Category Archive Cancer, Neoplasms and Palliative Care A – Z

Soft Tissue Tumors /Soft tissue sarcomas are cancerous (malignant) tumors that originate in the soft tissues of your body. This illustration shows a soft tissue sarcoma of the thigh muscle just above the knee. Soft tissue sarcoma is a rare type of cancer that begins in the tissues that connect, support, and surround other body structures

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Pleomorphic liposarcoma (PLS )is a rare and aggressive, fast-growing tumor and high-grade malignancy with high recurrence, poor prognosis, and its treatment is still highly controversial. A rare, fast-growing type of cancer that begins in fat cells. It usually forms in the deep soft tissues of the arms or legs, but it may also form in the abdomen or chest. Pleomorphic liposarcoma often recurs (comes back) after treatment and spreads to other parts of the body, including the lungs.

Pleomorphic liposarcoma is characterized as the growth of a progressively painless mass, and it is easily ignored until the mass is big enough or there are some other compressive manifestations.  It is known that this neoplasm is usually aggressive, occurring in adulthood, and usually in the limbs. Pleomorphic liposarcoma can occur in the mediastinum, liver, orbit, paratesticular region, and also as a purely dermal tumor [rx,rx,rx–rx]PLS could occur in various organs, but the most common sites are proximal extremities, especially in the lower extremities, and in other uncommon sites including the retroperitoneum, the abdominal wall, the chest wall, the mesentery, the pelvic cavity, the spermatic cord, the mediastinum, the parietal pleura, the pericardium, the foot, the spine, the head, and neck region.^[rx,rx–rx]

Grading

According to the guidelines of the ADASP, pleomorphic liposarcoma is considered high grade

French Federation of Cancer Centers System grading scheme for adult sarcomas

• Tumor differentiation score = 3 for pleomorphic liposarcoma
• Mitotic index
  • Score 1 0-9 mitoses per 10 hpf (0.1744 sq mm)
  • Score 2 10-19 mitoses per 10 hpf
  • Score 3 >19 mitoses per 10 hpf
• Tumor cell necrosis
  • Score 0 No necrosis on any slide (one slide per 2 cm tumor diameter)
  • Score 1 <50% of tumor is necrotic on slides examined
  • Score 2 >50% of tumor is necrotic on slides examined
• Final Grade (add the three scores above)
  • Grade 1 Sum of scores = 2 or 3
  • Grade 2 Sum of scores = 4 or 5
  • Grade 3 Sum of scores = 6 or more

Symptoms of Pleomorphic Liposarcoma

As previously mentioned, most patients are diagnosed with pleomorphic liposarcoma do not have any early symptoms and it can go unnoticed during the initial and primary stages of the disease until the tumor has grown to a large enough size to compress neighboring tissues and cause pain or decreased function.

Tumors in the retroperitoneal, abdominal, and pelvic cavities were larger than those near the body surface such as the subcutaneous and intermuscular tissues.

Diagnosis of Pleomorphic Liposarcoma

Accessory examinations such as CT, ultrasound, and magnetic resonance imaging are critical for surgical methods by assessing the size of the tumor and the degree of tumor infiltration into the surrounding tissues. However, it is difficult to distinguish PLS/Pleomorphic liposarcoma from other liposarcoma and sarcoma using these accessory examinations. The definite diagnosis of PLS still depends on the pathological examination, which reveals highly meta topic cells with granular and/or foamy small vacuoles in cytoplasm, mono-/poly-nuclear giant cells with a deep

Conventional chemotherapy pleomorphic liposarcoma is of low efficiency, so new drugs and target therapy might be good options. For example, eribulin and pazopanib are new treatment options for patients with metastatic STS.^[rx,rx] Eribulin mesylate was reported to have selective activity in LPS.^[rx] However, the adverse effects of eribulin were severe. In a phase III trial, treatment-emergent adverse events occurred in 224 (99%) of 226 patients who received eribulin. Grade 3/4 adverse events were 152 (67%) who received eribulin.^[rx] The Food and Drug Administration (FDA) approved pazopanib as second-line chemotherapy for the treatment of patients with advanced nonlipogenic STS, but still not yet for LPS.^[rx] In addition, eribulin and pazopanib have not been approved for clinical use in China.

Meanwhile, antiangiogenic targeted drugs such as sunitinib, sorafenib, and pazopanib all appeared to demonstrate acceptable antitumor activity in liposarcomas.^[rx–rx] Moreover, several articles reported that apatinib had a good effect on angiosarcoma^[rx] and round cell liposarcoma.^[rx]

Newer drugs for

Halaven® (eribulin) and Yondelis® (trabedectin) are approved for people who have not responded to earlier treatment, have widespread liposarcoma, or have cancers that cannot be removed via surgery.

References

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Myxoid liposarcoma (MLS) is a subtype of liposarcoma that represents a distinct pathological entity characterized morphologically by tumor cells within a myxoid stroma with a rich, branching thin-walled vasculature, and focal lipomatous differentiation.

Myxoid liposarcoma is the second most common subtype (MLs). It accounts for 15–20% of liposarcomas and represents about 5% of all soft tissue sarcomas in adults. Histologically MLS shows a continuous spectrum of lesions with low-grade forms and others poorly differentiated round cell forms [rx]. The tumoral site (upper limb, lower limb, and trunk) did not result in a significant risk factor, even though the few numbers of patients with trunk localization could have hampered statistical significance. It is an important factor of this usually slow-growing, deep-seated tumor mainly located in the lower extremities is the propensity to metastasize to nonpulmonary soft-tissues as the retroperitoneum, the bone, or the contralateral limb [rx]. Furthermore, myxoid liposarcoma is particularly radiosensitive thus neoadjuvant radiation protocols may be very effective [rx–rx].

Causes of Myxoid Liposarcoma

Low grade:

• Atypical lipomatous tumor / well differentiated liposarcoma (ALT / WDL):
  • ALT / WDL can be myxoid and focally indistinguishable from myxoid liposarcoma
  • ALT / WDL usually has some degree of stromal atypia however and will lack the plexiform vasculature
  • ALT / WDL has amplification of chromosome 12q14 (including the MDM2 gene) vs. the FUS rearrangement seen in myxoid liposarcoma
  • Myxoid liposarcomas are also more likely to show a predilection for signet ring lipoblasts
• Extraskeletal myxoid chondrosarcoma (EMC):
  • Composed of cords of epithelioid malignant cells set in a similar chondromyxoid matrix
  • There are no cytoplasmic fat vacuoles and less prominent vasculature
  • Immunohistochemical staining is not helpful (both are S100 positive)
  • Cytogenetics can be helpful but care must be taken
  • EMC have t(9;22)(q22;q12) gene rearrangements in most cases that result in an EWSR1-NR4A3 fusion
  • EWSR1 FISH will be positive but can lead to confusion with the 2 – 5% of myxoid liposarcomas that rarely have EWSR1 rearrangements
  • PCR applications can be particularly helpful in this setting
  • In the lung, primary pulmonary myxoid sarcoma should be considered (Pathology 2017;49:792)
• Lipoblastoma / lipoblastomatosis:
  • Can show similar histology but usually are present in patients less than 5 years old
  • Will have PLAG1 gene rearrangements instead of FUS or EWSR1 rearrangements
• Lipoblastoma-like tumor of the vulva:
  • This is a recently described entity that occurs in the vulva and shares remarkable histologic overlap with lipoblastoma and myxoid liposarcoma
  • These lesions have been shown to have Rb loss like the spindle cell lipoma family of tumors
  • They do not have PLAG1 or FUS rearrangements (Int J Gynecol Pathol 2018 Jan 3 [Epub ahead of print], Am J Surg Pathol 2015;39:1290)
  • There is a significant difference in treatment and clinical outcome (only a limited ability to locally recur) and these lesions should be distinguished wherever possible
• Myxoid dermatofibrosarcoma protuberans (DFSP):
  • Typically these are located superficially, which is uncommon in myxoid liposarcoma
  • Look carefully to distinguish between entrapped fat versus true signet ring lip blasts
  • Immunohistochemical staining and molecular testing can help
  • DFSP will be CD34 positive, S100 negative, with the inverse seen in myxoid liposarcoma and DFSP, will harbor the t(17;22)(q22;q13) COL1A1-PDGFB gene fusion
  • Some large reference labs offer PDGFB as a break-apart FISH assay
• Myxoma:
  • Extremely paucicellular, lacks a prominent vascular component and no lipoblasts are found
  • Associated with GNAS mutations (Mod Pathol 2009;22:718)

