections (e.g. CMV, EBV, VZV, HIV, HCV, Parvovirus B19)
    • Tick-Borne Illness ()
    • Dengue Fever
    • Malaria
    • Rickettsial Disease
    • Hemolytic Uremic Syndrome (HUS)
    • Thrombotic Thrombocytopenic Purpura (TTP)
  • Weight loss or Night Sweats
    • HIV Infection
    • Leukemia
    • Myelodysplastic Syndrome

Diagnosis of Secondary Thrombocytosis

History and Physical

Most patients are asymptomatic and are usually identified on routine laboratory results. History should evaluate the condition that may have precipitated the thrombocytosis or complications of thrombocytosis:

  • Prior trauma or surgery
  • History of splenectomy or hemolysis
  • Findings suggesting infection or inflammation
  • History of bleeding (e.g., menorrhagia, gastrointestinal) or iron deficiency
  • History of arterial or venous thrombosis
  • Medications
  • Smoking and alcohol consumption
  • Prior diagnosis of a chronic hematologic disorder
  • Unexplained fever, sweats, weight loss, fatigue, or other systemic complaints suggesting malignancy

No distinguishing features of secondary thrombocytosis (reactive thrombocytosis) are found on physical examination but should look for

  • Cutaneous or mucosal bleeding/bruising
  • Lymphadenopathy
  • Hepatosplenomegaly
  • Signs of arterial or venous thrombosis

Lab Test And Imaging

The laboratory workup  of secondary thrombocytosis (reactive thrombocytosis) includes the following:

  • Complete blood count shows an increased platelet count
  • Peripheral Blood Smear
  • Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP)
  • Antinuclear antibody (ANA), rheumatoid factor (RF)
  • Iron studies (serum iron, serum ferritin)

If the clinical condition does not differentiate between primary and secondary thrombocytosis, further tests like genetic testing and a bone marrow biopsy may be indicated.

Evaluation of patients with isolated thrombocytopenia includes obtaining a CBC, peripheral blood smear, HIV, and HCV tests.

  • Repeat CBC to confirm that thrombocytopenia is real.
  • Anemia and thrombocytopenia occur with infections, DIC, sepsis, thrombotic microangiopathy, autoimmune disorders like Felty syndrome.
  • Leucocytosis and thrombocytopenia can present in infection, malignancy, chronic inflammatory conditions.
  • Pancytopenia occurs in myelodysplastic syndromes.
  • In patients with symptoms or signs of autoimmune disorders like SLE, antiphospholipid antibody syndrome (APS), obtain anti-nuclear antibodies and antiphospholipid antibodies, respectively.
  • In patients with thrombosis, one should consider heparin-induced thrombocytopenia (obtain platelet factor 4 antibodies), APS (check antiphospholipid antibodies ), DIC and PNH (check PT,aPTT, fibrinogen, LDH)
  • Check liver enzymes and coagulation tests in patients with liver disease.
  • A blood smear is used to check the appearance of your platelets under a microscope. For this test, a small amount of blood is drawn from a blood vessel, usually in your arm.
  • Blood clot test a blood clot test measures the time it takes blood to clot. These tests include partial thromboplastin time (PTT) and prothrombin time (PT).
  • Bone marrow biopsy is indicated in conditions when the cause of thrombocytopenia is unclear, and when a hematologic disorder is suspected.
    • A normal number or rise in megakaryocytes in bone marrow is a presenting feature in conditions with increased platelet destruction.
    • The decrease in megakaryocytes, along with an overall reduction in other cells, is seen in aplastic anemia.
    • In SLE, severe reduction or absence of megakaryocytes is seen due to an autoantibody directed against the thrombopoietin receptor.
    • Megaloblastic changes in RBC and granulocytes occur in vitamin B12, folate, and copper deficiency. In myelodysplasia, cells are dysplastic.
  • Single-gene testing – Gene-targeted deletion/duplication analysis of RBM8A is performed first, followed by sequence analysis of RBM8A if no deletion is found. Although the diagnosis of TAR syndrome can be established by identification of a heterozygous minimally deleted 200-kb region at chromosome band 1q21.1, sequence analysis of RBM8A can be done subsequently in individuals with the deletion to confirm the presence of a second pathogenic variant (hypomorphic allele) and allow family studies. Homozygous RBM8A null alleles (e.g., deletions) are thought to be lethal.
  • More comprehensive genomic testing – (when available) including exome sequencing and genome sequencing may be considered if single-gene testing (and/or use of a multigene panel that includes RBM8A) fails to confirm a diagnosis in an individual with features of TAR syndrome. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation).

Treatment of Secondary Thrombocytosis

Secondary thrombocytosis has no specific treatment, but the identification of reactive conditions and appropriate therapy of the underlying disorder is most relevant. For example, the normalization of platelet counts can be achieved by iron supplementation in inflammatory bowel patients.

Treatment with anti-platelets like aspirin is usually not indicated as the risk of thrombosis is very low in secondary thrombocytosis. Still, it can be considered for patients with platelets more than 1,000,000/μL, and complications of thrombocytosis are present, or to be at risk of developing complications. The platelet-reducing effect of the plateletpheresis is done in patients with evidence of thrombosis and active bleeding. Though plateletpheresis is temporary, it helps in the rapid reduction of the platelet count.

Corticosteroids

Dexamethasone or prednisone is typically prescribed to raise your platelet count. You take it once a day in the form of a pill or tablet. An increased or normalized platelet count is generally seen within 2 weeks of therapy, particularly with high-dose dexamethasone. Your doctor will then likely cut your dose gradually over the next 4 to 8 weeks. The treatment may have to be repeated, but once your platelet count is normal, none is needed again.

Blood Transfusion

It temporarily increases platelet levels in your blood. Platelets are transfused only if the platelet count is extremely low. (Transfused platelets only last about three days in the circulation.)

Primary Immune Thrombocytopenia

This condition is a diagnosis of exclusion. First-line treatment includes glucocorticoids and intravenous immune globulins; these agents inhibit autoantibody production and platelet degradation. Second-line treatment includes rituximab, immunosuppressive drugs, and splenectomy. Third line agents are thrombopoietin receptor agonists, which stimulate platelet production.

Drug-Induced Thrombocytopenia

  • Withholding the causative drug usually results in improvement of platelet counts in cases of drug-induced thrombocytopenia.
  • The mainstay of treatment in HIT is to withdraw all heparin products and to initiate anti-thrombin and anti-Xa activity anticoagulant agents. Dicoumarol agents added once platelet count reaches normal.

TTP gets treated with plasma exchange.

In patients with secondary ITP managing the underlying condition is recommended, like, in SLE, SLE treatment is with immunosuppressive agents, and in patients with H. pylori-associated thrombocytopenia, eradication of H.pylori increases the platelet count.

Platelet Transfusions

Platelet transfusions may be suggested for people who have a low platelet count due to thrombocytopenia.[rx]

Thrombotic Thrombocytopenic Purpura

Treatment of thrombotic thrombocytopenic purpura (TTP) is a medical emergency since the associated hemolytic anemia and platelet activation can lead to kidney failure and changes in the level of consciousness. Treatment of TTP was revolutionized in the 1980s with the application of plasmapheresis. According to the Furlan-Tsai hypothesis,[28] this treatment works by removing antibodies against the von Willebrand factor-cleaving protease ADAMTS-13. The plasmapheresis procedure also adds active ADAMTS-13 protease proteins to the patient, restoring a normal level of von Willebrand factor multimers. Patients with persistent antibodies against ADAMTS-13 do not always manifest TTP, and these antibodies alone are not sufficient to explain how plasmapheresis treats TTP.[rx]

Immune Thrombocytopenic Purpura

Oral petechiae/purpura – Immune thrombocytopenic purpura

Many cases of immune thrombocytopenic purpura (ITP) also known as idiopathic thrombocytopenic purpura, can be left untreated, and spontaneous remission (especially in children) is not uncommon. However, counts under 50,000 are usually monitored with regular blood tests, and those with counts under 10,000 are usually treated, as the risk of serious spontaneous bleeding is high with such low platelet counts. Any patient experiencing severe bleeding symptoms is also usually treated. The threshold for treating ITP has decreased since the 1990s; hematologists recognize that patients rarely spontaneously bleed with platelet counts greater than 10,000, although exceptions to this observation have been documented.[rx][rx]

Thrombopoietin analogs have been tested extensively for the treatment of ITP. These agents had previously shown promise but had been found to stimulate antibodies against endogenous thrombopoietin or lead to thrombosis. Romiplostim (trade name Nplate, formerly AMG 531) was found to be safe and effective for the treatment of ITP in refractory patients, especially those who relapsed following splenectomy.[rx]

Heparin-Induced Thrombocytopenia

Discontinuation of heparin is critical in a case of heparin-induced thrombocytopenia (HIT). Beyond that, however, clinicians generally treat to avoid thrombosis.[rx] Treatment may include a direct thrombin inhibitor, such as lepirudin or argatroban. Other blood thinners sometimes used in this setting include bivalirudin and fondaparinux. Platelet transfusions are not routinely used to treat HIT because thrombosis, not bleeding, is the primary problem.[rx] Warfarin is not recommended until platelets have normalized.[rx]

Congenital Amegakaryocytic Thrombocytopenia

Bone marrow/stem cell transplants are the only known cures for this genetic disease. Frequent platelet transfusions are required to keep the patient from bleeding to death before the transplant can be performed, although this is not always the case.[rx]

Human-Induced Pluripotent Stem Cell-Derived Platelets

Human-induced pluripotent stem cell-derived platelets is a technology currently being researched by the private sector, in association with the Biomedical Advanced Research and Development Authority and the U.S. Department of Health and Human Services, that would create platelets outside the human body.[rx]

Complications

Physicians need to be familiar with the complications associated with thrombocytosis. However, complications due to secondary thrombocytosis are rare.

  • Arterial and venous thrombosis leading to stroke, myocardial infarction, mesenteric ischemia
  • Bleeding
  • Spontaneous abortion
  • IUD- intrauterine death/ intrauterine growth retardation
  • Transformation to AML and primary myelofibrosis

References

Reactive Thrombocytosis – Causes, Symptoms, Treatment

Reactive thrombocytosis, defined as an abnormally high platelet count in the absence of chronic myeloproliferative disease, secondary to an infection, inflammation, and hemorrhage. Secondary thrombocytosis is usually identified in routine laboratory testing, as most patients are asymptomatic. This activity highlights the role of the interprofessional team in the evaluation and management of secondary thrombocytosis.

Platelets are a component of blood produced in the bone marrow that plays a vital role in the blood clotting process. The normal platelet count in adults and children is 150,000/microL to 450,000/microL (150 to 450 x 10/L), but the normal range may vary in different clinical laboratories. Thrombocytosis is a condition where the platelet count exceeds 450,000/μl. It is also referred to as thrombocythemia. Thrombocytosis can be divided into two groups:  primary thrombocytosis and secondary (or reactive) thrombocytosis.

This distinction between primary and secondary thrombocytosis is important as it carries implications for evaluation, prognosis, and treatment. Primary thrombocytosis is due to the unregulated abnormality of platelet production of bone marrow progenitor cells. They are usually associated with the myeloproliferative neoplasms group. Primary thrombocytosis, especially essential thrombocythemia and polycythemia vera, has an increased risk of thrombosis and bleeding compared to secondary thrombocytosis.

Secondary thrombocytosis, also known as reactive thrombocytosis defined as an abnormally high platelet count due to underlying events, disease, or the use of certain medications. Secondary thrombocytosis is the more common type and is usually identified in routine laboratory results. Among individuals with thrombocytosis, 80% to 90% are known to have secondary thrombocytosis. Reactive causes of thrombocytosis include transient processes such as acute blood loss, acute infection, or sustained forms of reactive thrombocytosis include iron deficiency, asplenia, cancer, chronic inflammatory, or infectious diseases. Secondary thrombocytosis (reactive thrombocytosis) is a laboratory anomaly that resolves when the underlying causative condition is addressed.

In most cases, the symptoms are due to an underlying disorder and not the thrombocytosis itself. Extreme thrombocytosis may rarely result in thrombotic events such as acute myocardial infarction, mesenteric vein thrombosis, and pulmonary embolism. Even though secondary thrombocytosis is benign, the underlying etiology of thrombocytosis (e.g., malignancy, connective tissue disorders, chronic infections) can be associated with an increased risk of adverse outcomes.

Causes of Reactive Thrombocytosis

Common causes of secondary thrombocytosis

  • Infections (acute bacterial and viral infections/chronic infections like tuberculosis)
  • Inflammation
  • Functional and surgical asplenia
  • Hemorrhage/ iron deficiency
  • Drugs- aztreonam, ceftazidime, ibuprofen, epinephrine, glucocorticoids
  • Rheumatoid arthritis, IBD (Inflammatory bowel disease), sarcoidosis
  • Hemolysis
  • Metastatic cancer/lymphoma
  • Allergic reactions
  • Exercise

Symptoms Of Reactive Thrombocytosis

  • Limb anomalies can affect both upper and lower limbs, although upper limb involvement tends to be more severe than lower limb involvement. Individuals with thrombocytopenia absent radius (TAR) syndrome almost always have a bilateral absence of the radius. The thumbs are always present. The thumbs in individuals with TAR syndrome are of near-normal size but are somewhat wider and flatter than usual. They are also held in flexion against the palm and tend to have limited function, particularly in terms of grasp and pinch activities []. The upper limbs may also have hypoplasia or absence of the ulnae, humeri, and shoulder girdles. Fingers may show syndactyly, and fifth finger clinodactyly is common. Lower limbs are affected in almost half of those with TAR syndrome; hip dislocation, coxa valga, femoral and/or tibial torsion, genu varum, and absence of the patella are common findings. The most severe limb involvement is tetraphocomelia.
  • Thrombocytopenia may be congenital or may develop within the first few weeks to months of life. In one review, it was noted that thrombocytopenia developed during the first week of life in only 59% []. In general, thrombocytopenic episodes decrease with age, with most children with TAR syndrome having normal platelet counts by school age. However, cow’s milk allergy is common and can be associated with the exacerbation of thrombocytopenia.
  • Bleeding, most often from the gums or nose. Women with thrombocytopenia may have heavier or longer periods or breakthrough bleeding. You may also see blood in your pee or poop.
  • Red, flat spots on your skin, about the size of a pinhead. You see these mostly on your legs and feet, and they may appear in clumps. Your doctor may call them petechiae.
  • Blotches and bruises. You might have large areas of bleeding under the skin that don’t turn white when you press on them. You also might see what look like the bruises you get from a bump or being hit. They could be blue or purple and change to yellow or green over time. These are caused from the inside, by the sudden leaking from tiny blood vessels. The medical name for these is purpura.
  • Cardiac anomalies affect 15%-22% [] and usually include septal defects rather than complex cardiac malformations.
  • Gastrointestinal involvement includes cow’s milk allergy and gastroenteritis. Both tend to improve with age.
  • Genitourinary anomalies include renal anomalies (both structural and functional) and rarely, Mayer-Rokitansky-Kuster-Hauser syndrome (agenesis of uterus, cervix, and upper part of the vagina) [].
  • Leukemoid reactions have been reported in some individuals with TAR syndrome, with white blood cell counts exceeding 35,000 cells/mm3. These leukemoid reactions are generally transient [].
  • Cognitive development is usually normal in individuals with TAR syndrome.
  • Growth. Most have height on or below the 50th centile.
  • Other skeletal manifestations, including rib and cervical vertebral anomalies (e.g., cervical rib, fused cervical vertebrae), tend to be relatively rare.