High grade:

• Myxofibrosarcoma:
  • Older adults, often superficial, infiltrative and there are no true cytoplasmic fat vacuoles (although they can contain pseudolipoblasts)
  • There is significantly more nuclear atypia, thicker curvilinear vessels and frequent mitotic figures can be found
• Pleomorphic liposarcoma (PLS):
  • The entirely different entity that shares similarity in name only
  • PLS is a high-grade pleomorphic sarcoma with scattered atypical lip blasts
  • Atypia far in excess of what is seen in round cell liposarcoma, which retains its monotony (a clue to a tumor driven by a translocation)
  • PLS typically has a complex karyotype
• Round cell sarcomas (Ewing, BCOR-CCNB3, CIC-DUX4, etc.):
  • There are numerous round cell sarcomas that may morphologically resemble high-grade myxoid liposarcoma
  • Low-grade areas and lip blasts can be particularly informative
  • Immunohistochemical and molecular differences can also be exploited (Ewing sarcoma has different partner genes than does myxoid liposarcoma, a feature that can be taken advantage of via sequencing or PCR)

Symptoms of Myxoid Liposarcoma

Most patients with myxoid liposarcoma have no symptoms until the tumor is large and invades the neighboring organs or tissues, causing tenderness, pain, or functional problems.

Diagnosis of Myxoid Liposarcoma

Treatment of Myxoid Liposarcoma

A standard fraction schedule was used: 2 Gy per fraction, 5 days a week.

Chemotherapy was performed in patients with more than two of these unfavorable prognostic factors: high-grade disease, tumor size > 5 cm, deep sited tumors, and positive surgical margins. Chemotherapy consisted of three or five cycles of epirubicin (60 mg/m2, Days 1-2) and ifosfamide (3 g/m2, Days 1–3) administered every 21 days.

Treatments for liposarcoma include

• Surgery – The goal of surgery is to remove all of the cancer cells. Whenever possible, surgeons work to remove the entire liposarcoma. If a liposarcoma grows to involve nearby organs, removal of the entire liposarcoma may not be possible. In those situations, your doctor may recommend other treatments to shrink the liposarcoma to make it easier to remove during an operation.
• Radiation therapy – Radiation therapy uses powerful energy beams, such as X-rays and protons, to kill cancer cells. Radiation may be used after surgery to kill any cancer cells that remain. Radiation may also be used before surgery to shrink a tumor in order to make it more likely that surgeons can remove the entire tumor.
• Chemotherapy – Chemotherapy uses drugs to kill cancer cells. Not all types of liposarcoma are sensitive to chemotherapy drugs. Careful analysis of your cancer cells by an expert pathologist can determine whether chemotherapy is likely to help you. Chemotherapy may be used after surgery to kill any cancer cells that remain or before surgery to shrink a tumor. Chemotherapy is sometimes combined with radiation therapy.

Newer drugs for

Halaven® (eribulin) and Yondelis® (trabedectin) are approved for people who have not responded to earlier treatment, have widespread liposarcoma, or have cancers that cannot be removed via surgery.

References

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Liposarcoma is a malignant tumor of mesenchymal origin a significant tissue diversity tumor of lip blasts, rare mesenchymal neoplasm and involves deep soft tissues including retroperitoneum and popliteal fossa [rx]. It is cancer that arises in the fat cells in soft tissue, such as that inside the thigh or in the retroperitoneum portion of the body.^[rx] The relative frequency of liposarcoma in various body sites and it is much dependent on the tumor subtypes. For example, dedifferentiated liposarcoma is much the most common in retroperitoneal locations, while myxoid liposarcoma occurs in the lower extremities maximum times[rx]. Liposarcoma is exceedingly rare in the esophagus [rx][rx]. Esophageal liposarcoma typically behaves as a slow-growing tumor and involves the upper part of the throat.

Liposarcoma is a tumor that arises from fat tissue in the human body. This tumor most often occurs in the thigh, legs, behind the knee, or in the abdomen, but it can be found in other parts of the body frequently, in the retroperitoneum; and, less often, in the head and neck area. Their primary occurrence in the skin is rarer. Because liposarcoma may grow into surrounding tissues or organs in the body, it is considered a malignant tumor frequently.^[rx]

Although surgical removal of the tumor is the curative treatment, some patients may benefit from chemotherapy and radiation.^[rx]

Types of Liposarcoma

The World Health Organization classification of soft tissue tumors recognizes 5 types of liposarcomas. There are five types of liposarcoma, each with its own unique characteristics and behaviors.

• Well-differentiated liposarcoma – It’s the most common type, and it spread to grow slowly. It has another characteristic that usually doesn’t spread to other parts of your body. Low-grade tumor cells look much like normal fat cells under the microscope.
• Myxoid liposarcoma – It is an intermediate to high-grade tumor. Its cells look less normal under the microscope and may have a high-grade component. It can grow faster than well-differentiated tumors, and it’s more likely to spread to other parts of your body. Its cells can form a unique shape or pattern.
• Pleomorphic liposarcoma – It is the rarest or uncommon type and is a high-grade tumor with cells that look very different from normal cells. It is a less-common form of cancer and often spreads very quickly.
• Dedifferentiated liposarcoma – It gradually occurs when a low-grade tumor changes and the newer cells in the tumor are high-grade. This type of tumor is a slow-growing tumor that starts to change to a faster-growing, more aggressive type.
• Round cell – It often develops in the thigh and can involve changes in the chromosomes (proteins that carry genetic information) in cells. This type can also grow faster than well-differentiated tumors and is often found in the arms or legs.

Stages

The risk of recurrence and metastasis with liposarcoma increases with a higher grade.  The following are the different stages:

• Stage 1A – the tumor is 5 cm or less in size, grade 1, and cancer has not spread to lymph nodes or distant sites
• Stage 1B – the tumor is larger than 5 cm, grade 1, and cancer has not spread to lymph nodes or distant sites
• Stage 2A – the tumor is 5 cm or less, grade 2 or 3, and cancer has not spread to lymph nodes or distant sites
• Stage 2B – the tumor is larger than 5 cm, grade 2, and cancer has not spread to lymph nodes or distant sites
• Stage 3A – the tumor is larger than 5 cm, grade 3, and cancer has not spread to lymph nodes or distant sites OR the tumor is any size and cancer has spread to nearby lymph nodes but not other sites
• Stage 4 – the tumor is any size and any grade, and has spread to lymph nodes and/or to other sites

Causes of Liposarcoma

The specific cause of liposarcoma is still unknown to us. But clinically, it can be first noticed particularly in the extremity in an area of recent trauma, injured soft tissue where the patient may find a large mass, however, the cause and effect are quite likely purely coincidental. Liposarcoma generally contributes to a change in some of the genes that are normally present in fat cells. A series of abnormalities in these genes (mutations or DNA alterations) can lead to malignant cancerous changes characterized by uncontrollable growth.

Some inherited or acquired DNA mutations are found, or defects can make you more prone to developing a soft tissue sarcoma

• Basal cell nevus syndrome increases the risk of basal cell skin cancer, rhabdomyosarcoma, and fibrosarcoma.
• Inherited retinoblastoma in the eyes causes a kind of childhood eye cancer, but it can also increase the risk of other soft tissue sarcomas.
• The Li-Fraumeni syndrome increases the risk of many kinds of cancer, often from radiation exposure.
• Gardner’s syndrome leads to cancers in the stomach or bowel and gastrointestinal area.
• Neurofibromatosis can cause nerve sheath tumors.
• Tuberous sclerosis can cause rhabdomyosarcoma.
• Werner’s syndrome can cause many health problems, including an increased risk of all soft tissue sarcomas.
• Exposure to certain toxins, such as dioxin, vinyl chloride, arsenic, and herbicides that contain phenoxy acetic acid at high doses may increase your risk of developing soft tissue sarcomas.
• Radiation exposure, especially from radiation therapy, can be a risk factor. Radiation therapy often treats more common cancers such as breast cancer, prostate cancer, or lymphomas. However, this effective therapy can increase your risk of developing certain other forms of cancer, such as a soft tissue sarcoma.