Symptoms: Clues To Thrombocytopenia Causes

  • Abdominal Pain
    • HELLP Syndrome (pregnancy)
    • Hemolytic Uremic Syndrome (HUS)
    • Platelet Sequestration (Splenomegaly)
  • Bloody Diarrhea
    1. Hemolytic Uremic Syndrome (HUS)
  • Fever
    • Viral Infections (e.g. CMV, EBV, VZV, HIV, HCV, Parvovirus B19)
    • Tick-Borne Illness ()
    • Dengue Fever
    • Malaria
    • Rickettsial Disease
    • Hemolytic Uremic Syndrome (HUS)
    • Thrombotic Thrombocytopenic Purpura (TTP)
  • Weight loss or Night Sweats
    • HIV Infection
    • Leukemia
    • Myelodysplastic Syndrome

Diagnosis of Reactive Thrombocytosis

History and Physical

Most patients are asymptomatic and are usually identified on routine laboratory results. History should evaluate the condition that may have precipitated the thrombocytosis or complications of thrombocytosis:

  • Prior trauma or surgery
  • History of splenectomy or hemolysis
  • Findings suggesting infection or inflammation
  • History of bleeding (e.g., menorrhagia, gastrointestinal) or iron deficiency
  • History of arterial or venous thrombosis
  • Medications
  • Smoking and alcohol consumption
  • Prior diagnosis of a chronic hematologic disorder
  • Unexplained fever, sweats, weight loss, fatigue, or other systemic complaints suggesting malignancy

No distinguishing features of secondary thrombocytosis (reactive thrombocytosis) are found on physical examination but should look for

  • Cutaneous or mucosal bleeding/bruising
  • Lymphadenopathy
  • Hepatosplenomegaly
  • Signs of arterial or venous thrombosis

Lab Test And Imaging

The laboratory workup  of secondary thrombocytosis (reactive thrombocytosis) includes the following:

  • Complete blood count shows an increased platelet count
  • Peripheral Blood Smear
  • Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP)
  • Antinuclear antibody (ANA), rheumatoid factor (RF)
  • Iron studies (serum iron, serum ferritin)

If the clinical condition does not differentiate between primary and secondary thrombocytosis, further tests like genetic testing and a bone marrow biopsy may be indicated.

Evaluation of patients with isolated thrombocytopenia includes obtaining a CBC, peripheral blood smear, HIV, and HCV tests.

  • Repeat CBC to confirm that thrombocytopenia is real.
  • Anemia and thrombocytopenia occur with infections, DIC, sepsis, thrombotic microangiopathy, autoimmune disorders like Felty syndrome.
  • Leucocytosis and thrombocytopenia can present in infection, malignancy, chronic inflammatory conditions.
  • Pancytopenia occurs in myelodysplastic syndromes.
  • In patients with symptoms or signs of autoimmune disorders like SLE, antiphospholipid antibody syndrome (APS), obtain anti-nuclear antibodies and antiphospholipid antibodies, respectively.
  • In patients with thrombosis, one should consider heparin-induced thrombocytopenia (obtain platelet factor 4 antibodies), APS (check antiphospholipid antibodies ), DIC and PNH (check PT,aPTT, fibrinogen, LDH)
  • Check liver enzymes and coagulation tests in patients with liver disease.
  • A blood smear is used to check the appearance of your platelets under a microscope. For this test, a small amount of blood is drawn from a blood vessel, usually in your arm.
  • Blood clot test a blood clot test measures the time it takes blood to clot. These tests include partial thromboplastin time (PTT) and prothrombin time (PT).
  • Bone marrow biopsy is indicated in conditions when the cause of thrombocytopenia is unclear, and when a hematologic disorder is suspected.

    • A normal number or rise in megakaryocytes in bone marrow is a presenting feature in conditions with increased platelet destruction.
    • The decrease in megakaryocytes, along with an overall reduction in other cells, is seen in aplastic anemia.
    • In SLE, severe reduction or absence of megakaryocytes is seen due to an autoantibody directed against the thrombopoietin receptor.
    • Megaloblastic changes in RBC and granulocytes occur in vitamin B12, folate, and copper deficiency. In myelodysplasia, cells are dysplastic.
  • Single-gene testing – Gene-targeted deletion/duplication analysis of RBM8A is performed first, followed by sequence analysis of RBM8A if no deletion is found. Although the diagnosis of TAR syndrome can be established by identification of a heterozygous minimally deleted 200-kb region at chromosome band 1q21.1, sequence analysis of RBM8A can be done subsequently in individuals with the deletion to confirm the presence of a second pathogenic variant (hypomorphic allele) and allow family studies. Homozygous RBM8A null alleles (e.g., deletions) are thought to be lethal.
  • More comprehensive genomic testing – (when available) including exome sequencing and genome sequencing may be considered if single-gene testing (and/or use of a multigene panel that includes RBM8A) fails to confirm a diagnosis in an individual with features of TAR syndrome. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation).

Treatment of Reactive Thrombocytosis

Secondary thrombocytosis has no specific treatment, but the identification of reactive conditions and appropriate therapy of the underlying disorder is most relevant. For example, the normalization of platelet counts can be achieved by iron supplementation in inflammatory bowel patients.

Treatment with anti-platelets like aspirin is usually not indicated as the risk of thrombosis is very low in secondary thrombocytosis. Still, it can be considered for patients with platelets more than 1,000,000/μL, and complications of thrombocytosis are present, or to be at risk of developing complications. The platelet-reducing effect of the plateletpheresis is done in patients with evidence of thrombosis and active bleeding. Though plateletpheresis is temporary, it helps in the rapid reduction of the platelet count.

Corticosteroids

Dexamethasone or prednisone is typically prescribed to raise your platelet count. You take it once a day in the form of a pill or tablet. An increased or normalized platelet count is generally seen within 2 weeks of therapy, particularly with high-dose dexamethasone. Your doctor will then likely cut your dose gradually over the next 4 to 8 weeks. The treatment may have to be repeated, but once your platelet count is normal, none is needed again.

Blood Transfusion

It temporarily increases platelet levels in your blood. Platelets are transfused only if the platelet count is extremely low. (Transfused platelets only last about three days in the circulation.)

Primary Immune Thrombocytopenia

This condition is a diagnosis of exclusion. First-line treatment includes glucocorticoids and intravenous immune globulins; these agents inhibit autoantibody production and platelet degradation. Second-line treatment includes rituximab, immunosuppressive drugs, and splenectomy. Third line agents are thrombopoietin receptor agonists, which stimulate platelet production.

Drug-Induced Thrombocytopenia

  • Withholding the causative drug usually results in improvement of platelet counts in cases of drug-induced thrombocytopenia.
  • The mainstay of treatment in HIT is to withdraw all heparin products and to initiate anti-thrombin and anti-Xa activity anticoagulant agents. Dicoumarol agents added once platelet count reaches normal.

TTP gets treated with plasma exchange.

In patients with secondary ITP managing the underlying condition is recommended, like, in SLE, SLE treatment is with immunosuppressive agents, and in patients with H. pylori-associated thrombocytopenia, eradication of H.pylori increases the platelet count.

Platelet Transfusions

Platelet transfusions may be suggested for people who have a low platelet count due to thrombocytopenia.[rx]

Thrombotic Thrombocytopenic Purpura

Treatment of thrombotic thrombocytopenic purpura (TTP) is a medical emergency since the associated hemolytic anemia and platelet activation can lead to kidney failure and changes in the level of consciousness. Treatment of TTP was revolutionized in the 1980s with the application of plasmapheresis. According to the Furlan-Tsai hypothesis,[28] this treatment works by removing antibodies against the von Willebrand factor-cleaving protease ADAMTS-13. The plasmapheresis procedure also adds active ADAMTS-13 protease proteins to the patient, restoring a normal level of von Willebrand factor multimers. Patients with persistent antibodies against ADAMTS-13 do not always manifest TTP, and these antibodies alone are not sufficient to explain how plasmapheresis treats TTP.[rx]

Immune Thrombocytopenic Purpura

Oral petechiae/purpura – Immune thrombocytopenic purpura

Many cases of immune thrombocytopenic purpura (ITP) also known as idiopathic thrombocytopenic purpura, can be left untreated, and spontaneous remission (especially in children) is not uncommon. However, counts under 50,000 are usually monitored with regular blood tests, and those with counts under 10,000 are usually treated, as the risk of serious spontaneous bleeding is high with such low platelet counts. Any patient experiencing severe bleeding symptoms is also usually treated. The threshold for treating ITP has decreased since the 1990s; hematologists recognize that patients rarely spontaneously bleed with platelet counts greater than 10,000, although exceptions to this observation have been documented.[rx][rx]

Thrombopoietin analogs have been tested extensively for the treatment of ITP. These agents had previously shown promise but had been found to stimulate antibodies against endogenous thrombopoietin or lead to thrombosis. Romiplostim (trade name Nplate, formerly AMG 531) was found to be safe and effective for the treatment of ITP in refractory patients, especially those who relapsed following splenectomy.[rx]

Heparin-Induced Thrombocytopenia

Discontinuation of heparin is critical in a case of heparin-induced thrombocytopenia (HIT). Beyond that, however, clinicians generally treat to avoid thrombosis.[rx] Treatment may include a direct thrombin inhibitor, such as lepirudin or argatroban. Other blood thinners sometimes used in this setting include bivalirudin and fondaparinux. Platelet transfusions are not routinely used to treat HIT because thrombosis, not bleeding, is the primary problem.[rx] Warfarin is not recommended until platelets have normalized.[rx]

Congenital Amegakaryocytic Thrombocytopenia

Bone marrow/stem cell transplants are the only known cures for this genetic disease. Frequent platelet transfusions are required to keep the patient from bleeding to death before the transplant can be performed, although this is not always the case.[rx]

Human-Induced Pluripotent Stem Cell-Derived Platelets

Human-induced pluripotent stem cell-derived platelets is a technology currently being researched by the private sector, in association with the Biomedical Advanced Research and Development Authority and the U.S. Department of Health and Human Services, that would create platelets outside the human body.[rx]

Complications

Physicians need to be familiar with the complications associated with thrombocytosis. However, complications due to secondary thrombocytosis are rare.

  • Arterial and venous thrombosis leading to stroke, myocardial infarction, mesenteric ischemia
  • Bleeding
  • Spontaneous abortion
  • IUD- intrauterine death/ intrauterine growth retardation
  • Transformation to AML and primary myelofibrosis

References

Thrombocytopenia – Causes, Symptoms, Diagnosis, Treatment

Thrombocytopenia is a platelet count below the lower limit of normal, i.e., 150000/microliter (for adults). This activity reviews the etiology, evaluation, and management of thrombocytopenia and highlights the role of the interprofessional team in improving care for patients with this condition.

Thrombocytopenia is a condition in which you have a low blood platelet count. Platelets (thrombocytes) are colorless blood cells that help blood clot. Platelets stop bleeding by clumping and forming plugs in blood vessel injuries

A platelet count that falls below the lower limit of normal, i.e., 150000/microliter (for adults) is defined as thrombocytopenia. Platelets are blood cells that help in blood clotting and wound healing — risks associated with thrombocytopenia range from no risk at all to bleeding risks and thrombosis. The correlation of severity of thrombocytopenia and bleeding risk is uncertain. Spontaneous bleeding can occur with a platelet count under 10000/microliter and surgical bleeding with counts below 50000/microL. Thrombocytopenia is associated with risk of thrombosis in conditions like heparin-induced thrombocytopenia (HIT), antiphospholipid antibody syndrome (APS), disseminated intravascular coagulation (DIC), thrombotic microangiopathy (TMA), paroxysmal nocturnal hemoglobinuria (PNH).

Causes of Thrombocytopenia

Common causes of thrombocytopenia

  • Primary immune thrombocytopenia (primary ITP). An autoimmune condition where antibodies are produced against platelets resulting in platelet destruction.
  • Drug-induced immune thrombocytopenia:
    • Heparin-induced thrombocytopenia (HIT) – in this condition, anti-platelet antibodies activate platelets resulting in thrombosis (both arterial and venous)
    • Quinine
    • Sulfonamides, ampicillin, vancomycin, piperacillin
    • Acetaminophen, ibuprofen, naproxen
    • Cimetidine
    • Glycoprotein IIb/IIIa inhibitors
    • Other over the counter remedies, supplements, foods like African bean, sesame seeds, walnuts) and beverages (herbal teas and cranberry juice)
  • Drug-induced non-immune thrombocytopenia. Drugs like valproic acid, daptomycin, linezolid cause thrombocytopenia by dose-dependent suppression of platelet production.
  • Infections:
    • Viral: HIV, hepatitis C, Ebstein-Barr virus, parvovirus, mumps, varicella, rubella, Zika viral infections can cause thrombocytopenia.
    • Sepsis causes bone marrow suppression.
    • Helicobacter pylori
    • Leptospirosis, brucellosis, anaplasmosis, and other tick-borne infections are associated with thrombocytopenia.
    • Malaria, babesiosis intracellular parasite infections are associated with thrombocytopenia and hemolytic anemia
  • Hypersplenism due to chronic liver disease
  • Chronic alcohol abuse
  • Nutrient deficiencies (folate, vitamin B12, copper)
  • Autoimmune disorders like systemic lupus erythematosus, rheumatoid arthritis associated with secondary ITP
  • Pregnancy. Mild thrombocytopenia presents in gestational thrombocytopenia; moderate-severe thrombocytopenia can occur in preeclampsia and HELLP (hemolysis, elevated liver enzymes, low platelet count) syndrome

Other causes

  • Myelodysplasia
  • Malignancy: cancer with chronic DIC, cancer with marrow suppression (leukemia, lymphoma, solid tumors)
  • Paroxysmal nocturnal hemoglobinuria (PNH)
  • Thrombotic microangiopathy (TMA)
    • Thrombotic thrombocytopenic purpura (TTP), a condition manifested by fever, renal failure, thrombocytopenia, microangiopathic hemolytic anemia with or without neurologic manifestations
    • A hemolytic uremic syndrome (HUS) caused by Shiga toxin-producing organism (E. coli and Shigella), seen in children.
    • Drug-induced TMA: quinine, specific chemotherapy agents
    • Antiphospholipid antibody syndrome
  • Aplastic anemia
  • Inherited thrombocytopenia. Often seen in children, rare in adults

    • Von Willebrand disease type 2
    • Alport syndrome
    • Wiskott-Aldrich syndrome
    • Fanconi syndrome.
    • Thrombocytopenia-absent radius syndrome
    • Bernard–Soulier syndrome
    • May-Hegglin anomaly

Decreased platelet production

  • Bone marrow failure presents in aplastic anemia, PNH
  • Bone marrow suppression is a feature with exposure to certain drugs, such as valproic acid, daptomycin, certain chemotherapy agents, and irradiation
  • Chronic alcohol abuse
  • Inherited thrombocytopenia)
  • Viral infection
  • Systemic conditions like nutrient deficiencies (folate, vitamin B12), sepsis, myelodysplastic syndrome impairs platelet production in the bone marrow – these conditions also associated with decreased production of other cell lines leading to anemia and leukopenia

Increased platelet destruction

  • In normal conditions, platelets get removed by monocytes/macrophages of the reticuloendothelial system. The life span of platelets is 8 to 10 days.
  • In immune-mediated thrombocytopenia, anti-platelet autoantibodies bind to platelets and megakaryocytes, resulting in increased platelet destruction by the reticuloendothelial system and decreased platelet production.
  • Anti-platelets antibodies are present in primary ITP, drug-induced ITP, lymphoproliferative disorders, autoimmune conditions like SLE and in chronic infections like HEP C, HIV, and Helicobacter pylori.
  • Non-immune mediated increased platelet destruction occurs in mechanical valve replacement patients, preeclampsia/HELLP syndrome, DIC, and thrombotic microangiopathy. In conditions like DIC and thrombotic microangiopathy, increased platelet consumption within thrombi takes place.