Symptoms of Liposarcoma

Most patients with liposarcoma have no symptoms until the tumor is large and invades the neighboring organs or tissues, causing tenderness, pain, or functional problems.

Treatment of Liposarcoma

Treatments for liposarcoma include

• Surgery – The goal of surgery is to remove all of the cancer cells. Whenever possible, surgeons work to remove the entire liposarcoma. If a liposarcoma grows to involve nearby organs, removal of the entire liposarcoma may not be possible. In those situations, your doctor may recommend other treatments to shrink the liposarcoma to make it easier to remove during an operation.
• Radiation therapy – Radiation therapy uses powerful energy beams, such as X-rays and protons, to kill cancer cells. Radiation may be used after surgery to kill any cancer cells that remain. Radiation may also be used before surgery to shrink a tumor in order to make it more likely that surgeons can remove the entire tumor.
• Chemotherapy – Chemotherapy uses drugs to kill cancer cells. Not all types of liposarcoma are sensitive to chemotherapy drugs. Careful analysis of your cancer cells by an expert pathologist can determine whether chemotherapy is likely to help you. Chemotherapy may be used after surgery to kill any cancer cells that remain or before surgery to shrink a tumor. Chemotherapy is sometimes combined with radiation therapy.

Newer drugs for liposarcoma

Halaven® (eribulin) and Yondelis® (trabedectin) are approved for people who have not responded to earlier treatment, have widespread liposarcoma, or have cancers that cannot be removed via surgery.

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Pleomorphic Liposarcoma – Causes, Symptoms, Diagnosis, Treatment Myxoid Liposarcoma (MLS) – Causes, Symptoms, Treatment Soft Tissue Tumors – Types, Causes, Symptoms, Treatment Tumor – Types, Classification, Treatment Cancer – Causes, Symptoms, Diagnosis, Treatment Angiolipoma – Causes, Symptoms, Diagnosis, Treatment Types of Soft Tissue Tumors – WHO Classification Fibrolipoma – Causes, Symptoms, Diagnosis, Treatment Spinal Tumor – Causes, Symptoms, Diagnosis, Treatment Leiomyosarcoma – Causes, Symptoms, Diagnosis, Treatment Chondroid Lipoma – Causes, Symptoms, Treatment Penile Cancer – Causes, Symptoms, Diagnosis, Treatment

Key points about giant cell tumors

A giant cell tumor is a rare, aggressive non-cancerous tumor. It usually develops near a joint at the end of the bone. Most occur in the long bones of the legs and arms.

• Giant cell tumors most often occur in young adults when skeletal bone growth is complete.
• The exact cause of giant cell tumors remains unknown.
• Symptoms may include joint pain, swelling, and limited movement.
• Diagnostic tests may include X-rays, biopsy, and bone scans.
• The goal for treatment of a giant cell tumor is to remove the tumor and prevent damage to the affected bone.
• Tumors that can’t be removed surgically can often be controlled and sometimes destroyed with radiation therapy.
• Giant cell tumors can come back.

Next steps

Tips to help you get the most from a visit to your healthcare provider:

• Know the reason for your visit and what you want to happen.
• Before your visit, write down questions you want answered.
• Bring someone with you to help you ask questions and remember what your healthcare provider tells you.
• At the visit, write down the name of a new diagnosis, and any new medicines, treatments, or tests. Also write down any new instructions your provider gives you.
• Know why a new medicine or treatment is prescribed, and how it will help you. Also know what the side effects are.
• Ask if your condition can be treated in other ways.
• Know why a test or procedure is recommended and what the results could mean.
• Know what to expect if you do not take the medicine or have the test or procedure.
• If you have a follow-up appointment, write down the date, time, and purpose for that visit.
• Know how you can contact your healthcare provider if you have questions.

References

1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4733230/
2. https://www.cambridge.org/core/books/pearls-and-pitfalls-in-musculoskeletal-imaging/giant-cell-tumor-gct/B0DDA9D9D7C1ECF4F49757604DDA8DAC
3. https://www.ncbi.nlm.nih.gov/books/NBK551681/
4. https://www.cancer.gov/types/extracranial-germ-cell/hp/germ-cell-treatment-pdq
5. https://www.hopkinsmedicine.org/health/conditions-and-diseases/giant-cell-tumo
6. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5598212/
7. https://www.urmc.rochester.edu/encyclopedia/content.aspx?

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A spinal tumor is an abnormal mass of tissue within or surrounding the spinal cord and/or spinal column. These cells grow and multiply uncontrollably, seemingly unchecked by the mechanisms that control normal cells. Spinal tumors can be benign (non-cancerous) or malignant (cancerous). Primary tumors originate in the spine or spinal cord, and metastatic or secondary tumors result from cancer spreading from another site to the spine.

Spine tumors may arise from any of the structures of the spine or the spinal column. They may arise in the cervical (neck), thoracic (mid-back), or lumbosacral (low back) regions. They may originate in the spinal cord itself, the spinal roots, the dural sac which surrounds the spinal cord, or the vertebrae (bones). They may be primary—originating from the spine or spinal cord—or metastatic, originating elsewhere (ie, lung, breast, etc).

Tumors of the brain and spinal cord are abnormal growths of tissue found inside the skull or the bony spinal column.  The brain and spinal cord are the primary components of the central nervous system (CNS). Benign tumors are noncancerous, and malignant tumors are cancerous. The CNS is housed within rigid, bony quarters (i.e., the skull and spinal column), so any abnormal growth, whether benign or malignant, can place pressure on sensitive tissues and impair function. Tumors that originate in the brain or spinal cord are called primary tumors. Most primary tumors are caused by out-of-control growth among cells that surround and support neurons, specific genetic diseases (such as neurofibromatosis type 1 and tuberous sclerosis), or exposure to radiation or cancer-causing chemicals. Metastatic, or secondary, tumors in the CNS are caused by cancer cells that break away from a primary tumor located in another region of the body. Tumors can place pressure on sensitive tissues and impair function. Symptoms of brain tumors include headaches, seizures, nausea and vomiting, poor vision or hearing, changes in behavior, unclear thinking, and unsteadiness.  Spinal cord tumor symptoms include pain, numbness, and paralysis. Diagnosis is made after a neurological examination, special imaging techniques (computed tomography, and magnetic resonance imaging, positron emission tomography), laboratory tests, and a biopsy (in which a sample of tissue is taken from a suspected tumor and examined).

Types of Spinal Tumor

By the region of the spine in which they occur. These basic areas are cervical, thoracic, lumbar, and sacrum. By their location within the spine.

• Intradural-extramedullary – The tumor is located inside the thin covering of the spinal cord (the dura), but outside the actual spinal cord. The frequency of occurrence in this location is 40%. The most common of these types of tumors develop in the spinal cord’s arachnoid membrane (meningiomas), in the nerve roots that extend out from the spinal cord (schwannomas and neurofibromas), or at the spinal cord base (filum terminale ependymomas). Although meningiomas are often benign, they can be difficult to remove and may recur. Nerve root tumors are also generally benign, although neurofibromas may become malignant over time. Ependymomas at the end of the spinal cord can be large, and the delicate nature of fine neural structures in that area may make removal difficult.
• Intramedullary – These tumors grow inside the spinal cord. They typically derive from glial or ependymal cells (a type of glial cell) that are found throughout the interstitium of the spinal cord. The frequency of occurrence in this location is approximately 5%. Astrocytomas and ependymomas are the two most common types. Astrocytomas are more common in the thoracic region followed by the cervical. Ependymomas are most common in the filum (bottom region of the spinal cord), followed by the cervical region. They are often benign (compared to intracranial), but can be difficult to remove. Intramedullary lipomas are rare congenital tumors most commonly located in the cervicothoracic spinal cord.
• Extradural – The tumor is located outside the dura, which is the thin covering surrounding the spinal cord. The frequency of occurrence in this location vs the ones above is approximately 55%. These lesions are typically attributed to metastatic cancer or less commonly schwannomas derived from the cells covering the nerve roots. Occasionally, an extradural tumor extends through the intervertebral foramina, lying partially within and partially outside of the spinal canal.

The bony spinal column is the most common site for bone metastasis. Estimates indicate that at least 30% and as high as 70% of patients with cancer will experience the spread of cancer to their spine. The most common primary spine tumor (originated in the bony spine) is vertebral hemangiomas. These are benign lesions and rarely cause symptoms such as pain.