Dilutional thrombocytopenia

  • Dilutional thrombocytopenia presents in massive fluid resuscitation and massive blood transfusion.

Redistribution of platelets

  • In normal individuals, one-third of platelet mass is in the spleen. In conditions that cause splenomegaly and increases spleen congestion (cirrhosis) results in increased platelet mass in the spleen and a decrease in circulating platelets.

or

Thrombocytopenia can be inherited or acquired.[rx]

Decreased production

Abnormally low platelet production may be caused by:[rx]

  • Dehydration, Vitamin B12 or folic acid deficiency
  • Leukemia, myelodysplastic syndrome, or aplastic anemia
  • Decreased production of thrombopoietin by the liver in liver failure
  • Sepsis, systemic viral or bacterial infection
  • Leptospirosis
  • Hereditary syndromes
    • ACTN1-related thrombocytopenia
    • Amegakaryocytic thrombocytopenia with radio-ulnar synostosis
    • ANKRD26 related thrombocytopenia
    • Autosomal dominant thrombocytopenia
    • Bernard–Soulier syndrome (associated with giant platelet disorder)
    • Congenital amegakaryocytic thrombocytopenia
    • Congenital amegakaryocytic thrombocytopenia and radioulnar synostosis
    • CYCS-related thrombocytopenia
    • Epstein syndrome (associated with giant platelet disorder)
    • ETV6 related thrombocytopenia
    • Fanconi anemia
    • Filaminopathies A
    • FYB related thrombocytopenia
    • Glanzmann’s thrombasthenia
    • GNE myopathy with congenital thrombocytopenia
    • Gray platelet syndrome (associated with giant platelet disorder)
    • Harris platelet syndrome (associated with giant platelet disorder)
    • Macrothrombocytopenia and hearing loss
    • May–Hegglin anomaly (associated with giant platelet disorder)
    • MYH9-related disease]] (associated with giant platelet disorder)
    • PRKACG-related thrombocytopenia
    • Paris-Trousseau thrombocytopenia/Jacobsen syndrome
    • Sebastian syndrome
    • SLFN14-related thrombocytopenia
    • Stormorken syndrome
    • TRPM7-related thrombocytopenia
    • Thrombocytopenia absent radius syndrome
    • Tropomyosin 4-related thrombocytopenia
    • TUBB1-related thrombocytopenia
    • Upshaw–Schulman syndrome
    • Wiskott–Aldrich syndrome
    • X-linked thrombocytopenia
    • X-linked thrombocytopenia with thalassemia

Increased destruction

TTP

Abnormally high rates of platelet destruction may be due to immune or nonimmune conditions, including

  • Immune thrombocytopenic purpura
  • Thrombotic thrombocytopenic purpura
  • Hemolytic–uremic syndrome
  • Disseminated intravascular coagulation
  • Paroxysmal nocturnal hemoglobinuria
  • Antiphospholipid syndrome
  • Systemic lupus erythematosus
  • Post-transfusion purpura
  • Neonatal alloimmune thrombocytopenia
  • Hypersplenism
  • Dengue fever
  • Gaucher’s disease
  • Zika virus

Medication-induced

These medications can induce thrombocytopenia through direct myelosuppression

  • Valproic acid
  • Methotrexate
  • Carboplatin
  • Interferon
  • Isotretinoin
  • Panobinostat
  • H2 blockers and proton-pump inhibitors

Other causes

  • Lab error, possibly due to the anticoagulant EDTA in CBC specimen tubes; a citrated platelet count is a useful follow-up study
  • Snakebite
  • Niacin toxicity
  • Lyme disease[rx]
  • Thrombocytapheresis (also called plateletpheresis)
  • Niemann–Pick disease[rx][rx]

Symptoms of Thrombocytopenia

  • Limb anomalies can affect both upper and lower limbs, although upper limb involvement tends to be more severe than lower limb involvement. Individuals with thrombocytopenia absent radius (TAR) syndrome almost always have a bilateral absence of the radius. The thumbs are always present. The thumbs in individuals with TAR syndrome are of near-normal size but are somewhat wider and flatter than usual. They are also held in flexion against the palm and tend to have limited function, particularly in terms of grasp and pinch activities []. The upper limbs may also have hypoplasia or absence of the ulnae, humeri, and shoulder girdles. Fingers may show syndactyly, and fifth finger clinodactyly is common. Lower limbs are affected in almost half of those with TAR syndrome; hip dislocation, coxa valga, femoral and/or tibial torsion, genu varum, and absence of the patella are common findings. The most severe limb involvement is tetraphocomelia.
  • Thrombocytopenia may be congenital or may develop within the first few weeks to months of life. In one review, it was noted that thrombocytopenia developed during the first week of life in only 59% []. In general, thrombocytopenic episodes decrease with age, with most children with TAR syndrome having normal platelet counts by school age. However, cow’s milk allergy is common and can be associated with the exacerbation of thrombocytopenia.
  • Bleeding, most often from the gums or nose. Women with thrombocytopenia may have heavier or longer periods or breakthrough bleeding. You may also see blood in your pee or poop.
  • Red, flat spots on your skin, about the size of a pinhead. You see these mostly on your legs and feet, and they may appear in clumps. Your doctor may call them petechiae.
  • Blotches and bruises. You might have large areas of bleeding under the skin that don’t turn white when you press on them. You also might see what look like the bruises you get from a bump or being hit. They could be blue or purple and change to yellow or green over time. These are caused from the inside, by the sudden leaking from tiny blood vessels. The medical name for these is purpura.
  • Cardiac anomalies affect 15%-22% [] and usually include septal defects rather than complex cardiac malformations.
  • Gastrointestinal involvement includes cow’s milk allergy and gastroenteritis. Both tend to improve with age.
  • Genitourinary anomalies include renal anomalies (both structural and functional) and rarely, Mayer-Rokitansky-Kuster-Hauser syndrome (agenesis of uterus, cervix, and upper part of the vagina) [].
  • Leukemoid reactions have been reported in some individuals with TAR syndrome, with white blood cell counts exceeding 35,000 cells/mm3. These leukemoid reactions are generally transient [].
  • Cognitive development is usually normal in individuals with TAR syndrome.
  • Growth. Most have height on or below the 50th centile.
  • Other skeletal manifestations, including rib and cervical vertebral anomalies (e.g., cervical rib, fused cervical vertebrae), tend to be relatively rare.

Symptoms: Clues to Thrombocytopenia Causes

  • Abdominal Pain
    • HELLP Syndrome (pregnancy)
    • Hemolytic Uremic Syndrome (HUS)
    • Platelet Sequestration (Splenomegaly)
  • Bloody Diarrhea
    1. Hemolytic Uremic Syndrome (HUS)
  • Fever
    • Viral Infections (e.g. CMV, EBV, VZV, HIV, HCV, Parvovirus B19)
    • Tick-Borne Illness ()
    • Dengue Fever
    • Malaria
    • Rickettsial Disease
    • Hemolytic Uremic Syndrome (HUS)
    • Thrombotic Thrombocytopenic Purpura (TTP)
  • Weight loss or Night Sweats
    • HIV Infection
    • Leukemia
    • Myelodysplastic Syndrome

Diagnosis of Thrombocytopenia

History

Your doctor may ask about factors that can affect your platelets, such as:

  • The medicines you take, including over-the-counter medicines and herbal remedies, and whether you drink beverages that contain quinine. Quinine is a substance often found in tonic water and nutritional health products.
  • Your general eating habits, including the amount of alcohol you normally drink.
  • Your risk for AIDS, including questions about blood transfusions, sexual partners, intravenous (IV) drugs, and exposure to infectious blood or bodily fluids at work.
  • Any family history of low platelet counts.

Obtaining a thorough history helps to identify the etiology of thrombocytopenia. Patients with platelets greater than 50000/mL, rarely have symptoms. Patients with platelets under 20000/mL most likely have spontaneous bleeding.

  • Ask the patient about the prior blood count testing and baseline platelet count. The recent drop in platelet count is concerning.
  • Ask for the history of bleeding (petechiae, hemorrhagic bleeding, gingival bleeding, epistaxis)
  • Ask for any potential exposure and symptoms of infections (viral, bacterial, rickettsial). Assess risk factors for HIV infection. Ask about travel to an area endemic for malaria  , dengue virus, and Ebola.
  • Obtain a diet history to detect any nutritional deficiencies.
  • Ask about other conditions like SLE, RA, bariatric surgery, and blood transfusion.
  • Review the medication list. Ask whether the patient is taking over-the-counter medications, quinine-containing beverages, and herbal teas.
  • In the hospitalized patient, look for exposure to heparin products.
  • Check for a family history of thrombocytopenia or bleeding disorders.
  • In pregnant patients ask for headaches, visual symptoms, abdominal pain, flu-like symptoms; these patients may have preeclampsia/HELLP syndrome.

Physical Examination

  • Its includes examining the skin and other sites of bleeding and examination of the liver, spleen, and lymph nodes. Bleeding caused by thrombocytopenia characteristically demonstrates petechiae, nonpalpable purpura, and ecchymosis. Dry purpura refers to purpura in the skin; wet purpura refers to purpura in the mucosa. Examine for hepatomegaly and splenomegaly which occur in lymphoma, chronic liver disease, and other hematologic conditions. Enlarged lymph nodes are present in infections, autoimmune disorders, lymphoma, and other malignancies.

Review of peripheral blood smear

Analysis of platelet size and morphology helps in identifying conditions that are associated with platelet destruction and increased platelet consumption.

  • Clumping of platelets occurs when EDTA is used as an anticoagulant causing pseudo thrombocytopenia.
  • Adhesion of platelets to polymorphonuclear cells is known as “platelet satellites” can be identified by a review of a peripheral blood smear.
  • Giant platelets present in inherited conditions like Bernard-Soulier syndrome.

A review of WBC and RBC morphology may suggest a specific condition.

  • Schistocytes are a feature in thrombotic microangiopathic conditions.
  • Teardrop cells, nucleated RBCs, leukoerythroblastic findings suggest bone marrow infiltrative process.
  • Immature WBCs suggest leukemia.
  • Megaloblastic process characterized by hypersegmented neutrophils seen in nutritional deficiencies.

Lab and Imaging Test

Labs: Platelet Count Interpretation

  • Platelet Count 70,000 to 150,000 per uL
    1. Mild Thrombocytopenia
  • Platelet Count 50,000 to 70,000 per uL
    1. Asymptomatic Moderate Thrombocytopenia
  • Platelet Count 30,000 to 50,000 per uL
    1. Symptomatic Moderate Thrombocytopenia with excessive bleeding on Traumatic Injury
  • Platelet Count 30,000 to 50,000 per uL
    1. Symptomatic Moderate Thrombocytopenia with excessive bleeding on Traumatic Injury
  • Platelet Count 10,000 to 30,000 per uL
    1. Severe Thrombocytopenia with excessive bleeding with minimal Skin Trauma
  • Platelet Count 5,000 to 10,000 per uL
    1. Severe Thrombocytopenia with risk of spontaneous bleeding, Bruising, or Petechiae
    2. Spontaneous bleeding requiring intervention (e.g. Nasal Packing for Epistaxis) required in 42% of patients
  • Platelet Count below 5,000 per uL
    1. Emergent Thrombocytopenia with a high risk of major spontaneous bleeding (e.g. gastrointestinal tract, genitourinary tract)

Labs: Initial Evaluation of Thrombocytopenia

  • Complete Blood Count (CBC)
  • Basic chemistry panel (chem8)
    • Evaluate for associated Renal Failure (e.g. TTP, HUS)
    • Expand to the comprehensive panel in Hemolysis
      1. Indirect Bilirubin increased in Hemolysis
      2. Serum Lactate Dehydrogenase and Haptoglobin increased in HUS and TTP
  • Coagulation tests (INR, PTT, Fibrinogen)
    • Normal in isolated Thrombocytopenia, ITP, TTP, HUS
    • Prolonged in DIC, liver disease, Massive Transfusion and Trauma
    • Fibrinogen is decreased in DIC and Trauma
  • Peripheral Blood Smear
    • See Platelet Morphology
    • See Peripheral Blood Smear
    • Schistocytes are present in DIC and Microangiopathic Hemolytic Anemia (TTP, HUS), but not ITP
    • Consider Parasite stains (Tick-Borne Illness, Malaria)
    • Hemolysis will raise Indirect Bilirubin
  • Platelet Count
    • Rule-out Pseudothrombocytopenia
      • Review Peripheral Smear to evaluate for clumping (Pseudothrombocytopenia)
      • Repeat Platelet Count in non-EDTA Anticoagulant (citrate, blue tube)
    • Repeat Platelet Count timing (adjust based on chronicity, stability and bleeding complications)
      • Repeat immediately for developing bleeding complications
      • Repeat in days to 1 week if Platelet Count <50,000 per uL
      • Repeat in 2 weeks if Platelet Count <100,000 per uL
      • Repeat in 4 weeks if Platelet Count <150,000 per uL

Evaluation of patients with isolated thrombocytopenia includes obtaining a CBC, peripheral blood smear, HIV, and HCV tests.

  • Repeat CBC to confirm that thrombocytopenia is real.
  • Anemia and thrombocytopenia occur with infections, DIC, sepsis, thrombotic microangiopathy, autoimmune disorders like Felty syndrome.
  • Leucocytosis and thrombocytopenia can present in infection, malignancy, chronic inflammatory conditions.
  • Pancytopenia occurs in myelodysplastic syndromes.
  • In patients with symptoms or signs of autoimmune disorders like SLE, antiphospholipid antibody syndrome (APS), obtain anti-nuclear antibodies and antiphospholipid antibodies, respectively.
  • In patients with thrombosis, one should consider heparin-induced thrombocytopenia (obtain platelet factor 4 antibodies), APS (check antiphospholipid antibodies ), DIC and PNH (check PT,aPTT, fibrinogen, LDH)
  • Check liver enzymes and coagulation tests in patients with liver disease.
  • A blood smear is used to check the appearance of your platelets under a microscope. For this test, a small amount of blood is drawn from a blood vessel, usually in your arm.
  • Blood clot test a blood clot test measures the time it takes blood to clot. These tests include partial thromboplastin time (PTT) and prothrombin time (PT).
  • Bone marrow biopsy is indicated in conditions when the cause of thrombocytopenia is unclear, and when a hematologic disorder is suspected.
    • A normal number or rise in megakaryocytes in bone marrow is a presenting feature in conditions with increased platelet destruction.
    • The decrease in megakaryocytes, along with an overall reduction in other cells, is seen in aplastic anemia.
    • In SLE, severe reduction or absence of megakaryocytes is seen due to an autoantibody directed against the thrombopoietin receptor.
    • Megaloblastic changes in RBC and granulocytes occur in vitamin B12, folate, and copper deficiency. In myelodysplasia, cells are dysplastic.
  • Single-gene testing – Gene-targeted deletion/duplication analysis of RBM8A is performed first, followed by sequence analysis of RBM8A if no deletion is found. Although the diagnosis of TAR syndrome can be established by identification of a heterozygous minimally deleted 200-kb region at chromosome band 1q21.1, sequence analysis of RBM8A can be done subsequently in individuals with the deletion to confirm the presence of a second pathogenic variant (hypomorphic allele) and allow family studies. Homozygous RBM8A null alleles (e.g., deletions) are thought to be lethal.
  • More comprehensive genomic testing – (when available) including exome sequencing and genome sequencing may be considered if single-gene testing (and/or use of a multigene panel that includes RBM8A) fails to confirm a diagnosis in an individual with features of TAR syndrome. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation).

Treatment of Thrombocytopenia

In asymptomatic, mild thrombocytopenia patients, repeat CBC and routine monitoring is the recommended process.

Thrombocytopenic emergencies that require immediate action include conditions of suspected HIT, TTP, HUS, drug-induced ITP, pregnancy with severe thrombocytopenia, bleeding with severe thrombocytopenia, urgently needed an invasive procedure in the presence of severe thrombocytopenia, leukopenia, and aplastic anemia. In patients with bleeding and severe thrombocytopenia, treatment includes platelet transfusion. Management includes identifying the underlying cause and treating it.

Corticosteroids

Dexamethasone or prednisone is typically prescribed to raise your platelet count. You take it once a day in the form of a pill or tablet. An increased or normalized platelet count is generally seen within 2 weeks of therapy, particularly with high-dose dexamethasone. Your doctor will then likely cut your dose gradually over the next 4 to 8 weeks. The treatment may have to be repeated, but once your platelet count is normal, none is needed again.

Blood transfusion

It temporarily increases platelet levels in your blood. Platelets are transfused only if the platelet count is extremely low. (Transfused platelets only last about three days in the circulation.)

Primary immune thrombocytopenia

This condition is a diagnosis of exclusion. First-line treatment includes glucocorticoids and intravenous immune globulins; these agents inhibit autoantibody production and platelet degradation. Second-line treatment includes rituximab, immunosuppressive drugs, and splenectomy. Third line agents are thrombopoietin receptor agonists, which stimulate platelet production.

IVIG (intravenous immune globulin)

If you can’t get your platelet count up with prednisone, if you cannot tolerate steroids, or if your count drops after you’re done with your treatment, your doctor may suggest IVIG. You take this medication through an IV, usually for several hours a day for 1 to 5 days.

Rho(D) immune globulin

This treatment, which you also take through an IV, is an alternative to traditional IVIG in people who have Rh+ blood. It generally takes less than half an hour. The side effects are similar to IVIG. If corticosteroids, IVIG, and Rho(D) aren’t improving your platelet count and you’re having bleeding problems, your doctor may switch to a second set of options. There are pros and cons for each. They include:

Thrombopoietin (TPO) receptor agonists

These drugs are also called platelet growth factors. If you have severely low platelets even after treatment with steroids, surgery to remove the spleen, or rituximab, you will likely do well on these medicines, but you may need to take them long-term.

Drug-induced thrombocytopenia

  • Withholding the causative drug usually results in improvement of platelet counts in cases of drug-induced thrombocytopenia.
  • The mainstay of treatment in HIT is to withdraw all heparin products and to initiate anti-thrombin and anti-Xa activity anticoagulant agents. Dicoumarol agents added once platelet count reaches normal.

TTP gets treated with plasma exchange.

In patients with secondary ITP managing the underlying condition is recommended, like, in SLE, SLE treatment is with immunosuppressive agents, and in patients with H. pylori-associated thrombocytopenia, eradication of H.pylori increases the platelet count.

Platelet transfusions

Platelet transfusions may be suggested for people who have a low platelet count due to thrombocytopenia.[rx]

Thrombotic thrombocytopenic purpura

Treatment of thrombotic thrombocytopenic purpura (TTP) is a medical emergency since the associated hemolytic anemia and platelet activation can lead to kidney failure and changes in the level of consciousness. Treatment of TTP was revolutionized in the 1980s with the application of plasmapheresis. According to the Furlan-Tsai hypothesis,[28] this treatment works by removing antibodies against the von Willebrand factor-cleaving protease ADAMTS-13. The plasmapheresis procedure also adds active ADAMTS-13 protease proteins to the patient, restoring a normal level of von Willebrand factor multimers. Patients with persistent antibodies against ADAMTS-13 do not always manifest TTP, and these antibodies alone are not sufficient to explain how plasmapheresis treats TTP.[rx]

Immune thrombocytopenic purpura

Oral petechiae/purpura – Immune thrombocytopenic purpura

Many cases of immune thrombocytopenic purpura (ITP) also known as idiopathic thrombocytopenic purpura, can be left untreated, and spontaneous remission (especially in children) is not uncommon. However, counts under 50,000 are usually monitored with regular blood tests, and those with counts under 10,000 are usually treated, as the risk of serious spontaneous bleeding is high with such low platelet counts. Any patient experiencing severe bleeding symptoms is also usually treated. The threshold for treating ITP has decreased since the 1990s; hematologists recognize that patients rarely spontaneously bleed with platelet counts greater than 10,000, although exceptions to this observation have been documented.[rx][rx]

Thrombopoietin analogs have been tested extensively for the treatment of ITP. These agents had previously shown promise but had been found to stimulate antibodies against endogenous thrombopoietin or lead to thrombosis. Romiplostim (trade name Nplate, formerly AMG 531) was found to be safe and effective for the treatment of ITP in refractory patients, especially those who relapsed following splenectomy.[rx]

Heparin-induced thrombocytopenia

Discontinuation of heparin is critical in a case of heparin-induced thrombocytopenia (HIT). Beyond that, however, clinicians generally treat to avoid thrombosis.[rx] Treatment may include a direct thrombin inhibitor, such as lepirudin or argatroban. Other blood thinners sometimes used in this setting include bivalirudin and fondaparinux. Platelet transfusions are not routinely used to treat HIT because thrombosis, not bleeding, is the primary problem.[rx] Warfarin is not recommended until platelets have normalized.[rx]

Congenital amegakaryocytic thrombocytopenia

Bone marrow/stem cell transplants are the only known cures for this genetic disease. Frequent platelet transfusions are required to keep the patient from bleeding to death before the transplant can be performed, although this is not always the case.[rx]

Human-induced pluripotent stem cell-derived platelets

Human-induced pluripotent stem cell-derived platelets is a technology currently being researched by the private sector, in association with the Biomedical Advanced Research and Development Authority and the U.S. Department of Health and Human Services, that would create platelets outside the human body.[rx]

References

Lymphocytosis – Causes, Symptoms, Diagnosis, Treatment

Lymphocytosis, defined by an increase in absolute lymphocyte count (ALC) to more than 4000 lymphocytes/microL in adult patients, is a common hematologic abnormality. This activity reviews the evaluation of patients presenting with lymphocytosis, discusses the differential diagnosis for this condition, and highlights the role of the healthcare team, including primary care physicians and hematologists in evaluating and managing patients with this condition.

Lymphocytosis, defined by an increase in absolute lymphocyte count (ALC) to more than 4000 lymphocytes/microL in adult patients, is a common hematologic abnormality. ALC calculates as the total white blood cell count (WBC) multiplied by the percentage of lymphocytes in the peripheral blood. Different lymphocyte subsets (T cells, B cells, or NK cells) may be increased depending on the particular etiology. Lymphocytes represent around 20 to 40% of WBC. The definition of relative lymphocytosis is an increase in WBC of more than 40% in the presence of a normal absolute white cell count. In this review, we present the most common causes in adult patients, in addition to a general approach to diagnosis and management of frequently encountered etiologies.

Causes of Lymphocytosis

Distinguishing reactive from malignant lymphocytosis can be challenging and may vary depending on age and other demographics. The following is a list of the most common etiologies.

  • Infectious:

    • Viral infections:

      • Epstein-Barr Virus (EBV): Infectious Mononucleosis (IM) is a classic example of viral infections associated with lymphocytosis. Acute IM is a disease characterized by fever, lymphadenopathy, pharyngitis, splenomegaly, and various hematologic manifestations, among which lymphocytosis is the most common and presents in up to two-thirds of cases.
      • Cytomegalovirus (CMV): CMV can cause a disease indistinguishable from EBV IM.
      • Human Immunodeficiency Virus (HIV): Although chronic HIV infection resulted in lymphopenia and decreased CD4+ lymphocytes count, primary HIV infection can lead to an acute febrile mononucleosis-like illness with associated lymphocytosis. A negative heterophile test can help distinguish the two.
      • Other Viruses: Influenza, hepatitis, mumps, measles, rubella, and human T Lymphocytic virus type 1 (HTLV-1), adenovirus, to name a few.
    • Bacterial Infections: Most of the acute bacterial infections will cause neutrophilia; however, notable exceptions include:

      • Bartonella henselaeBartonella henselae leads to cat scratch disease, a disease transmitted by scratch or bite from an infected cat, that leads mostly to self-limited lymphadenopathy, but can be associated with ocular or neurologic manifestations. Lymphocytes are large and atypical.
      • Bordetella Pertussis: Pertussis is characterized by increased lymphocytes that are small with a deeply cleaved nucleus, clinical correlation is needed to differentiate from some lymphoid malignancies that might share the morphologic appearance.
      • Other: Brucellosis, syphilis, malaria
    • Parasitic Infections:

      • Toxoplasma Gondii: symptomatic toxoplasmosis occurs most commonly in immunocompromised hosts. Lymphocytosis with atypical lymphocytes is a hematologic hallmark of the disease, that can present as a mononucleosis-like illness.
      • Other: Babesiosis
    • Mycobacterial Tuberculosis
  • Lymphoproliferative disorders: Lymphocytes tend to be monomorphic in malignant causes in contradiction to the pleomorphic lymphocytes in reactive causes. Some common etiologies are listed here:

    • Chronic Lymphocytic Leukemia (CLL): CLL is the most common leukemia in adult patients in the USA. Lymphocytes are over 5000 cells/microL per definition and are typically small mature looking with dense nuclei and compact chromatin, also called “soccer ball” cells. Numerous smudge cells resulting from damage during the preparation of peripheral blood smear slides are characteristic of patients diagnosed with CLL.
    • Non-Hodgkin Lymphoma (NHL): Bone marrow can have involvement in around 30% of cases, and peripheral blood lymphocytosis varies between different types. Lymphoma cells can have different sizes or shapes depending on the lymphoma type. The following are some examples of NHL associated with lymphocytosis:

      • Mantle cell lymphoma (MCL): MCL is an uncommon NHL; however, it frequently correlates with lymphocytosis. The cells of the blastoid variant of MCL are typically large with a moderate amount of cytoplasm and indented nuclei.
      • Marginal Zone Lymphoma (MZL): Lymphocytosis is associated with anemia and thrombocytopenia. Typical lymphocytes in MZL have villous cytoplasmic projections.
      • Hairy Cell Leukemia: “hairy cells” have regular cytoplasmic projections through the entire periphery of the cell that may resemble “villous” cells; however, the typical immunophenotype is different (discussed below).
      • Follicular Lymphoma (FL): FL cells are larger than typical normal lymphocytes but smaller than MCL cells. “Cleaved” lymphocytosis can occur, which refers to the cleft appearing nuclei. Other disorders with angulated or cleaved lymphocytes include pertussis and MCL as above in addition to Sezary Syndrome and Adult T cell lymphoma/leukemia (ATLL).
      • Sezary Syndrome: It represents the leukemic phase of cutaneous T cell lymphoma. Characteristic Sezary cells have cribriform nuclei with compact chromatin.
    • ATLL: this is aggressive leukemia caused by HTLV-1. It is common in Japan, the Caribbean, and the southeastern US.
    • Large Granular Lymphocyte Leukemia (LGL): T-LGL cells are typically large with multiple azurophilic granules, and the disease is associated with pancytopenia symptoms, splenomegaly, and Rheumatoid Arthritis.
    • Acute lymphoblastic lymphoma (ALL): It is associated with increased lymphoblasts rather than more mature lymphocytes.
  • Drugs and drug hypersensitivity reactions: Certain medications such as allopurinol, carbamazepine, vancomycin, and sulfa drugs may have correlated drug reactions with eosinophilia and systemic symptoms (DRESS), and this can be related to lymphocytosis. The relatively new CLL medication Bruton tyrosine kinase (BTK) inhibitor Ibrutinib has resulted in impressive responses; however, it correlates with the worsening of lymphocytosis upon initiation of the medication. It likely represents a redistribution of CLL cells from lymphoid tissues to the peripheral blood and does not indicate a suboptimal response to therapy.
  • Monoclonal B Lymphocytosis (MBL): this refers to the presence of monoclonal B cells at a level less than 5000 cells/microL in the absence of features of lymphoproliferative disorders, splenomegaly or cytopenias. These B cells most commonly have the same phenotype of those seen in CLL (CLL-like); however, their phenotype may be different (atypical MBL).
  • Congenital B cell Lymphocytosis: this is due to germline heterozygous missense mutation in CARD11, a scaffolding protein required for nuclear factor kappa B (NF-KB) in both B and T lymphocytes. It typically progresses to CLL by the 4th decade of life.
  • Persistent B-cell polyclonal B-Lymphocytosis: It is a rare clinical entity described as polyclonal binucleated lymphocytes occurring predominantly in young smoker woman. Unlike CLL or MBL, lymphocytes are polyclonal with the expression of both kappa and lambda chains. It is associated with HLA DR-7 and IgM polyclonal gammopathy and exhibits a stable clinical and biological course.
  • Stress: Severe and emergency medical conditions may correlate with transient lymphocytosis that would precede neutrophilia. Most patients had cardiac conditions, status epileptics, or epinephrine use.
  • Asplenia: similar to other blood components, lymphocyte count, may increase post-splenectomy but typically stays stable for years.

Lymphocytosis is a feature of infection, particularly in children. In the elderly, lymphoproliferative disorders, including chronic lymphocytic leukemia and lymphomas, often present with lymphadenopathy and lymphocytosis.

Causes of absolute lymphocytosis include:

  • acute viral infections, such as infectious mononucleosis (glandular fever), hepatitis[rx] and Cytomegalovirus infection[rx]
  • other acute infections such as pertussis[rx]
  • some protozoal infections, such as toxoplasmosis and American trypanosomiasis (Chagas disease)
  • chronic intracellular bacterial infections such as tuberculosis[rx] or brucellosis[rx]
  • chronic lymphocytic leukemia
  • acute lymphoblastic leukemia
  • lymphoma
  • post-splenectomy state[rx]
  • CARD11-related congenital B cell lymphocytosis (rare, also known as BENTA disease)[rx]

Causes of relative lymphocytosis include:

  • age less than 2 years;
  • acute viral infections;
  • connective tissue diseases,
  • thyrotoxicosis,
  • Addison’s disease,
  • splenomegaly with splenic sequestration of granulocytes.

Pathophysiology

The pathophysiology of lymphocytosis varies by etiology. Increased lymphocyte production may be either due to a clonal process or a reactive process. Also, redistribution of lymphoid cells may be the primary etiology in some patients presenting with lymphocytosis. The mechanism of some of the most common causes follows:

  • EBV: During the early stages of IM, EBV infects resting B-cells, and a large number of infected B cells circulate the blood. The atypical lymphocytes, however, are activated cytotoxic CD8+ cells that appear 1 to 3 weeks after the onset of symptoms. In the patients infected with EBV, memory B-cells are latently infected and lead to chronic infection with possible reactivation and predisposition to lymphoproliferative disorders.
  • Pertussis: the mechanism of lymphocytosis in pertussis may be due to decreased extravasation of lymphocytes from peripheral blood to lymphoid organs and/or expansion of morphologically normal CD4+ T cells.
  • Congenital B-cell lymphocytosis: as discussed above, this is related to mutations in CARD11, a scaffolding protein required for nuclear factor Kappa B (NF-KB) in both B and T lymphocytes.
  • CLL: several genetic and chromosomal lesions paly a role in the malignant development of CLL B lymphocytes, in addition to antigens that could play a role in malignant cell selection. Examples of genetic mutations include NOTCH1, a regulator of hematopoietic progenitor cells differentiation, and TP53, a tumor suppressor gene. A full appraisal of the pathogenesis of this disorder is beyond the scope of this review.
  • NHL: several chromosomal abnormalities are present, depending on the type of lymphoma. Classic examples include t(11,14) in MCL and associated overexpression of cyclin D1, a cell cycle regulator, and t(14,18) in FL, leading to overexpression of BCL2, an anti-apoptotic protein.