Common primary cancers that spread to the spine are lung, breast, and prostate. Lung cancer is the most common cancer to metastasize to the bone in men, and breast cancer is the most common in women. Other cancers that spread to the spine include multiple myeloma, lymphoma, melanoma, and sarcoma, as well as cancers of the gastrointestinal tract, kidney, and thyroid. Prompt diagnosis and identification of the primary malignancy are crucial to overall treatment. Numerous factors can affect outcomes, including the nature of primary cancer, the number of lesions, the presence of distant non-skeletal metastases, and the presence and/or severity of spinal cord compression.

Non-mechanical back pain, especially in the middle or lower back, is the most frequent symptom of both benign and malignant spinal tumors. This back pain is not specifically attributed to injury, stress or physical activity. However, the pain may increase with activity and can be worse at night when lying down. Pain may spread beyond the back to the hips, legs, feet or arms and may worsen over time — even when treated by conservative, nonsurgical methods that can often help alleviate back pain attributed to mechanical causes. Depending on the location and type of tumor, other signs and symptoms can develop, especially as a tumor grows and compresses on the spinal cord, the nerve roots, blood vessels or bones of the spine.

Additional symptoms can include the following:

• Loss of sensation or muscle weakness in the legs, arms, or chest
• Stiff neck or back
• Pain and/or neurologic symptoms (such as tingling) increase with the Valsalva maneuver
• Difficulty walking, which may cause falls
• Decreased sensitivity to pain, heat, and cold
• Loss of bowel or bladder function
• Paralysis may occur in varying degrees and in different parts of the body, depending on which nerves are compressed
• Scoliosis or other spinal deformity resulting from a large and/or destructive tumor

A thorough medical examination with emphasis on back pain and neurological deficits is the first step to diagnosing a spinal tumor. Radiological tests are required for an accurate and positive diagnosis.

• X-ray – Application of radiation to produce a film or picture of a part of the body can show the structure of the vertebrae and the outline of the joints. X-rays of the spine are obtained to search for other potential causes of pain, i.e. tumors, infections, fractures, etc. X-rays, however, are not very reliable in diagnosing tumors.
• Computed tomography scan (CT or CAT scan) – A diagnostic image created after a computer reads X-rays, a CT/CAT scan can show the shape and size of the spinal canal, its contents, and the structures around it. It also is very good at visualizing bony structures.
• Magnetic resonance imaging (MRI) – A diagnostic test that produces three-dimensional images of body structures using powerful magnets and computer technology. An MRI can show the spinal cord, nerve roots, and surrounding areas, as well as enlargement, degeneration, and tumors.
• Bone Scan – A diagnostic test using Technetium-99. Helpful as an adjunct for identification of bone tumors (such as primary bone tumors of the spine), infection, and diseases involving abnormal bone metabolism.

Radiology studies noted above provide imaging findings that suggest the most likely tumor type. In some cases, however, a biopsy may be needed if the diagnosis is unclear or if concern for malignancy vs benign tumor type. If the tumor is malignant, a biopsy also helps determine cancer’s type, which subsequently determines treatment options.

Staging classifies neoplasms (abnormal tissue) according to the extent of the tumor, assessing bony, soft tissue, and spinal canal involvement. A doctor may order a whole-body scan utilizing nuclear technology, as well as a CT scan of the lungs and abdomen for staging purposes. To confirm the diagnosis, a doctor compares laboratory test results and findings from the aforementioned scans to the patient’s symptoms.

Treatment decision-making is often multidisciplinary, incorporating the expertise of spinal surgeons, medical oncologists, radiation oncologists, and other medical specialists. The selection of treatments including both surgical and non-surgical is therefore made keeping in mind the various aspects of the patient’s overall health and goals of care.

Non-Surgical Treatments

Nonsurgical treatment options include observation, chemotherapy, and radiation therapy. Tumors that are asymptomatic or mildly symptomatic and do not appear to be changing or progressing may be observed and monitored with regular MRIs. Some tumors respond well to chemotherapy and others to radiation therapy. However, there are specific types of metastatic tumors that are inherently radioresistant (i.e. gastrointestinal tract and kidney): in those cases, surgery may be the only viable treatment option.

Surgery

Indications for surgery vary depending on the type of tumor. Primary (non-metastatic) spinal tumors may be removed through complete en bloc resection for a possible cure. In patients with metastatic tumors, treatment is primarily palliative, with the goal of restoring or preserving neurological function, stabilizing the spine, and alleviating pain. Generally, surgery is only considered as an option for patients with metastases when they are expected to live 3 – 4 months or longer, and the tumor is resistant to radiation or chemotherapy. Indications for surgery include intractable pain, spinal cord compression, and the need for stabilization of pathological fractures.

For cases in which surgical resection is possible, preoperative embolization may be used to enable an easier resection. This procedure involves the insertion of a catheter or tube through an artery in the groin. The catheter is guided up through the blood vessels to the site of the tumor, where it delivers a glue-like liquid embolic agent that blocks the vessels that feed the tumor. When the blood vessels that feed the tumor are blocked off, bleeding can often be controlled better during surgery, helping to decrease surgical risks.

If surgery is considered, the approach to the tumor is determined by the tumor’s location within the spinal canal.  The posterior (back) approach allows for the identification of the dura and exposure of the nerve roots. This approach is commonly used for tumors in the posterior aspect of the spinal column or to expose tumors inside the dura.   Multiple levels can be decompressed, and multilevel segmental fixation can be performed if necessary. The anterior (front) approach is excellent for tumors in the front of the spine. This approach also allows for the reconstruction of defects caused by the removal of the vertebral bodies. This approach also allows the placement of short-segment fixation devices. Thoracic and lumbar spinal tumors that affect both the anterior and posterior vertebral columns can be a challenge to resect completely. Not infrequently, a posterior (back) approach followed by a separately staged anterior (front) approach has been utilized surgically to treat these complex lesions.

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Cervical Cancer Surgery is a disease in which cells in the body grow out of control. Cancer is always named for the part of the body where it starts, even if it spreads to other body parts later. When cancer starts in the cervix, it is called cervical cancer. The cervix connects the vagina (birth canal) to the upper part of the uterus. The uterus (or womb) is where a baby grows when a woman is pregnant.

Cervical cancer is cancer arising from the cervix. It is due to the abnormal growth of cells that have the ability to invade or spread to other parts of the body.^[rx] Early on, typically no symptoms are seen.^[rx] Later symptoms may include abnormal vaginal bleeding, pelvic pain or pain during sexual intercourse.^[rx] While bleeding after sex may not be serious, it may also indicate the presence of cervical cancer.^[rx]

Cervical cancer usually develops slowly over time. Before cancer appears in the cervix, the cells of the cervix go through changes known as dysplasia, in which abnormal cells begin to appear in the cervical tissue. Over time, the abnormal cells may become cancer cells and start to grow and spread more deeply into the cervix and to surrounding areas.

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Cervical cancer is the fourth most common cancer in women worldwide, and it has the fourth highest mortality rate among cancers in women.[rx] Most cases of cervical cancer are preventable by routine screening and by treatment of precancerous lesions. As a result, most of the cervical cancer cases are diagnosed in women who live in regions with inadequate screening protocols.

Incidence and Mortality

Estimated new cases and deaths from cervical (uterine cervix) cancer in the United States in 2020:[rx]

• New cases: 13,800.
• Deaths: 4,290.

Anatomy of Cervical Cancer

The uterine cervix is contiguous with the uterine body, and it acts as the opening to the body of the uterus. The uterine cervix is a cylindrical, fibrous organ that is an average of 3 to 4 cm in length. The portio of the cervix is the part of the cervix that is visible on vaginal inspection. The opening of the cervix is termed the external os. The os is the beginning of the endocervical canal, which forms the inner aspect of the cervix. At the upper aspect of the endocervical canal is the internal os, a narrowing of the endocervical canal. The narrowing marks the transition from the cervix to the uterine body. The endocervical canal beyond the internal os is termed the endometrial canal.

The cervix is lined by two types of epithelial cells: squamous cells at the outer aspect, and columnar, glandular cells along the inner canal. The transition between squamous cells and columnar cells is an area termed the squamocolumnar junction. Most the precancerous and cancerous changes arise in this zone.

Pathogenesis

Cervical carcinoma has its origins at the squamous-columnar junction; it can involve the outer squamous cells, the inner glandular cells, or both. The precursor lesion is dysplasia: cervical intraepithelial neoplasia (CIN) or adenocarcinoma in situ, which can subsequently become invasive cancer. This process can be quite slow. Longitudinal studies have shown that in patients with untreated in situ cervical cancer, 30% to 70% will develop invasive carcinoma over a period of 10 to 12 years. However, in about 10% of patients, lesions can progress from in situ to invasive in a period of less than 1 year. As it becomes invasive, the tumor breaks through the basement membrane and invades the cervical stroma. Extension of the tumor in the cervix may ultimately manifest as ulceration, exophytic tumor, or extensive infiltration of underlying tissue, including the bladder or rectum.

Risk Factors

Increasing age is the most important risk factor for most cancers. The primary risk factor for cervical cancer is human papillomavirus (HPV) infection.[rx–rx]

Other risk factors for cervical cancer include the following:

• High parity and HPV infection.[rx]
• Smoking cigarettes and HPV infection.[rx]
• Long-term use of oral contraceptives and HPV infection.[rx,rx]
• Immunosuppression.[rx,rx]
• Having first sexual encounter at a young age.[rx]
• High number of sexual partners.[rx]
• Exposure to diethylstilbestrol (DES) in utero.[rx]

Human papillomavirus (HPV) infection

HPV infection is a necessary step in the development of virtually all precancerous and cancerous lesions. Epidemiologic studies convincingly demonstrate that the major risk factor for the development of preinvasive or invasive carcinoma of the cervix is HPV infection, far outweighing other known risk factors.

More than 6 million women in the United States are estimated to be infected with HPV. Transient HPV infection is common, particularly in young women,[rx] while cervical cancer is rare. The persistence of an HPV infection leads to an increased risk of developing precancerous and cancerous lesions.[rx,rx]

The strain of HPV infection is also important in conferring risk. There are multiple subtypes of HPV that infect humans; of these, subtypes 16 and 18 have been most closely associated with high-grade dysplasia and cancer. Studies suggest that acute infection with HPV types 16 and 18 conferred an 11-fold to 16.9-fold risk of rapid development of high-grade CIN.[rx–rx] Further studies have shown that infection with either HPV 16 or 18 is more predictive than cytologic screening of high-grade CIN or greater disease, and that the predictive ability is seen for up to 18 years after the initial test.[rx–rx]

There are two commercially available vaccines that target anogenital-related strains of HPV. The vaccines are directed towards HPV-naïve girls and young women, and although penetration of the vaccine has been moderate, significant decreases in HPV-related diseases have been documented.[rx]

Symptoms of Cervical Cancer

Early cervical cancer may not cause noticeable signs or symptoms.

Possible signs and symptoms of cervical cancer include the following:

• Vaginal bleeding.
• Unusual vaginal discharge.
• Pelvic pain.
• Dyspareunia.
• Postcoital bleeding.

Diagnosis of Cervical Cancer

The following procedures may be used to diagnose cervical cancer:

• History and physical exam.
• Pelvic exam.
• Cervical cytology (Pap smear).
• HPV test.
• Endocervical curettage.
• Colposcopy.
• Biopsy.

HPV testing

Cervical cytology (Pap smear) has been the mainstay of cervical cancer screening since its introduction. However, molecular techniques for the identification of HPV DNA are highly sensitive and specific. Current screening options include the following:

• Cytology alone.
• Cytology and HPV testing.

HPV testing is suggested when it is likely to successfully triage patients into low- and high-risk groups for a high-grade dysplasia or greater lesion.

HPV DNA tests are unlikely to separate patients with low-grade squamous intraepithelial lesions into those who do and those who do not need further evaluation. A study of 642 women found that 83% had one or more tumorigenic HPV types when cervical cytologic specimens were assayed by a sensitive (hybrid capture) technique.[rx] The authors of the study and of an accompanying editorial concluded that using HPV DNA testing in this setting does not add sufficient information to justify its cost.[rx]

HPV DNA testing has proven useful in triaging patients with atypical squamous cells of undetermined significance to colposcopy and has been integrated into current screening guidelines.[rx–rx]

Other studies show that patients with low-risk cytology and high-risk HPV infection with types 16, 18, and 31 are more likely to have CIN or micro-invasive histopathology on biopsy.[rx,rx–rx] One method has also shown that integration of HPV types 16 and 18 into the genome, leading to transcription of viral and cellular messages, may predict patients who are at greater risk for high-grade dysplasia and invasive cancer.[rx]

For women older than 30 years who are more likely to have persistent HPV infection, HPV typing can successfully triage women into high- and low-risk groups for CIN 3 or worse disease. In this age group, HPV DNA testing is more effective than cytology alone in predicting the risk of developing CIN 3 or worse.[rx] Other studies have shown the effectiveness of a primary HPV DNA–screening strategy with cytology triage over the previously used cytology-based screening algorithms.[rx,rx]

Prognostic Factors

The prognosis for patients with cervical cancer is markedly affected by the extent of disease at the time of diagnosis. More than 90% of cervical cancer cases can be detected early through the use of the Pap test and HPV testing.[35] Pap and HPV testing are not performed on approximately 33% of eligible women, which results in a higher-than-expected death rate.

Clinical stage

Clinical stage as a prognostic factor is supplemented by several gross and microscopic pathologic findings in surgically treated patients.

Evidence (clinical stage and other findings):

In a large, surgicopathologic staging study of patients with clinical stage IB disease reported by the Gynecologic Oncology Group (GOG) (GOG-49), the factors that most prominently predicted for lymph node metastases and a decrease in disease-free survival were capillary-lymphatic space involvement by tumor, increasing tumor size, and increasing depth of stromal invasion, with the latter being the most important and reproducible.[rx,rx]

In a study of 1,028 patients treated with radical surgery, survival rates correlated more consistently with tumor volume (as determined by precise volumetry of the tumor) than with clinical or histologic stage.[rx]

A multivariate analysis of prognostic variables in 626 patients with locally advanced disease (primarily stages II, III, and IV) studied by the GOG identified the following variables that were significant for progression-free interval and survival:[rx]

• Periaortic and pelvic lymph node status.
• Tumor size.
• Patient age.
• Performance status.
• Bilateral disease.
• Clinical stage.

The study confirmed the overriding importance of positive periaortic nodes and suggested further evaluation of these nodes in locally advanced cervical cancer. The status of the pelvic nodes was important only if the periaortic nodes were negative. This was also true for tumor size.

It is controversial whether adenocarcinoma of the cervix carries a significantly worse prognosis than squamous cell carcinoma of the cervix.[rx] Several population-based and retrospective studies show a worse outcome for patients with adenocarcinoma, with an increase in distant metastasis noted, when compared with those with squamous histology.[rx–rx] Reports conflict about the effect of adenosquamous cell type on the outcome.[rx,rx] One report showed that approximately 25% of apparent squamous tumors have demonstrable mucin production and behave more aggressively than their pure squamous counterparts, suggesting that any adenomatous differentiation may confer a negative prognosis.[rx]

In a large series of cervical cancer patients treated by radiation therapy, the incidence of distant metastases (most frequently to the lung, abdominal cavity, liver, and gastrointestinal tract) was shown to increase as the stage of disease increased, from 3% in stage IA to 75% in stage IVA.[rx] A multivariate analysis of factors influencing the incidence of distant metastases showed stage, an endometrial extension of tumor, and pelvic tumor control to be significant indicators of distant dissemination.[rx]

GOG studies have indicated that prognostic factors vary depending on whether clinical or surgical staging are utilized and with different treatments. Delay in radiation delivery completion is associated with poorer progression-free survival when clinical staging is used. To-date, stage, tumor grade, race, and age are uncertain prognostic factors in studies utilizing chemoradiation.[rx]

Other prognostic factors

Other prognostic factors that may affect outcome include the following:

• HIV status: Women with HIV have more aggressive and advanced disease and a poorer prognosis.[rx]
• C-myc overexpression: A study of patients with known invasive squamous carcinoma of the cervix found that overexpression of the C-myc oncogene was associated with a poorer prognosis.[rx]
• Number of cells in S phase: The number of cells in S phase may also have prognostic significance in early cervical carcinoma.[rx]
• HPV-18 DNA: HPV-18 DNA has been found to be an independent adverse molecular prognostic factor. Two studies have shown a worse outcome when HPV-18 was identified in cervical cancers of patients undergoing radical hysterectomy and pelvic lymphadenectomy.[rx,rx]
• A polymorphism in the Gamma-glutamyl hydrolase enzyme, which is related to folate metabolism, has been shown to decrease response to cisplatin, and as a result is associated with poorer outcomes.[rx]

Follow-up After Treatment

High-quality studies are lacking, and the optimal treatment follow-up for patients after treatment for cervical cancer is unknown. Retrospective studies have shown that patients who recur are most likely to do so within the first 2 years.[rx] As a result, most guidelines suggest routine follow-up every 3 to 4 months for the first 2 years, followed by evaluations every 6 months. Most recurrences are diagnosed secondary to new patient symptoms and signs,[57,58] and the usefulness of routine testing including a Pap smear and chest x-ray is unclear.