Diagnosis of Lymphocytosis

History and physical (H&P) is an essential part of the evaluation as it might reveal the underlying etiology, or may help to point out the need for an expedited evaluation. Some of the critical points in H&P include:

  • The clinical setting is crucial as it occurs in patients presenting to the emergency department following seizures, trauma, or cardiac events.
  • The patient has a personal or family history of a lymphoproliferative disorder.
  • The patient has a history of B-symptoms (fever, weight loss, and night sweats) that could point out a clonal process.
  • Demographics: age is an important feature, as some cases occur in specific populations (e.g., CLL is mainly a disease of the elderly), while others are more common in certain groups (for example, AIM is common in young adults).
  • Surgical history: Splenectomy is associated with lymphocytosis.
  • Medications review.
  • History for methods of transmissions if certain viral infections are suspected (e.g., sexual history in HIV).
  • The physical exam findings should be interpreted in the clinical context as rash, lymphadenopathy, or splenomegaly can occur in different malignant or reactive disorders.

Evaluation

The evaluation of lymphocytosis begins with a detailed history and physical examination. The complete blood count (CBC) and review of the peripheral blood smear (PBS) are essential to start an appropriate workup.

  • CBC: CBC review will help to confirm the presence of absolute lymphocytosis and to delineate abnormalities in other blood components such as hemoglobin and platelets. Anemia and thrombocytopenia might indicate a clonal disorder such as CLL or lymphoma. Also, the magnitude of the rise and the presence of abnormal or immature forms of cells (e.g., blasts) will help dictate the urgency of evaluation.
  • PBS: examples of distinct lymphocyte forms that may be identifiable on PBS include:

    • Small mature looking lymphocytes and “smudge cells” in CLL and MBL
    • Atypical large lymphocytes are visible in EBV and other viral infections such as CMV or early HIV
    • Lymphocytes that are cleaved angulated, or have indented nuclei can be associated with pertussis or malignancies such as follicular lymphoma.
    • “Hairy cells” with regular cytoplasmic projections are seen in hairy cell leukemia
    • Sezary Cells have cribriform nuclei with compact chromatin
    • “Villous” lymphocytes are seen in MZL
    • Large lymphocytes with multiple azurophilic granules are present in T-LGL
    • Lymphoblasts in ALL
  • Additional testing:

    • Flow Cytometry: Peripheral blood flow cytometry is essential to determine the proliferation of monoclonal cells. It is a costly test and should not be ordered routinely on all patients with lymphocytosis.

      • Certain features on peripheral blood smear or on review of CBC which prompt a physician to order flow cytometry include:

        • The presence of lymphoblasts on the peripheral blood smear, suggesting ALL- This should also prompt a referral to a tertiary care center to obtain further workup.
        • The presence of other abnormal lymphocyte morphology on PBS as detailed above
        • ALC more than 30000 cells/microL
        • Persistent unexplained lymphocytosis for more than one month
        • Abnormalities in other cell lines including anemia and thrombocytopenia
        • Presence of lymphadenopathy and/or hepatosplenomegaly in the right clinical context where reactive causes have been ruled out
      • Flow cytometry patterns are beneficial in delineating clonality and differentiating clonal disorders as follows:

        • CLL: lymphocytes are CD5+, CD23+, CD20 (dim), CD10-, cyclin D1-, weak sIg (surface immunoglobulin), FMC -, CD200 +
        • MCL: lymphocytes are CD5+, CD23-, CD10-, CD20+, sIg +, cyclin D1 +, FMC +, CD200-
        • FL: lymphocytes are CD5-, CD10+, CD20+, sIg+ and often BCL2+, BCL6+
        • MZL: lymphocytes are CD5-, CD10-, CD20+, sIg+, cyclin D1-
        • HCL: lymphocytes are CD5-, CD10-, CD20+, sIg+, CD11c+, CD25+, CD103+
        • T-LGL: lymphocytes are CD3+, CD8+, CD16+, CD56+
    • Fluorescence in situ hybridization (FISH), karyotype, and mutation analysis: FISH, karyotype, and certain mutation analysis help diagnose and risk stratification of hematologic malignancies, especially CLL and lymphomas. The FISH can not only help to ascertain the clonal nature of lymphocytosis but also helps to confirm the diagnosis of certain lymphomas. Examples include:

      • FL: characterized by t(14,18)
      • MCL: characterized by t(11,14)
      • HCL: characterized by the presence of BRAF mutation
      • CLL: different karyotypic abnormalities including del 17p, del 11q, trisomy 12, and del 13q14.

Treatment

The management of lymphocytosis depends on the underlying etiology. While some causes reflect only a reactive or physiologic process that does not need any intervention (e.g., stress or asplenia), others indicate a malignant or clonal process that might require intervention.

  • Acute infectious mononucleosis: The management is typically supportive, with analgesics and/or non-steroidal anti-inflammatory drugs (NSAIDs). As the majority of patients have splenomegaly, they should be instructed to avoid contact sports during the early acute stage to avoid splenic rupture. The use of corticosteroids is controversial, and the current body of literature does not provide enough evidence to support its use for symptomatic relief.
  • Other infectious causes: The management of the underlying etiology directs the treatment. For example; The management of pertussis differs from infants to adolescents and adults. Antibiotics (e.g., azithromycin or clarithromycin) are generally indicated in adult patients when presenting within three weeks of the cough onset. Likewise, appropriate antimicrobials are an option for Bartonella Henselae, MTB, HIV, or toxoplasmosis.
  • CLL: The management of CLL has moved towards the use of targeted therapies such as BTK inhibitors (Ibrutinib), BCL-2 inhibitor (Venetoclax), and PI3K inhibitors (Idelalisib). In general, the first step in CLL management is by appropriate selection of patients needing therapy. These are patients with progressive cytopenias, constitutional symptoms, progressive or symptomatic lymphadenopathy, and hepatosplenomegaly. The second important step in CLL management relies on risk stratification and predictive factors. Particularly, the presence of 17p del or TP53 mutation predicts for lack of response from standard chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab (FCR) or bendamustine plus rituximab (BR). These patients are better suited for the use of BTK inhibitors (Ibrutinib) or Venetoclax in combination with the humanized anti-CD20 monoclonal antibody obinutuzumab. The phase III ECOG-E1912 has proved the superiority of the combination of Ibrutinib and rituximab (IbRx) over the FCR regimen in younger patients (age less than 70 years) diagnosed with CLL without del17 mutation. The progression-free survival (89.4% in the box arm vs. 72.9% in the FCR arm at 3 years; hazard ratio for progression or death, 0.35; 95% confidence interval [CI], 0.22 to 0.56; P<0.001)and overall survival (98.8% in the box arm vs. 91.5% in FCR arm at 3 years; hazard ratio for death, 0.17; 95% CI, 0.05 to 0.54; P<0.001) were significantly prolonged in patients diagnosed with CLL, even in those with IGHV mutation.
  • NHL: The management of NHL management depends on histology. For instance, where a patient diagnosed with ‘double-hit DLBCL may require prompt initiation of treatment, a patient diagnosed with low-grade FL can be monitored clinically for signs of growth or transformation. The treatment options for NHL have increased with the advent of targeted agents. The typical medications, namely, rituximab, doxorubicin, cyclophosphamide, vincristine, and steroids (either prednisone or dexamethasone) are still in use as first-line treatment in various permutations and combinations. However, newer drugs like brentuximab vedotin (anti-CD-30 and drug conjugate), lenalidomide, obinutuzumab, etc. are being tested and approved in both first-line and second-line setting to improve patient outcomes. The treatment of MCL requires more intense chemotherapy, with a possibility of performing autologous stem cell transplantation in consolidation. Purine analogs (cladribine and pentostatin) are standard treatments for HCL. Methotrexate is usually the initial drug for T-LGL patients requiring therapy.
  • MBL: All patients diagnosed with MBL can receive clinical monitoring. Typically, they follow up with their hematologist twice a year for the first two years for high count CLL-like MBL and atypical MBL, which can extend longer for stable patients. Only symptomatic patients or those whose blood tests show a worsening lymphocytosis warrant further imaging and bone marrow aspirate and biopsy.
  • DRESS: The first step in managing patients with DRESS is to withdraw the offending drug. Supportive measures usually suffice. Topical or systemic corticosteroids may be needed depending on the extent of involvement of the skin and/or other organs.

Complications

The complications from lymphocytosis coincide with the underlying etiology where leukemia is the most common underlying disease.

  • Hyperleukocytosis: Defined as a white cell count above 100000 cells/microL. It is more commonly seen in patients diagnosed with acute myeloid leukemia but can appear in patients presenting with acute lymphoblastic leukemia as well as CML. Hyperleukocytosis can lead to leukostasis and consequent symptoms like vision loss, stroke, myocardial infarction, etc. Prompt initiation of white-cell lowering treatment (either hydroxyurea or leukapheresis) is required to relieve the symptoms.
  • Infectious mononucleosis: splenic rupture and chronic fatigue are short-term complications that may happen in patients with infectious mononucleosis. B-cell malignancies are potential long-term sequelae of EBV infection, including PTLD, HL, and NHL, which usually occur in immunocompromised patients.
  • CLL: Leukostasis is uncommon in CLL. Autoimmune processes may complicate CLL, including autoimmune hemolytic anemia and immune thrombocytopenia. Hypogammaglobulinemia, with or without recurrent infections, is also common. CLL patients are also at a higher risk of developing secondary malignancies, including solid and hematologic ones.
  • DRESS: DRESS patients may have different organ involvement, including liver, lung, and kidneys. Further, these patients are reported to have a higher subsequent incidence of autoimmune diseases as well as future drug reactions to potentially structurally unrelated medications.

References

What are Brain and Spinal Cord Tumors? – Symptoms, Treatment

What are Brain and Spinal Cord Tumors?/A tumor is a mass of abnormal cells that either form into new growth or the growth was there when you were born (congenital).  Tumors occur when something goes wrong with genes that regulate cell growth, allowing cells to grow and divide out of control. Tumors can form anywhere in your body. Brain and spinal cord tumors form in the tissue inside your brain or spinal cord, which make up the central nervous system (CNS).

Depending on its type, a growing tumor may not cause any symptoms or can kill or displace healthy cells or disrupt their function. A tumor can move or press on sensitive tissue and block the flow of blood and other fluid, causing pain and inflammation.  A tumor can also block the normal flow of activity in the brain or signal to and from the brain.  Some tumors don’t cause any changes.

Types of Brain and Spinal Cord Tumors

Tumors can be noncancerous (benign) or cancerous (malignant).

  • Benign tumors can grow slowly or fast, don’t spread to other parts of the body, and often can be removed surgically.
  • Malignant tumors can invade surrounding tissue.  Some cancerous brain tumors can be removed entirely through surgery. Some malignant tumors have edges that are hard ot define, which makes it difficult for surgeons to remove the entire tumor.

Tumors can be primary or secondary.

  • Primary tumors of the CNS are growths that begin in your brain or spinal cord.  They can be either malignant or benign.
  • Metastatic tumors, or secondary tumors, of the CNS are caused by cancer cells that break away from a primary tumor somewhere else in your body and spread to the CNS.  They are more common than primary tumors of the CNS and occur more often in adults than in children.

There are more than 120 types of brain and spinal cord tumors.  Some are named by the type of normal cell they most closely resemble or by location.  Brain and spinal cord tumors are not contagious or, at this time, preventable.

There are different types of brain and spinal cord tumors.

Brain and spinal cord tumors are named based on the type of cell they formed in and where the tumor first formed in the CNS. The grade of a tumor may be used to tell the difference between slow-growing and fast-growing types of the tumor. The  (WHO) tumor grades are based on how abnormal the cancer cells look under a microscope and how quickly the tumor is likely to grow and spread.

WHO Tumor Grading System

  • Grade I (low-grade) — The tumor cells look more like normal cells under a microscope and grow and spread more slowly than grade II, III, and IV tumor cells. They rarely spread into nearby tissues. Grade I brain tumors may be cured if they are completely removed by surgery.
  • Grade II — The tumor cells grow and spread more slowly than grade III and IV tumor cells. They may spread into nearby tissue and may recur (come back). Some tumors may become higher-grade tumor.
  • Grade III — The tumor cells look very different from normal cells under a microscope and grow more quickly than grade I and II tumor cells. They are likely to spread into nearby tissue.
  • Grade IV (high-grade) — The tumor cells do not look like normal cells under a microscope and grow and spread very quickly. There may be areas of dead cells in the tumor. Grade IV tumors usually cannot be cured.

Astrocytic Tumors

An astrocytic tumor begins in star-shaped brain cells called astrocytes, which help keep nerve cells healthy. An astrocyte is a type of glial cell. Glial cells sometimes form tumors called gliomas. Astrocytic tumors include the following:

  • Brain stem glioma (usually high grade) – A brain stem glioma forms in the brain stem, which is the part of the brain connected to the spinal cord. It is often a high-grade tumor, which spreads widely through the brain stem and is hard to cure. Brain stem gliomas are rare in adults. (See the PDQ summary on Childhood Brain Stem Glioma Treatment for more information.)
  • A pineal astrocytic tumor (any grade) – A pineal astrocytic tumor forms in tissue around the pineal gland and may be any grade. The pineal gland is a tiny organ in the brain that makes melatonin, a hormone that helps control the sleeping and waking cycle.
  • Pilocytic astrocytoma (grade I) – A pilocytic astrocytoma grows slowly in the brain or spinal cord. It may be in the form of a cyst and rarely spreads into nearby tissues. Pilocytic astrocytomas can often be cured.
  • Diffuse astrocytoma (grade II) – A diffuse astrocytoma grows slowly, but often spreads into nearby tissues. The tumor cells look something like normal cells. In some cases, a diffuse astrocytoma can be cured. It is also called a low-grade diffuse astrocytoma.
  • Anaplastic astrocytoma (grade III) – An anaplastic astrocytoma grows quickly and spreads into nearby tissues. The tumor cells look different from normal cells. This type of tumor usually cannot be cured. An anaplastic astrocytoma is also called a malignant astrocytoma or high-grade astrocytoma.
  • Glioblastoma (grade IV) – A glioblastoma grows and spreads very quickly. The tumor cells look very different from normal cells. This type of tumor usually cannot be cured. It is also called glioblastoma multiforme.

Overview of the brain and spinal cord

The brain has three major parts:

  • brain stem—This lowest part of the brain (above the neck) connects to the spinal cord and relays information between the brain and the body using bundles of long nerves.  It controls basic life-sustaining functions, including blood pressure, heartbeat, breathing, consciousness, swallowing, and body temperature.
  • cerebrum—This largest and outermost part of the brain processes information from our senses to tell the body how to respond.  It controls functions including movement, touch, judgment, learning, speech, emotions, and thinking.
  • cerebellum—Located at the lower rear of the brain, above the brain stem, the cerebellum controls balance, helps maintain equilibrium, and coordinates complex muscle movements like walking and talking.

The brain’s two halves, or hemispheres, use nerve cells (neurons) to speak with each other.  Each hemisphere has four sections, called lobes, which handle different neurological functions.

  • The frontal lobes manage voluntary movement, such as writing, and let us set and prioritize goals.  A frontal lobe tumor can cause changes in personality, intellect, reasoning, and behavior; affect coordination and walking, and cause speech loss.
  • The temporal lobes are linked to perception, memory, and understanding sounds and words.  A tumor here might cause speech and hearing problems, blackouts, seizures, or sensations such as a feeling of fear.
  • The parietal lobes let us simultaneously receive and understand sensations such as pressure and pain.  A parietal lobe tumor might cause difficulty understanding or speaking words, problems with coordination, seizures, and numbness or weakness on one side of the body.
  • The occipital lobes receive and process light and visual images and detect motion.  An occipital lobe tumor can affect the field of vision, usually on one side, and the way we understand written words.

The spinal cord—an extension of the brain—lies protected inside the bony spinal column.  It contains bundles of nerves that carry messages between the brain and other parts of the body, such as instructions to move an arm or information from the skin that signals pain.

A tumor that forms on or near the spinal cord can disrupt communication between the brain and the nerves or restrict the cord’s supply of blood.  Because the spinal column is narrow, a tumor here—unlike a brain tumor—can cause symptoms on both sides of the body.

Spinal cord tumors, regardless of location, often cause pain, numbness, weakness or lack of coordination in the arms and legs, usually on both sides of the body. They also often cause bladder or bowel problems.

Spinal cord tumors are described based on where on the cord the tumor is located and each vertebra (part of a series of bones that form the backbone) is numbered from top to bottom. The neck region is called cervical (C), the back region is called thoracic (T), and the lower back region is called lumbar (L) or sacral/cauda equina (S). Tumors are further described by whether the tumor begins in the cells inside the spinal cord (intramedullary) or outside the spinal cord (extramedullary). Extramedullary tumors grow in the membrane surrounding the spinal cord (intradural) or outside (extradural).

What causes CNS tumors?

Researchers really don’t know why primary brain and spinal cord tumors develop. Possible causes include viruses, defective genes, exposure to certain chemicals and other hazardous materials, and immune system disorders. Sometimes CNS tumors may result from specific genetic diseases, such as neurofibromatosis and tuberous sclerosis, or exposure to radiation.

Who is at risk?

Anyone can develop a primary brain or spinal cord tumor, but the overall risk is very small. Brain tumors occur more often in males than in females and are most common in middle-aged to older persons. Although uncommon in children, brain tumors tend to occur more often in children under age 9, and some tumors tend to run in families. Most brain tumors in children are primary tumors.

Other risk factors for developing a primary brain or spinal cord tumor include race (Caucasians are more likely to develop a CNS tumor) and occupation. Workers in jobs that require repeated contact with ionizing radiation or certain chemicals, including those materials used in building supplies or plastics and textiles, have a greater chance of developing a brain tumor.

How are tumors graded?

The grade of a tumor may be used to tell the difference between slow-growing and fast-growing types of the tumor.  The World Health Organization (WHO) tumor grades are based on how abnormal the cancer cells look under the microscope and how quickly the tumor is likely to grow and spread.  Some tumors change grade as they progress, usually to a higher grade.  The tumor is graded by a pathologist following a biopsy or during surgery.

  • Grade I (low grade) – The tumor cells look more like normal cells under a microscope and grow and spread more slowly than grade II, III, and IV tumor cells.  They rarely spread into nearby tissues.  Grade I brain tumors may be cured if they are completely removed by surgery.
  • Grade II – The tumor cells grow and spread more slowly than grade III and IV tumor cells.  They may spread into nearby tissue and may recur (come back).  Some tumors may become higher-grade tumors.
  • Grade III – The tumor cells tend to grow rapidly and can spread quickly into other CNS tissue. Tumor cells will look different than those in the surrounding tissue.
  • Grade IV – The tumor cells do not look like normal cells under a microscope and grow and spread very quickly.  There may be areas of dead cells in the tumor.  Grade IV tumors usually cannot be cured.

What are the possible symptoms?

Brain and spinal cord tumors cause many different symptoms, which can make detection tricky.  Symptoms depend on tumor type, location, size, and rate of growth.  Certain symptoms are quite specific because they result from damage to particular areas of the brain and spinal cord.  Symptoms generally develop slowly and worsen as the tumor grows.

Brain tumor

In infants, the most obvious sign of a brain tumor is a rapidly widening head or bulging crown. Other more common symptoms of a pediatric brain tumor can include:

  • Headaches that may become more frequent or severe
  • Seizures
  • Feelings of pressure inside the skull
  • Nausea and vomiting
  • Sudden onset of vision problems

In older children and adults, a tumor can cause a variety of symptoms, including headaches, seizures, balance problems, and personality changes.

  • Headaches are the most common symptom of a brain tumor.  Headaches may get worse over time, become more frequent or constant, and recur, often at irregular intervals.
  • Seizures.  Seizures that start in adulthood with no underlying cause are a key warning sign of a brain tumor.
  • Nausea and vomiting
  • Vision or hearing problems
  • Personality, behavior, and cognitive changes with psychotic episodes and problems with speech, language, thinking, and memory
  • Motor problems, including weakness or paralysis, lack of coordination, or gradual loss of sensation or movement in an arm or leg
  • Balance problems, including dizziness, trouble walking, clumsiness, or loss of equilibrium
  • Hydrocephalus and increased intracranial pressure are caused when a tumor blocks the flow of the cerebrospinal fluid (CSF) that bathes the brain and spinal cord.  This can cause headaches, nausea, and vomiting.

Other symptoms may include endocrine disorders or abnormal hormonal regulation, difficulty swallowing, facial paralysis and sagging eyelids, fatigue, weakened sense of smell, or disrupted sleep and changes in sleep patterns.

Spinal cord tumors

Common symptoms of a spinal cord tumor include:

  • Pain may occur in a specific area along the spine or can radiate from the spine to other parts of the body. The pain may be sharp or feel like burning or tingling feelings due to compression of nerves. The pain is often constant and progressive and may be severe. Back pain is a common early symptom of a spinal tumor.
  • Numbness or sensory changes can include decreased skin sensitivity to temperature and progressive numbness or a loss of sensation, particularly in the legs.
  • Motor problems and loss of muscle control can include muscle weakness, spasticity (in which the muscles stay stiffly contracted), and impaired bladder and/or bowel control.
  • Other symptoms, such as problems with bowel or bladder control or sexual dysfunction, can also occur but are less common.

The signs and symptoms of childhood brain and spinal cord tumors are not the same in every child.

Signs and symptoms depend on the following:

  • Where the tumor forms in the brain or spinal cord.
  • The size of the tumor.
  • How fast the tumor grows.
  • The child’s age and development.

Signs and symptoms may be caused by childhood brain and spinal cord tumors or by other conditions. Check with your child’s doctor if your child has any of the following:

Brain Tumor Signs and Symptoms

  • Morning headache or headache that goes away after vomiting.
  • Frequent  and vomiting.
  • Vision, hearing, and speech problems.
  • Loss of balance and trouble walking.
  • Unusual sleepiness or change in activity level.
  • Unusual changes in personality or behavior.
  • Seizures.
  • Increase in the head size (in infants).

Spinal Cord Tumor Signs and Symptoms

  • Back pain or pain that spreads from the back towards the arms or legs.
  • A change in bowel habits or trouble urinating.
  • Weakness in the legs.
  • Trouble walking.

In addition to these signs and symptoms of brain and spinal cord tumors, some children are unable to reach certain growth and development milestones such as sitting up, walking, and talking in sentences.

How are CNS tumors diagnosed?

If you are suspected of having a brain or spinal cord tumor, your doctor (usually a neurologist, oncologist, or neuro-oncologist) will perform a neurologic exam and may order a variety of tests based on your symptoms, personal and family medical history, and results of the physical exam.   Once a tumor is found on diagnostic imaging studies, surgery to obtain tissue for a biopsy or removal is often recommended.
Diagnosing the type of brain or spinal cord tumor is often difficult.  Some tumor types are rare and the molecular and genetic alterations of some tumors are not well understood.  You may want to ask your primary care doctor or oncologist for a second opinion from a comprehensive cancer center or neuro-oncologist with experience treating your diagnosis or tumor type.  Even a second opinion that confirms the original diagnosis can be reassuring and help you better prepare for your care and treatment.

  • A neurological exam – A neurological exam can be done in your doctor’s office. It assesses your movement and sensory skills, hearing and speech, reflexes, vision, coordination and balance, mental status, and changes in mood or behavior. Some advanced tests are performed and analyzed by a specialist.
  • Diagnostic imaging – Diagnostic imaging produces extremely detailed views of structures inside the body, including tissues, organs, bones, and nerves.  Such imaging can confirm the diagnosis and help doctors determine the tumor’s type, treatment options, and later, whether the treatment is working.

For a more complete description of the following tests

  • Computed Tomography (CT scan) – is no longer the standard for evaluating for a brain tumor.  However, CT scans can detect the buildup of calcium, which causes tissue to harden and develop into a tumor and can often detect hemorrhage (blood) or the development of hydrocephalus.  CT scans can be done in a few minutes so are often used in emergency situations.
  • Magnetic Resonance Imaging (MRI) – is the gold standard for diagnosing brain and spinal tumors and is more sensitive than a CT scan.  In addition to higher resolution and better anatomic detail, MRI can provide information about blood flow (perfusion), tumor cell density, and provide better pictures of tumors located near the bone. Usually, a contrast agent (such as a dye) is injected into a vein before a CT or MRI.  Many tumors become much easier to identify on the scan after the contrast is given.
  • Functional MRI (fMRI) – can help assess the distance between specific brain functions and tumors in particular areas of the brain.  This is useful in planning surgery in areas of the brain that contain important functions such as language.
  • Magnetic Resonance Spectroscopy (MRS) – can measure and analyze metabolic changes and the chemical make-up of a tissue sample.
  • Positron Emission Tomography (PET) – traces and measures the brain’s use of glucose (sugar, used by the brain for energy) that is attached to small amounts of radioactivity and injected into your bloodstream.  Because malignant tissue uses more glucose than normal tissue, it usually shows up on the scan as brighter than surrounding tissue.
  • Single Photon Emission Computed Tomography (SPECT) – studies blood flow to the tissue.  Certain tumors grow new blood vessels to increase their supply of blood and nutrients
  • Angiography (or arteriogram) – can distinguish certain types of tumors that have a characteristic pattern of blood vessels and blood flow.  A dye is injected into a major blood vessel and a series of x-rays is taken as the dye flows to your brain.  Often, MRI can be used to evaluate blood vessels, a procedure call MR angiography.

Laboratory and other tests

  • Testing blood, urine – and other substances can provide clues about the tumor and monitor levels of therapeutic drugs.
  • An electroencephalogram – or EEG, monitors brain activity through the skull (tumors can alter brain wave activity and cause seizures).
  • A spinal tap (also called a lumbar puncture or CSF analysis) – uses a special needle inserted into the spinal column to remove a small amount of the cerebrospinal fluid.  The fluid is examined for abnormal cells or unusual levels of various molecules such as glucose and protein that suggest a brain or spinal cord tumor.
  • Magnetoencephalography (MEG) – studies brain function by measuring the magnetic field generated by nerve cells in the brain.

Tests that examine the brain and spinal cord are used to detect (find) childhood brain and spinal cord tumors.

The following tests and procedures may be used:

  • Physical exam and health history – An exam of the body to check general signs of health, including checking for signs of disease, such as lumps or anything else that seems unusual. A history of the patient’s health habits and past illnesses and treatments will also be taken.
  • Neurological exam – A series of questions and tests to check the brain, spinal cord, and nerve function. The exam checks a person’s mental status, coordination, and ability to walk normally, and how well the muscles, nses, and reflexes work. This may also be called a neuro exam or a neurologic exam.
  • Light and electron microscopy – A laboratory test in which cells in a sample of tissue are viewed under regular and high-powered microscopes to look for certain changes in the cells.
  • Cytogenetic analysis – A laboratory test in which the chromosomes of cells in a sample of brain tissue are counted and checked for any changes, such as broken, missing, rearranged, or extra chromosomes. Changes in certain chromosomes may be a sign of cancer. Cytogenetic analysis is used to help diagnose cancer, plan treatment, or find out how well treatment is working.
  • Serum tumor marker test – A procedure in which a sample of blood is examined to measure the amounts of certain substances released into the blood by organs, tissues, or tumor cells in the body. Certain substances are linked to specific types of cancer when found in increased levels in the blood. These are called tumor markers.
  • Craniotomy – An opening is made in the skull and a piece of the skull is removed to show part of the brain.
  • Immunohistochemistry – A laboratory test that uses antibodies to check for certain antigens (markers) in a sample of a patient’s tissue. The antibodies are usually linked to an enzyme or a fluorescent dye. After the antibodies bind to a specific antigen in the tissue sample, the enzyme or dye is activated, and the antigen can then be seen under a microscope. This type of test is used to help diagnose cancer and to help tell one type of cancer from another type of cancer.
  • Biopsy – Biopsy confirmation to corroborate the suspected diagnosis of a primary brain tumor is critical, whether before surgery by needle biopsy or at the time of surgical resection. Cases in which the clinical and radiologic picture clearly point to a benign tumor, which could potentially be managed with active surveillance without biopsy or treatment, are the exception. For other cases, radiologic patterns may be misleading, and a definitive biopsy is needed to rule out other causes of space-occupying lesions, such as metastatic cancer or infection.
  • Stereotactic biopsy – When imaging tests show there may be a tumor deep in the brain in a hard-to-reach place, a stereotactic brain biopsy may be done. This kind of biopsy uses a computer and a 3-dimensional (3-D) scanning device to find the tumor and guide the needle used to remove the tissue. A small incision is made in the scalp and a small hole is drilled through the skull. A biopsy needle is inserted through the hole to remove cells or tissues so they can be viewed under a microscope by a pathologist to check for signs of cancer.
  • Open biopsy – When imaging tests show that there may be a tumor that can be removed by surgery, an open biopsy may be done. A part of the skull is removed in an operation called a craniotomy. A sample of brain tissue is removed and viewed under a microscope by a pathologist. If cancer cells are found, some or all of the tumors may be removed during the same surgery. Tests are done before surgery to find the areas around the tumor that are important for normal brain function. There are also ways to test brain function during surgery. The doctor will use the results of these tests to remove as much of the tumor as possible with the least damage to normal tissue in the brain.

How are the brain and spinal cord tumors treated?

A specialized team of doctors advises and assists individuals throughout treatment and rehabilitation.  These doctors may include:

  • A neuro-oncologist is a neurologist or oncologist who specializes in CNS tumors.
  • An oncologist is a doctor who specializes in cancer.
  • A neurologist is a doctor who specializes in CNS disorders.
  • A neuroradiologist is a doctor who specializes in the CNS and is trained in reading diagnostic imaging results.
  • A pathologist is a clinical doctor who diagnoses diseases of tissues or cells using a variety of laboratory tests.
  • A neurosurgeon is a brain or spinal cord surgeon. Specialized training in removal of central nervous system tumors may have been completed.
  • A radiation oncologist is a doctor who specializes in using radiation to treat cancer.

Your health care team will recommend a treatment plan based on the tumor’s location, type, size and aggressiveness, as well as medical history, age, and general health.  Malignant tumors require some form of treatment, while some small benign tumors may need only monitoring.  Treatment for a brain or spinal tumor can include surgery, radiation therapy, chemotherapy, targeted therapy, or a combination of treatments.
Initial treatment for a CNS tumor may involve a variety of drugs to treat or ease symptoms, including:

  • anticonvulsants to treat or prevent seizures
  • pain medications
  • steroids or other anti-inflammatory drugs to reduce swelling and improve blood flow
  • antidepressants to treat anxiety or depression that might occur following a tumor diagnosis
  • anti-nausea drugs

Neurosurgery

Surgery is usually the first treatment to both obtain tissue for diagnosis and remove as much tumor as can be done safely.  Surgery may be the only treatment you need if your tumor is considered benign or low grade.  Based on the type and grade (low versus high), doctors often recommend follow-up treatment, including radiation and chemotherapy, or experimental treatment.  You will be referred to the specialists above to provide guidance on this treatment.