Follow-up should be centered around a thorough history and physical examination with a careful review of symptoms; imaging should be reserved for evaluation of a positive finding. Patients should be asked about possible warning signs, including the following:

• Abdominal pain.
• Back pain.
• Painful or swollen leg.
• Problems with urination.
• Cough.
• Fatigue.

The follow-up examination should also screen for possible complications of previous treatment because of the multiple modalities (surgery, chemotherapy, and radiation) that patients often undergo during their treatment.

Stage Information for Cervical Cancer

Carcinoma of the cervix can spread via local invasion, the regional lymphatics, or bloodstream. Tumor dissemination is generally a function of the extent and invasiveness of the local lesion. While cancer of the cervix generally progresses in an orderly manner, occasionally a small tumor with distant metastasis is seen. For this reason, patients must be carefully evaluated for metastatic disease.

Pretreatment surgical staging is the most accurate method to determine the extent of disease,[1] but there is little evidence to demonstrate overall improved survival with routine surgical staging; the staging is usually performed only as part of a clinical trial. Pretreatment surgical staging in bulky but locally curable disease may be indicated in select cases when a nonsurgical search for metastatic disease is negative. If abnormal nodes are detected by computed tomography (CT) scan or lymphangiography, fine-needle aspiration should be negative before a surgical staging procedure is performed.

Tests and procedures to evaluate the extent of the disease include the following:

• CT scan.
• Positron emission tomography scan.
• Cystoscopy.
• Laparoscopy.
• Chest x-ray.
• Ultrasonography.[rx]
• Magnetic resonance imaging.[rx]

FIGO Stage Groupings and Definitions

The Fédération Internationale de Gynécologie et d’Obstétrique (FIGO) and the American Joint Committee on Cancer have designated staging to define cervical cancer; the FIGO system is most commonly used.[rx,rx]

Stage	Description	Illustration
FIGO = Fédération Internationale de Gynécologie et d’Obstétrique.
aAdapted from FIGO Committee for Gynecologic Oncology.[rx]
bImaging and pathology can be used, when available, to supplement clinical findings with respect to tumor size and extent, in all stages. Pathological findings supersede imaging and clinical findings.
cThe involvement of vascular/lymphatic spaces should not change the staging. The lateral extent of the lesion is no longer considered.
I	The carcinoma is strictly confined to the cervix (extension to the corpus should be disregarded).
IA	Invasive carcinoma that can be diagnosed only by microscopy, with maximum depth of invasion ≤5 mm.b
–IA1	–Measured stromal invasion ≤3 mm in depth.
–IA2	–Measured stromal invasion >3 mm and ≤5 mm in depth.
IB	Invasive carcinoma with measured deepest invasion >5 mm (greater than stage IA); lesion limited to the cervix uteri with size measured by maximum tumor diameter.c
–IB1	–Invasive carcinoma >5 mm depth of stromal invasion and ≤2 cm in greatest dimension.
–IB2	–Invasive carcinoma >2 cm and ≤4 cm in greatest dimension.
–IB3	–Invasive carcinoma >4 cm in greatest dimension.

Stage	Description	Illustration
FIGO = Fédération Internationale de Gynécologie et d’Obstétrique.
aAdapted from FIGO Committee for Gynecologic Oncology.[rx]
II	The cervical carcinoma invades beyond the uterus, but has not extended onto the lower third of the vagina or to the pelvic wall.
IIA	Involvement limited to the upper two-thirds of the vagina without parametrial involvement.
–IIA1	–Invasive carcinoma ≤4 cm in greatest dimension.
–IIA2	–Invasive carcinoma >4 cm in greatest dimension.
IIB	With parametrial involvement but not up to the pelvic wall.

Stage	Description	Illustration
FIGO = Fédération Internationale de Gynécologie et d’Obstétrique.
aAdapted from FIGO Committee for Gynecologic Oncology.[3]
bIsolated tumor cells do not change the stage but their presence should be recorded.
cAdding notation of r (imaging) and p (pathology) to indicate the findings that are used to allocate the case to stage IIIC. For example, if imaging indicates pelvic lymph node metastasis, the stage allocation would be stage IIIC1r; if confirmed by pathological findings, it would be stage IIIC1p. The type of imaging modality or pathology technique used should always be documented. When in doubt, the lower staging should be assigned.
III	The carcinoma involves the lower third of the vagina and/or extends to the pelvic wall and/or causes hydronephrosis or nonfunctioning kidney and/or involves pelvic and/or para-aortic lymph nodes.
IIIA	Carcinoma involves the lower third of the vagina, with no extension to the pelvic wall.
IIIB	Extension to the pelvic wall and/or hydronephrosis or nonfunctioning kidney (unless known to be due to another cause).
IIIC	Involvement of pelvic and/or para-aortic lymph nodes (including micrometastases)b, irrespective of tumor size and extent (with r and p notations).c
–IIIC1	–Pelvic lymph node metastasis only.
–IIIC2	–Para-aortic lymph node metastasis.

Stage	Description	Illustration
FIGO = Fédération Internationale de Gynécologie et d’Obstétrique.
aAdapted from FIGO Committee for Gynecologic Oncology.[rx]
IV	The carcinoma has extended beyond the true pelvis or has involved (biopsy proven) the mucosa of the bladder or rectum. A bullous edema, as such, does not permit a case to be allotted to stage IV.
IVA	Spread of the growth to adjacent organs.
IVB	Spread to distant organs.

References

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Adenomyosis is a uterine condition that is histologically characterized by the presence of ectopic endometrial glands and stroma within the myometrium, surrounded by hypertrophic and hyperplastic myometrial changes [rx]. For several decades, the diagnosis of adenomyosis was made in hysterectomy specimens either coincidentally, or in women treated surgically for chronic pelvic pain and/or abnormal uterine bleeding[rx].

Adenomyosis is a medical condition characterized by the growth of cells that build up the inside of the uterus (endometrium) atypically located within the cells that put up the uterine wall (myometrium),^[rx] as a result, thickening of the uterus occurs. As well as being misplaced in patients with this condition, endometrial tissue is completely functional. The tissue thickens, sheds, and bleeds during every menstrual cycle.^[rx]

Causes of Adenomyosis

• Adenomyosis and endometriosis are usually regarded as closely related, but
  • Microscopic appearance, and probably their pathogenesis, are somewhat different
  • They may occur independently of each other
  • Adenomyosis mostly is made up of nonfunctional (basal) endometrium and is frequently connected with the mucosa (vs. endometriosis, composed of functional layers)
  • Adenomyosis may represent a unique form of endometrial diverticulosis
• Hypothetical mechanisms include (Crum: Diagnostic Gynecologic and Obstetric Pathology, 2nd Edition, 2011)
  • Instillation of endometrium within the myometrium
  • In situ metaplasia of pluripotent stem cells retained in myometrium or
  • Improper partitioning of the endometrium from the myometrium
• Of note, del(7) (q21.2q31.2), a deletion found in typical leiomyoma, has been found in three cases of adenomyosis, suggesting some pathobiology overlap between leiomyomata and adenomyosis (Cancer Genet Cytogenet 1995;80:118)
• Invasive tissue growth – Some experts believe that endometrial cells from the lining of the uterus invade the muscle that forms the uterine walls. Uterine incisions made during an operation such as a cesarean section (C-section) might promote the direct invasion of the endometrial cells into the wall of the uterus.
• Developmental origins  – Other experts suspect that endometrial tissue is deposited in the uterine muscle when the uterus is first formed in the fetus.
• Uterine inflammation related to childbirth –  Another theory suggests a link between adenomyosis and childbirth. Inflammation of the uterine lining during the postpartum period might cause a break in the normal boundary of cells that line the uterus.
• Stem cell origins – A recent theory proposes that bone marrow stem cells might invade the uterine muscle, causing adenomyosis.

Symptoms of Adenomyosis

Adenomyosis can vary widely in the type and severity of symptoms that it causes, ranging from being entirely asymptomatic 33% of the time to being a severe and debilitating condition in some cases. Women with adenomyosis typically first report symptoms when they are between 40 and 50, but symptoms can occur in younger women.^[rx][rx]

Symptoms and the estimated percent affected may include:^[rx]

• Chronic pelvic pain (77%)
• Heavy menstrual bleeding (40-60%), which is more common in women with deeper adenomyosis. Blood loss may be significant enough to cause anemia, with associated symptoms of fatigue, dizziness, and moodiness.
• Abnormal uterine bleeding
• Painful cramping menstruation (15-30%)
• Painful vaginal intercourse (7%)
• A ‘bearing’ down feeling
• Pressure on bladder
• Dragging sensation down thighs and legs
• Uterine enlargement (30%), which in turn can lead to symptoms of pelvic fullness.
• Tender uterus
• Infertility or sub-fertility (11-12%) – In addition, adenomyosis is associated with an increased incidence of preterm labor and premature rupture of membranes.^[rx][rx]

Women with adenomyosis are also more likely to have other uterine conditions, including:

• Uterine fibroids (50%)
• Endometriosis (11%)
• Endometrial polyp (7%)
• Nonneoplastic condition presenting with palpably enlarged uterus
• Symptoms are nonspecific: dysmenorrhea, menorrhagia, abnormal uterine bleeding, dyspareunia, chronic pelvic pain associated with the menstrual period and infertility (Eur J Obstet Gynecol Reprod Biol 2009;143:103, N Engl J Med 2010;362:2389)
• Associated with deep infiltrating endometriosis, parity, intense dysmenorrhea and increasing age (Eur J Obstet Gynecol Reprod Biol 2014;181:289)
• Tends to regress after menopause (Hum Reprod 2012;27:3432)
• When extensive, it confers a potential risk of infarction and thrombosis and exacerbates menorrhagia via activation of coagulation and fibrinolysis during menstruation (Eur J Obstet Gynecol Reprod Biol 2016;204:99)
• Painful menstrual cramps (dysmenorrhea).
• Heavy menstrual bleeding (menorrhagia).
• Abnormal menstruation.
• Pelvic pain.
• Painful intercourse (dyspareunia).
• Infertility.
• Enlarged uterus.

Diagnosis of Adenomyosis

Histopathology

• The diagnosis of adenomyosis is through a pathologist microscopically examining small tissue samples of the uterus.^[rx] These tissue samples can come from a uterine biopsy or directly following a hysterectomy. Uterine biopsies can be obtained by either a laparoscopic procedure through the abdomen or hysteroscopy through the vagina and cervix.^[rx]
• The diagnosis is established when the pathologist finds invading clusters of endometrial tissue within the myometrium. Several diagnostic criteria can be used, but typically they require either the endometrial tissue to have invaded greater than 2% of the myometrium, or a minimum invasion depth between 2.5 to 8mm.^[rx] Histopathological image of uterine adenomyosis observed in the hysterectomy specimen. Hematoxylin & eosin stain.

Gross Findings

• Enlarged uterus
• Thickened uterine wall with a trabeculated appearance
• Hemorrhagic pinpoint or cystic spaces throughout wall^[rx]

Microscopic Findings

• Endometrial glands and stroma haphazardly distributed throughout the myometrium
• Concentric myometrial hyperplasia frequent around adenomyotic foci
• Variants: Gland-poor, stroma-poor, intravascular^[rx]

Laboratory Evaluation

Laboratory testing is useful to rule out other disease entities included in the differential diagnosis, in addition to identifying certain complicating features such as anemia due to heavy menstruation. While some biomarkers due exist, none are specific for adenomyosis.[rx]

Imaging

Adenomyosis can vary widely in the extent and location of its invasion within the uterus. As a result, there are no established pathognomonic features to allow for a definitive diagnosis of adenomyosis through non-invasive imaging. Nevertheless, non-invasive imaging techniques such as transvaginal ultrasonography (TVUS) and magnetic resonance imaging (MRI) can both be used to strongly suggest the diagnosis of adenomyosis, guide treatment options, and monitor response to treatment.^[rx] Indeed, TVUS and MRI are the only two practical means available to establish a pre-surgical diagnosis.^[rx]

Ultrasound

Transvaginal ultrasound is the preferred diagnostic imaging modality for adenomyosis. The characteristic findings reflect the histopathologic changes of the disease process and can be broken down into three categories:

• Endometrial infiltration – echogenic striations and nodules, myometrial cysts, and “lollipop” diverticula (cystic striations)
• Smooth muscle proliferation – focal or diffuse myometrial thickening with indistinct borders more commonly involving the posterior fundus and heterogenous echotexture manifesting as “Venetian blind” appearance of thin linear shadows
• Vascularity – color Doppler demonstrating an increased number of tortuous vessels throughout the involved myometrium as opposed to leiomyomas which displace vessels

A number of mimics can have similar findings on the ultrasound exam, including tamoxifen use, prior endometrial ablation, endometriosis, uterine contractions, vascular malformations, leiomyomas, and cancer. Certain techniques such as low-frequency, coronal reconstructions, 3-D ultrasound, cine-clips, color Doppler, and saline infusion sonohysterography (SIS) can be used to differentiate between these entities.

MRI

Characteristic findings on MRI parallel the same features seen on ultrasound[rx][rx]:

• On T2-weighted imaging, uterine enlargement characterized by ill-defined, low-signal-intensity regions within the junctional zone is reflective of smooth muscle hyperplasia (junctional zone thicker than 12mm is generally accepted as diagnostic)
• T2 hyperintense myometrial cysts reflecting regions of ectopic endometrial tissue (can also have increased intrinsic T1 signal or increased susceptibility in hemorrhagic foci)
• Contrast enhancement is generally not reliable for assessment of vascularity as compared to a color Doppler ultrasound
• Similar to ultrasound, a variety of mimics ranging from co-existing gynecologic pathologies to physiologic variants exist. Susceptibility weighted imaging, diffusion-weighted imaging, MR spectroscopy, cine MR imaging, and increased 3T field strength are all problem-solving strategies.[rx]
• It is important to obtain the MRI in the late proliferative or secretory phase (days 7 to 28) due to the decreased signal of normal myometrium during the early proliferative phase (days 1 to 6).[rx]

Transvaginal ultrasonography

Common transvaginal ultrasound findings in patients with adenomyosis include the following:^[rx][rx][rx]

• globular, enlarged, and/or asymmetric uterus
• abnormally dense or especially varied density within the myometrium
• myometrial cysts – pockets of fluid within the smooth muscle of the uterus
• linear, acoustic shadowing without the presence of a uterine fibroid
• echogenic linear striations – bright lines or stripes
• anterior/posterior wall asymmetry
• the diffuse spread of small vessels within the myometrium
• Lack of contour abnormality
• Absence of mass effect
• Ill-defined margins between a normal and abnormal myometrium