Surgery is usually the first step in treating an accessible tumor—one that can be removed without risk of neurological damage.  Many low-grade tumors and secondary (metastatic) cancerous tumors can be removed entirely.  Some tumors have a clearly defined shape and can be removed more easily.  Your surgeon will try removing (called resecting or excising) all or as much tumor as possible.  For malignant CNS tumors, this is best performed by a neurosurgeon.

An inaccessible or inoperable tumor is one that cannot be removed surgically because of the risk of severe nervous system damage during the operation.  These tumors are frequently located deep within the brain or near vital structures such as the brain stem and may not have well-defined edges. In these cases, a biopsy may be performed.

biopsy is sometimes performed to diagnose and help doctors determine how to treat a tumor.  Biopsies can sometimes be performed by inserting a needle through a small hole in the body and taking a small piece of the tumor tissue.  A pathologist will examine the tissue for certain changes that signal cancer and determine its stage or grade.

In some cases, a surgeon may need to insert a shunt into the skull to drain any dangerous buildup of CSF caused by the tumor.  A shunt is a flexible plastic tube that is used to divert the flow of CSF from the central nervous system to another part of the body, where it can be absorbed as part of the normal circulatory process.

During surgery, some tools used in the operating room include a surgical microscope, the endoscope (a small viewing tube attached to a video camera), and miniature precision instruments that allow surgery to be performed through a small incision in the brain or spine.  Other tools include:

  • Intraoperative MRI uses a special type of MRI to provide real-time monitoring and evaluation of the surgery.  Constantly updated images let doctors see how much of the tumor has been removed.
  • Navigation equipment used in computer-guided, or stereotactic, neurosurgery gives doctors a precise, three-dimensional map of the spine or brain as the operation progresses.  A computer uses pre-operative diagnostic images to reduce the risk of damage to surrounding tissue.
  • Intraoperative nerve monitoring tests use real-time recordings of nerve cell activity to determine the role of specific nerves and to monitor brain activity as the surgery progresses.  Some surgeries may be done while the individual is awake under monitored anesthesia care, rather than under general anesthesia.  This allows doctors to monitor the individual’s speech and motor functions as a tumor is being removed.

Radiation therapy

Radiation therapy usually involves repeated doses of high-energy beams such as x-rays or protons to kill cancer cells or keep them from multiplying.  Radiation therapy can shrink the tumor mass.  It can be used to treat surgically inaccessible tumors or tumor cells that may remain following surgery.

Radiation treatment can be delivered externally, using focused beams of energy or charged particles that are directed at the tumor, or from inside the body, using a surgically implanted device.  The stronger the radiation, the deeper it can penetrate to the target site.  Healthy cells may also be damaged by radiation therapy, but current radiation treatment is designed to minimize injury to normal tissue.

Treatment often begins soon after surgery and may continue for several weeks.  Depending on the tumor type and location, a person may be able to receive a modified form of therapy to lessen damage to healthy cells and improve the overall treatment.

Externally delivered radiation therapy poses no risk of radioactivity to the person or family and friends.  Types of external radiation therapy include:

  • Whole-brain radiation is generally used to shrink multiple cancerous tumors, rather than to target individual tumors.  It may be given as the sole form of treatment or in advance of other forms of radiation therapy and microsurgery.
  • Conventional external beam radiation aims a uniform dose of high-energy radiation at the tumor and surrounding tissue.  It is used to treat large tumors or those that may have spread into the surrounding tissue.
  • Three-dimensional conformal radiotherapy (3D-CRT) uses diagnostic imaging to prepare an accurate, computer-generated three-dimensional image of the tumor and surrounding tissue.  The computer then coordinates and sends multiple beams of radiation to the tumor’s exact location, sparing nearby organs and surrounding tissue.
  • Intensity-modulated radiation therapy (IMRT) is similar to 3D-CRT but varies in the intensity of the hundreds of radiation beams to deliver more precise doses to the tumor or its specific areas, with less exposure to surrounding tissue.
  • Hyperfractionation involves giving two or smaller amounts of radiation a day instead of a larger, single dose.  It can deliver more radiation to certain tumors and reduce damage to normal cells.
  • Proton beam therapy directs a beam of high-energy protons directly at the tumor site, without the spread of the radiation beyond the target.  The dosing is similar to standard radiation (also called photon radiation), but proton beam radiation is best for treating tumors near important structures such as the brain stem and spinal cord.  Proton beam therapy can be used as a stand-alone treatment or in combination with chemotherapy or as a follow-up to surgery.

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Radiosurgery

Radiosurgery is usually a one-time treatment using multiple, sharply focused radiation beams aimed at the brain or spinal cord tumor from multiple angles.  It does not cut into the person but, like other forms of radiation therapy, harms a tumor cell’s ability to grow and divide.  It is commonly used to treat surgically inaccessible tumors and may be used at the end of conventional radiation treatment.  Two common radiosurgery procedures are:

  • Linear-accelerated radiosurgery – (LINAC) uses radar-like technology to prepare and fire a single beam of high-energy x-rays into the tumor.  Also called high linear-energy transfer radiation, LINAC forms the beam to match the tumor’s shape, avoiding surrounding tissue.  A special machine that rotates around the head then fires a uniform dose of radiation into the tumor.
  • Radiosurgery – can be given by a number of techniques, all designed to provide a precise dose of radiation to a small area.  It has proven beneficial for tumors that do not spread into the surrounding brain, but radiosurgery is less beneficial for the common brain tumors that do spread into the brain.
  • Side effects of radiation – Side effects of radiation therapy vary from person to person and are usually temporary.  They typically begin about two weeks after treatment starts and may include fatigue, nausea, vomiting, reddened or sore skin in the treated area, headache, hearing loss, problems with sleep, and hair loss (although the hair usually grows back once the treatment has stopped).  Radiation therapy in young children, particularly those age three years or younger, can cause problems with learning, processing information, thinking, and growing.

There are late side effects of radiation that may occur months to years after treatment that include shrinkage (atrophy) of the brain or spinal cord region that was treated.

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Chemotherapy

Chemotherapy uses powerful drugs to kill cancer cells or stop them from growing or spreading.  These drugs are usually given orally, intravenously, or through a catheter or port and travel through the body to the cancerous cells.  Your oncologist will recommend a treatment plan based on the type of cancer, drug(s) to be used, the frequency of administration, and the number of cycles needed.  Chemotherapy is given in cycles to more effectively damage and kill cancer cells and give normal cells time to recover from any damage.

Individuals might receive chemotherapy to shrink the tumor before surgery called neo-adjuvant therapy (a first step treatment to shrink a tumor before the primary treatment).  Radiation therapy can also be given as neoadjuvant therapy.  After surgery or radiation treatment if radiation is the primary treatment, chemotherapy could be called adjuvant therapy (treatment in addition to the primary treatment).  Metronomic therapy involves continuous low-dose chemotherapy to block mechanisms that stimulate the growth of new blood vessels needed to feed the tumor.

Not all tumors are vulnerable to the same anticancer drugs, so a person’s treatment may include a combination of drugs.  Common CNS chemotherapies include temozolomide, carmustine (also called BCNU), lomustine (also called CCNU), and bevacizumab.  Individuals should be sure to discuss all options with their medical team.

Side effects of chemotherapy may include hair loss, nausea, digestive problems, reduced bone marrow production, and fatigue.  The treatment can also harm normal cells that are growing or dividing at the same time, but these cells usually recover and side effects often improve or stop once the treatment has ended.

Targeted therapy

Targeted therapy is a cancer treatment that uses drugs to target specific genes and proteins that are involved in tumor cell growth.  This helps slow uncontrolled growth and reduce the production of tumor cells. Targeted therapies include oncogenes, growth factors, and molecules aimed at blocking gene activity.

Alternative and complementary approaches

Alternative and complementary approaches may help tumor patients better cope with their diagnosis and treatment. Some of these therapies, however, may be harmful if used during or after cancer treatment and should be discussed in advance with a doctor. Common approaches include nutritional and herbal supplements, vitamins, special diets, and mental or physical techniques to reduce stress.

What research is being done?

Scientists continue to investigate ways to better understand, diagnose, and treat CNS tumors.  Several of today’s treatments were experimental therapies only a decade ago.
Clinical studies are research studies that test or observe how well medical approaches work in people. Some clinical studies test new treatments such as a new drug or medical therapy. Treatment studies help researchers learn if a new treatment is effective or less harmful than standard treatments. Studies can be considered at any point, from the time of diagnosis through recurrence.

Current clinical studies of genetic risk factors, environmental causes, and molecular mechanisms of cancers may translate into tomorrow’s treatment of, or perhaps cure for, these tumors.
Much of this work is supported by the National Institutes of Health (NIH), through the collaborative efforts of its National Institute of Neurological Disorders and Stroke (NINDS) and National Cancer Institute (NCI), as well as other federal agencies, nonprofit groups, pharmaceutical companies, and private institutions.  Some of this research is conducted through the collaborative neuroscience and cancer research community at the NIH or through research grants to academic centers throughout the United States.

The jointly sponsored NCI-NINDS Neuro-Oncology Branch coordinates research to develop and test the effectiveness and safety of novel therapies for people with CNS tumors.  These experimental treatment options may include new drugs, combination therapy, gene therapy, advanced imaging and artificial intelligence, biologic immuno-agents, surgery, and radiation.  Information about these trials, and trials for other disorders, can be accessed at the federal government’s database of clinical trials, ClinicalTrials.gov.

Scientists at NIH and universities across the United States are exploring a variety of approaches to treat CNS tumors.  These experimental approaches include boosting the immune system to better fight tumor cells, developing therapies that target the tumor cell while sparing normal cells, making improvements in radiation therapy, disabling the tumor using genes attached to viruses, and defining biomarkers that may predict the response of a CNS tumor to a particular treatment.

Biological therapy (also called immunotherapy) involves enhancing the body’s overall immune response to recognize and fight cancer cells.  The immune system is designed to attack foreign substances in the body, but because cancer cells aren’t foreign, they usually do not generate much of an immune response.  Researchers are using different methods to provoke a strong immune response to tumor cells, including:

  • Proteins such as interleukin and interferon and other substances that slow tumor growth
  • Antibodies (proteins that are normally produced by the body to ward off bacteria and viruses) that are linked to immunotoxin drugs that seek out tumor cells and deliver their toxin, with minimal damage to surrounding normal cells
  • Gene therapy, which uses a virus that can pass through the brain’s protective blood-brain barrier to deliver a suicide gene to the tumor cell
  • Vaccine therapy, which strengthens the immune response by inserting an antigen (a substance that triggers an immune system reaction) that the body will attack.  Some vaccines attempt to target multiple antigens which the tumor may express.

Targeted therapy uses molecularly targeted drugs that seek out the cellular changes that convert normal cells into cancer.  Targeted therapies include:

  • Compounds that block blood vessel growth and the flow of nutrients and oxygen to the tumor.  These compounds may also hamper cell signaling and stop tumor cells from spreading elsewhere in the body.
  • Developing diagnostic and therapeutic screening tools for oncogenes—transformed genes that are involved in cell growth and cause normal cells to divide uncontrollably and become malignant.
  • Kinase inhibitors—proteins that block growth-signaling enzymes without harming normal cells—that may make CNS tumors more sensitive to chemotherapy.

Biomarkers are molecules or other substances in the blood or tissue that can be used to diagnose or monitor a disorder.  Some CNS tumor biomarkers have been found, such as the epithelial growth factor receptor (EGRF) gene.  Researchers continue to search for additional clinical biomarkers of CNS tumors, to better assess risk from environmental toxins and other possible causes and monitor and predict the outcome of CNS tumor treatment.  Identifying biomarkers may also lead to the development of new disease models and novel therapies for tumor treatment.

Radiation therapy research includes testing several new anticancer drugs, either independently or in combination with other drugs.  Researchers are also investigating combined therapies including drugs, radiation, and radiosurgery to effectively treat CNS tumors.  Research areas under investigation include radiosensitizers—drugs that make rapidly dividing tumor tissue more vulnerable to radiation.

Chemotherapeutic drug research focuses on ways to better deliver drugs across the blood-brain barrier and into the site of the tumor.  Since chemotherapeutic drugs work in different ways to stop tumor cells from dividing, several trials are testing whether giving more than one drug, and perhaps giving them in different ways (such as staggered delivery and low-dose, long-term treatment), may kill more tumor cells without causing  damaging side effects than present therapy.  Researchers are examining different levels of chemotherapeutic drugs to determine whether they are less toxic to normal tissue when combined with other cancer treatments, and ways to make cancer cells more sensitive to chemotherapy.  Research areas include:

  • Drugs that change dividing cells into non-dividing cells and can halt tumor growth
  • Certain chemotherapeutic drugs that may kill cancer cells without harmful side effects
  • Convection enhanced delivery, which bypasses the blood-brain barrier by sending a continuous, uniform stream of toxic drugs into the tumor via catheters that are inserted into the brain during surgery.

Surgery studies are ongoing to better define the potential benefits of surgery, including better response to biologic therapy and chemotherapy, improved quality of life, and prolonged survival.

Clinical trials can help doctors and scientists discover whether new treatments are effective and safe for many people with spinal and brain tumors.  Both healthy people and those with a disease participate in clinical trials, which increases our understanding about diseases including brain and spinal tumors.  To learn more about clinical trials for CNS tumors and how to participate in them, visit www.clinicaltrials.gov, a database of thousands of studies, some of which include results and papers on findings.

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Appendix: Some CNS Tumors and Tumor-Related Conditions

There are many types of brain and spinal cord tumors.  These tumors are named by their location in the body, cell of origin, rate of growth, and malignancy.  Some tumor types are more prevalent in children than in adults.  Here is a listing of some common benign and malignant CNS tumors.

Glioma

Glioma tumors grow from several types of glial cells, which support the function of neurons.  Gliomas usually occur in the brain’s cerebral hemispheres but may also strike other areas.  Gliomas are classified based on the type of normal glial cells they resemble.

  • Astrocytoma These tumors, which have star-shaped glial cells called astrocytes, can be low-grade or malignant.  Astrocytomas tend to form in the cerebrum in adults and in most parts of the brain in children.  The most common forms of astrocytoma are:
    • Anaplastic astrocytoma, which grows rapidly and invades other tissue.
    • Ependymoma, which develops from cells that line the cavities of the brain and spinal canal where the cerebrospinal fluid (CSF) is made and stored.
    • Ganglioglioma, a very rare, slow-growing, benign tumor that forms from nerve cells and glial cells and can occur in the brain and the spine.
    • Glioblastoma multiforme, a malignant, highly invasive tumor that spreads quickly and often recurs following initial treatment.
    • Oligodendroglioma, a tumor that resembles glial cells within the cerebral hemispheres that help insulate the nerve fibers that transmit nerve impulses.
    • Pilocytic astrocytoma, a slow-growing tumor that rarely spreads into surrounding tissue.

Mixed gliomas contain more than one type of glial cell and are usually found in the cerebrum.  These tumors can spread to other sites in the brain.
Other gliomas are named after the part of the body they affect.  Among them are:

  • Brain stem gliomas are found at the lowest part of the brain, which controls many vital body functions.
  • Optic gliomas are found on or near the nerves that travel between the eye and brain vision centers and are particularly common in individuals who have neurofibromatosis.

Chordoma
Chordomas are rare congenital tumors which develop from remnants of the flexible spine-like structure that forms and dissolves early in fetal development (and is later replaced by the bones of the spine).  Chordomas often occur near the top or the bottom of the spine, outside the dura mater, and can invade the spinal canal and skull cavity.

Choroid plexus papilloma
This rare, usually benign childhood tumor develops slowly and can increase the production and block the flow of CSF, causing symptoms that include headaches and increased intracranial pressure.  A rarer cancerous form can spread via the cerebrospinal fluid.

Germ cell tumors
These very rare childhood tumors may start in cells that fail to leave the CNS during development.  Germ cell tumors usually form in the center of the brain and can spread elsewhere in the brain and spinal cord.  Different tumors are named after the type of germ cell.

Meningioma
Meningiomas are benign tumors that develop from the thin membranes, or meninges, that cover the brain and spinal cord.  Meningiomas usually grow slowly, generally do not invade surrounding normal tissue, and rarely spread to other parts of the CNS or body.

Pineal Tumors
These tumors form in the pineal gland, a small structure located between the cerebellum and the cerebrum.  The three most common types of pineal region tumors are gliomas, germ cell tumors, and pineal cell tumors

Pituitary Tumors (also called pituitary adenomas)
These small tumors form in the pituitary gland.  Most pituitary tumors are benign and their incidence increases with age.  Pituitary tumors are classified as either non-secreting or secreting (secreting tumors release unusually high levels of pituitary hormones, which can trigger neurological conditions and symptoms including Cushing’s syndrome—a harmful overproduction of the hormone cortisol).

Primitive Neuroectodermal Tumors (PNET)
These malignant tumors may spring from primitive or immature cells left over from early development of the nervous system.   PNETS can spread throughout the brain and spinal cord in a scattered, patchy pattern and, in rare cases, cause cancer outside the CNS.  The two most common PNETs are:

  • Medulloblastomas, which usually form in the cerebellum and can spread throughout the brain and along the spine.
  • Neuroblastomas, which generally appear above the adrenal glands but can be found in the brain and elsewhere in the body.

Vascular Tumors
These rare, noncancerous tumors arise from the blood vessels of the brain and spinal cord.  The most common vascular tumor is the hemangioblastoma, a cyst-like mass of tangled blood vessels, which does not usually spread.

Other Tumor-Related Conditions

  • Arachnoid cysts are benign, fluid-filled masses that form within a thin membrane lining (tumors are solid tissue masses).  Cysts in the CNS can cause tumor-like symptoms including headache and seizures.  Some cysts occur more often in the spinal cord than in the brain, and certain cysts are seen most frequently in children.

  • Hydrocephalus involves the build-up of cerebrospinal fluid in the brain.  The excessive fluid can cause harmful pressure, headaches, and nausea.

  • Meningeal carcinomatosis is caused by cancer cells that metastasize to the CNS and spread around the brain and spinal cord via the cerebrospinal fluid.  These cells can form colonies or small tumors in many places, including the roots of nerves, the surface of the brain, the cerebrum, the brain stem, and the spinal cord.

  • Neurofibromatosis refers to related genetic disorders that cause tumors to grow around nerves.  Most tumors are benign but can become malignant over time.  Neurofibromatosis type 1 usually causes tumors in nerves outside the CNS and affects the skin and bones.  Neurofibromatosis type 2 causes multiple CNS tumors that typically affect the nerves involved with hearing.

  • Pseudotumor cerebri, also called “false brain tumor,” mimics brain tumor symptoms and may be caused by the abnormal buildup of cerebrospinal fluid.

  • Tuberous sclerosis is a genetic disorder that causes numerous neurological and physical symptoms, including benign tumors of eyes and CNS.  It may be present at birth or develop over time.  About half of people who have tuberous sclerosis develop benign astrocytomas.

  • von Hippel-Lindau disease is a rare, genetic multi-system disorder characterized by tumors that grow in certain parts of the body.  Hemangioblastomas may develop in the brain and nervous system.

References

Polycythemia Vera – Causes, Symptoms, Treatment

Polycythemia Vera is an uncommon myeloproliferative neoplasm in which the bone marrow makes too many red blood cells. It may also result in the overproduction of white blood cells and platelets.

Polycythemia vera (PV) is a myeloproliferative neoplastic disorder involving uncontrolled red blood cell production resulting in elevated red blood cell (RBC) mass. There is often concurrent stimulation of myeloid and megakaryocytic lineages leading to increased white blood cell and platelet production, respectively. The current understanding of pathophysiology involves increased sensitivity to growth factors due to an abnormal hematopoietic cell clone. Signs and symptoms, including headache, dizziness, claudication, thrombosis, are a consequence of increased blood viscosity.

Pathophysiology

JAK2 kinase mutation likely leads to the signaling derangements resulting in Polycythemia vera. A valine to phenylalanine substitution at position 617 of the JAK2 gene, or JAK2V617F, leads to constitutively active cytokine receptors. This mutation is observed in over 90% of patients with PV, as well as 50% to 60% of primary myelofibrosis and 50% of essential thrombocythemia. This process leads to increased production of RBCs and platelets with associated complications of thrombosis and bleeding.

Peripheral blood smear findings can be different based on the stage of the disease. In pre-polycythemia and overt polycythemia, normochromic and normocytic red blood cells are seen. A hypochromic and microcytic pattern can accompany concomitant iron deficiency. Platelets and white blood cells can also be elevated. Leukocytosis, predominantly with neutrophils, can be seen without blast activity. In the post-polycythemic stage, myelofibrosis develops with teardrop red blood cells, poikilocytosis, and circulating nucleated red cells.

Bone marrow sampling typically shows hypercellularity with panproliferation. Again, histopathology is dependent on the stage of the disease. Erythrocytosis is seen with pre-polycythemia, increased red cell mass in overt polycythemia, and increased reticulin deposition in post-polycythemia with fibrosis, ineffective production, and extramedullary hematopoiesis.

Causes of Polycythemia Vera

The etiology of the disease process appears to be neoplastic proliferation. There is a signaling defect leading to an abnormal response to growth factors, and the abnormal clonal line interferes with normal lineage proliferation. The Janus kinase-2 (JAK2) gene involved with intracellular signaling is mutated in 90% of cases of PV.

Symptoms of Polycythemia Vera

Erythromelalgia is a rare symptom of PV, here present in a patient with longstanding polycythemia vera. Note reddish limbs and swelling.

People with polycythemia vera can be asymptomatic.[rx] A classic symptom of polycythemia vera is pruritus or itching, particularly after exposure to warm water (such as when taking a bath),[rx] which may be due to abnormal histamine release[rx][rx] or prostaglandin production.[rx] Such itching is present in approximately 40% of patients with polycythemia vera.[rx] Gouty arthritis may be present in up to 20% of patients.[rx] Peptic ulcer disease is also common in patients with polycythemia vera; most likely due to increased histamine from mast cells, but may be related to an increased susceptibility to infection with the ulcer-causing bacterium H. pylori.[rx] Another possible mechanism for the development of peptic ulcers is increased histamine release and gastric hyperacidity related with polycythemia vera.

A classic symptom of polycythemia vera (and the related myeloproliferative disease essential thrombocythemia) is erythromelalgia.[rx] This is a burning pain in the hands or feet, usually accompanied by a reddish or bluish coloration of the skin. Erythromelalgia is caused by an increased platelet count or increased platelet “stickiness” (aggregation), resulting in the formation of tiny blood clots in the vessels of the extremity; it responds rapidly to treatment with aspirin.[rx][rx]

Patients with polycythemia vera are prone to the development of blood clots (thrombosis). A major thrombotic complication (e.g. heart attack, stroke, deep venous thrombosis, or Budd-Chiari syndrome) may sometimes be the first symptom or indication that a person has polycythemia vera. Headaches, lack of concentration, and fatigue are common symptoms that occur in patients with polycythemia vera as well.

Diagnosis of Polycythemia Vera

History and Physical

Physical complaints can include fatigue, headache, dizziness, tinnitus, vision changes, insomnia, claudication, pruritus, gastritis, and early satiety. Aquagenic pruritus, which occurs during or after a hot shower, is a complaint in 40% of patients. The mechanism is likely from mast cell and basophil degranulation, causing a histamine surge. In a 2013 study with 1545 patients, pruritis was associated with better survival. Erythromelalgia is burning pain in the hands and feet with erythema or pallor. This can be seen in PV or essential thrombocythemia and responds well to low-dose aspirin. Bleeding and thrombotic complications are each observed in 1% of patients.  Bleeding events can include epistaxis, gum bleeding, and gastrointestinal (GI) bleeding.  Thrombotic events can include deep venoust thrombosis (DVT), pulmonary ebmolism (PE), Budd-Chiari syndrome, splanchnic vein thrombosis, stroke, and arterial thrombosis. Early satiety occurs from impaired gastric filling due to splenomegaly. GI discomfort and peptic ulcer disease are common, likely from increased histamine from basophils and increased viscosity in gastrointestinal blood supply.

On physical exam, patients can display plethora and flushing of the face and palms, conjunctival injection, and skin excoriation from pruritus. Splenomegaly and hepatomegaly are also often observed.

Evaluation

In the 1970s, the Polycythemia Vera Study Group (PVSG) set the first diagnostic criteria for PV. The diagnosis can be made if all three category A criteria are met, or if A1, A2, and 2 from category B are met.

Category A
  • Total red blood cell mass ≥36 mL/kg in males or ≥32 mL/kg in females
  • Arterial oxygen saturation ≥92%
  • Splenomegaly
Category B
  • Platelets >400,000/microliter
  • White blood cell count >12,000/microliter
  • Leukocyte alkaline phosphatase (ALP) >100 U/L
  • Serum vitamin B12 >900 pg/mL or binding capacity >2200 pg/mL

Measuring the red blood cell mass requires labeling with the 51Cr isotope, which is no longer readily available. Therefore, the PVSG guidelines have fallen out of favor, and the World Health Organization (WHO) published revised guidelines for diagnosing PV in 2016. These criteria are composed of three major and one minor criterion. Diagnosis can be made if all 3 major or 2 major and minor criteria are met.

Major
  • Hg >16.5 g/dL or Hct >49% in men, Hg >16 g/dL or Hct >48% in women; or red blood cell mass >25% above mean normal predicted
  • Bone marrow biopsy showing hypercellularity for age with trilineage growth (panmyelosis) including prominent erythroid, granulocytic, and megakaryocytic proliferation with pleomorphic, mature megakaryocytes (differences in size)
  • JAK2 V617For JAK2 exon 12 mutation
Minor
  • Serum erythropoietin level below the reference range for normal

These criteria should only be applied for diagnosis after secondary causes of polycythemia have been ruled out.

A mutation in the JAK2 kinase (V617F) is strongly associated with polycythemia vera.[rx][rx] JAK2 is a member of the Janus kinase family and makes the erythroid precursors hypersensitive to erythropoietin (EPO). This mutation may be helpful in making a diagnosis or as a target for future therapy.

Following history and examination, the British Committee for Standards in Haematology (BCSH)

Recommend the following tests are performed:

  • full blood count/film (raised hematocrit; neutrophils, basophils, platelets raised in half of patients)
  • JAK2 mutation
  • serum ferritin
  • renal and liver function tests

If the JAK2 mutation is negative and there is no obvious secondary causes the BCSH suggest the following tests:

  • red cell mass
  • arterial oxygen saturation
  • abdominal ultrasound
  • serum erythropoietin level
  • bone marrow aspirate and trephine
  • cytogenetic analysis
  • erythroid burst-forming unit (BFU-E) culture

Other features that may be seen in polycythemia vera include a low ESR and a raised leukocyte alkaline phosphatase.

The diagnostic criteria for polycythemia vera have recently been updated by the BCSH. This replaces the previous Polycythemia Vera Study Group criteria.

JAK2-positive polycythemia vera – diagnosis requires both criteria to be present
Criteria Notes
A1 High erythrocyte volume fraction (EVF or hematocrit) (>0.52 in men, >0.48 in women) OR raised red cell mass (>25% above predicted)
A2 Mutation in JAK2

JAK2-negative polycythemia vera – diagnosis requires A1 + A2 + A3 + either another A or two B criteria:

Criteria Notes
A1 Raised red cell mass (>25% above predicted) OR hematocrit>0.60 in men, >0.56 in women
A2 Absence of mutation in JAK2
A3 No cause of secondary erythrocytosis
A4 Palpable splenomegaly
A5 Presence of an acquired genetic abnormality (excluding BCR-ABL) in the hematopoietic cells
B1 Thrombocytosis (platelet count >450 * 109/l)
B2 Neutrophil leucocytosis (neutrophil count > 10 * 109/l in non-smokers; > 12.5*109/l in smokers)
B3 Radiological evidence of splenomegaly
B4 Endogenous erythroid colonies or low serum erythropoietin

Treatment of Polycythemia Vera

There is no cure for polycythemia vera; the goals of treatment are aimed at symptom relief and reducing the risk of disease complications, including thrombosis, bleeding, and hematologic transformation. There are currently no means for preventing transformation into myelofibrosis or acute leukemia/myelodysplastic syndrome, but there are known agents to avoid that can increase this risk.

Patients under the age of 60 without a history of thrombotic events are considered low risk and treatment recommendations include:

  • Phlebotomy, target hematocrit to less than 45%
  • Daily low-dose aspirin, if no contraindications
  • Treat aspirin refractory symptoms
  • Optimizing cardiovascular (CV) health such as weight loss, exercise, tobacco cessation, blood pressure control.

As the condition cannot be cured, treatment focuses on treating symptoms and reducing thrombotic complications by reducing the erythrocyte levels.

  • Phlebotomy  – is one form of treatment, which often may be combined with other therapies. The removal of blood from the body induces iron deficiency, thereby decreasing the hemoglobin/hematocrit level, and reducing the risk of blood clots. Phlebotomy is typically performed to bring their hematocrit (red blood cell percentage) down below 45 for men or 42 for women.[rx] It has been observed that phlebotomy also improves cognitive impairment.[rx]
  • Low dose aspirin (75–81 mg daily) – is often prescribed. Research has shown that aspirin reduces the risk for various thrombotic complications.
  • Chemotherapy for polycythemia  – may be used, either for maintenance, or when the rate of bloodlettings required to maintain normal hematocrit is not acceptable, or when there is significant thrombocytosis or intractable pruritus. This is usually with a “cytoreductive agent” (hydroxyurea, also known as hydroxycarbamide). The tendency of some practitioners to avoid chemotherapy if possible, especially in young patients, is a result of research indicating a possible increased risk of transformation to acute myelogenous leukemia (AML). While hydroxyurea is considered safer in this aspect, there is still some debate about its long-term safety.[rx]
  • Injection of radioactive isotopes (principally phosphorus-32) – was used as another means to suppress the bone marrow. Such treatment is now avoided due to a high rate of AML transformation.
  • Other therapies include interferon injections – and in cases where secondary thrombocytosis (high platelet count) is present, anagrelide may be prescribed.
  • Bone marrow transplants  – are rarely undertaken in people with polycythemia; since this condition is non-fatal if treated and monitored, the benefits rarely outweigh the risks involved in such a procedure. There are indications that with certain genetic markers, erlotinib may be an additional treatment option for this condition.[rx] The JAK2 inhibitor, ruxolitinib, is also used to treat polycythemia.[rx]

Patients 60 years of age or older and/or who have a history of thrombosis are considered high risk, and recommendations are the same as for low-risk patients with the addition of cytoreductive therapy (hydroxyurea, interferon, busulfan) and treating disease-specific complications.

References

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