Others Study

• The power Doppler or Doppler ultrasonography function – can be used during transvaginal ultrasonography to help differentiate adenomyomas from uterine fibroids.^[rx][rx][rx] This is because uterine fibroids typically have blood vessels circling the fibroid’s capsule. In contrast, adenomyomas are characterized by widespread blood vessels within the lesion.^[rx] Doppler ultrasonography also serves to differentiate the static fluid within myometrial cysts from flowing blood within vessels.^[rx]
• The junction zone (JZ) – or a small distinct hormone-dependent region at the endometrial-myometrial interface, may be assessed by three-dimensional transvaginal ultrasound (3D TVUS) and MRI. Features of adenomyosis are disruption, thickening, enlargement or invasion of the junctional zone.^[rx]
• Sagittal MRI of a woman’s pelvis – showing a uterus with adenomyosis in the posterior wall. Gross enlargement of the posterior wall is noted, with many foci of hyperintensity.
• Shear Wave Elastography – A recent study also showed that using Aixplorer (Supersonic Imagine, France) scanner with the application of shear wave elastography during transvaginal scanning may improve the diagnostic accuracy of adenomyosis [rx]. This study found that adenomyosis was associated with a significant increase of the myometrial stiffness estimated with shear wave elastography. Further studies are required to verify the clinical usefulness of such an approach.
• Hysterosalpingography – Hysterosalpingography is seldom used to diagnose adenomyosis. However, in patients undergoing infertility assessment, the occasional finding of speculations measuring 1–4 mm in length, arising from the endometrium towards the myometrium, or a uterus with the “tuba erecta” finding may be suggestive of adenomyosis [rx].
• Hysteroscopy – Several hysteroscopic appearances have been found to be associated with adenomyosis, including irregular endometrium with endometrial defects or superficial openings, hypervascularization, strawberry pattern, or cystic hemorrhagic lesions [rx]. Nevertheless, there is limited data available on the diagnostic accuracy of these various features.
• Hysteroscopic and Laparoscopic Myometrial Biopsy – The study found that the depth of adenomyosis was correlated with the severity of menorrhagia. Of the 90 patients studied, 50 patients had normal hysteroscopy in which 55% of them had significant adenomyosis (greater than 1 mm) when compared to controls (0.8 mm).
• Laparoscopic Myometrial Biopsy – In a prospective, nonrandomized study conducted by Jeng et al. [rx] evaluating 100 patients with clinical signs and symptoms strongly suggestive of adenomyosis, the sensitivity of myometrial biopsy were 98% and the specificity 100%; the positive predictive value was 100% and the negative predictive value 80%, which were superior to those of transvaginal sonography, serum CA-125 determination, or the combination of both. The group suggested that a laparoscopy-guided myometrial biopsy is a valuable tool in the diagnosis of diffuse adenomyosis in women presenting with infertility, dysmenorrhea, or chronic pelvic pain.

Treatment of Adenomyosis

Adenomyosis can only be cured definitively with surgical removal of the uterus. As adenomyosis is responsive to reproductive hormones, it reasonably abates following menopause when these hormones decrease. For women in their reproductive years, adenomyosis can typically be managed with the goals to provide pain relief, to restrict progression of the process, and to reduce significant menstrual bleeding.

Medications

• NSAIDs – Nonsteroidal anti-inflammatory drugs, such as ibuprofen and naproxen, are commonly used in conjunction with other therapies for pain relief. NSAIDs inhibit the production of prostaglandins by decreasing the activity of the enzyme cyclooxygenase. Prostaglandins have been shown to be primarily responsible for dysmenorrhea or the cramping pelvic pain associated with menses.
• Analgesic – Nonsteroidal anti-inflammatory drugs (NSAIDs) work by inhibiting the cyclooxygenase (COX-1 and COX-2) and decreasing the production of prostaglandins. NSAIDs have been proved to be effective in the treatment of primary dysmenorrhea by Gambone et al. [rx]. It is usually the first-line treatment for symptomatic pain relief for adenomyosis.
• Oral Contraceptive Pills (OCPs) – Combined oral contraceptive pills work by inhibiting ovulation by suppressing the release of gonadotropins. Many studies have shown that they are effective in the treatment of dysmenorrhea. A prospective observational trial showed that continuous low-dose OCP was more effective than cyclical low-dose OCP in controlling symptoms in patients after surgical treatment for endometriosis [rx].
• Danazol – Danazol is an isoxazole derivative of 12 alpha-ethinyl testosterone. It causes a hypogonadal state and thus is widely used for the treatment of endometriosis and abnormal uterine bleeding [rx]. However, data on its use in adenomyosis remains limited. This may be due to its unwanted adverse effects after systemic treatment.
• Dienogest – Dienogest is a selective synthetic oral progestin that combines the pharmacological properties of 17-alpha-progesterone and 19 nor-progesterone with a pronounced local effect on endometrial tissue. Dienogest has been shown to be effective in the treatment of endometriosis-associated pelvic pain. A prospective clinical trial has shown dienogest to be a valuable alternative to depot triptorelin acetate for the treatment of premenopausal pelvic pains in women with uterine adenomyosis. [rx]
• Levonorgestrel-Releasing Intrauterine Device (LNG-IUD) – LNG-IUD is an intrauterine device, which releases 20 micrograms of levonorgestrel per day. It has been shown to be an effective treatment for abnormal uterine bleeding. LNG-IUD acts locally and causes decidualization of the endometrium and adenomyotic deposits. LNG-IUD alleviates dysmenorrhea by improving uterine contractility and reducing local prostaglandin production within the endometrium. LNG-IUD appears to be an effective method in relieving dysmenorrhea associated with adenomyosis [rx] and more effective than the combined OC pill [rx], improved the quality of life [rx], and appears to be a promising alternative treatment to hysterectomy.
• LNG-IUD – may be used in conjunction with other treatment modalities such as GnRH analog [rx] or transcervical resection of the endometrium (TCRE) [rx]. In the latter study, it was found that TCRE combined with LNG-IUD was more effective in reducing menstrual flow compared with the LNG-IUD alone although there was no significant difference in the amount of pain reduction between the two treatment strategies.
• GnRH Agonists – GnRH agonists are effective in alleviating dysmenorrhea and relieving menorrhagia associated with adenomyosis [rx]. However, due to the undesirable climacteric side effects and risk of osteoporosis, treatment with GnRH agonists is usually restricted to a short duration of 3–6 months although the duration of use may be extended if add-back estrogen therapy is employed [rx]. Discontinuation of treatment usually leads to regrowth of the lesions and recurrence of symptoms.
• Selective Estrogen Receptor Modulator (SERM) – Selective estrogen receptor modulators like tamoxifen or raloxifene have been tried in the treatment of endometriosis [rx] based on observations that SERMs may reduce endometriosis lesion in mouse [rx]; however, their value in the treatment of adenomyoma has not been formally explored.
• Aromatase Inhibitors – Like endometriosis, adenomyotic deposits are estrogen-dependent. Aromatase inhibitors inhibit the conversion of estrogen from androgens, thereby lowering the synthesis of estrogen. A prospective randomized controlled study found that the efficacy of aromatase inhibitors (letrozole 2.5 mg/day) in reducing the volume of adenomyoma as well as improving adenomyosis symptoms was similar to that of GnRH agonists (goserelin 3.6 mg/month) [rx] [rx].
• Ulipristal Acetate – Ulipristal acetate (UPA) is a potent selective progesterone receptor modulator. There is good evidence to suggest that it can be used to shrink fibroid and control menorrhagia [rx, rx]. It is possible that it may be similarly effective in the treatment of adenomyoma but literature data is lacking.
• Antiplatelet Therapy – There is new evidence to suggest the role of antiplatelet therapy in treating adenomyosis. Emerging evidence suggests that endometriotic lesions are wounds undergoing repeated tissue injury and repair (ReTIAR), and platelets induce epithelial-mesenchymal transition (EMT) and fibroblast-to-myofibroblast transdifferentiation (FMT), leading ultimately to fibrosis. Adenomyotic lesions are thought to have similar pathogenesis to that of endometriosis. A recent study in mice suggests that antiplatelet treatment may suppress myometrial infiltration, improve generalized hyperalgesia, and reduce uterine hyperactivity [rx].
• Uterine Artery Embolization – Uterine artery embolization (UAE) has been used to treat symptomatic fibroids since the 1990s. There is increasing evidence to suggest that it is also effective in the treatment of the management of adenomyosis. [rx][rx].
• High-Intensity Focused Ultrasound – High intensity focused ultrasound (HIFU) is another nonsurgical treatment for uterine fibroids that focuses high-intensity ultrasound on the target lesion causing coagulative necrosis and shrinkage of the lesion. Both MRI and USG can be used for guidance for the procedure. MRI has better real-time thermal mapping during the HIFU treatment. [rx, rx] [rx].
• Endomyometrial Ablation or Resection – There is a limited report on the use of laparoscopic or hysteroscopic endometrial in treating adenomyosis in the literature. The success rate of myometrial electrocoagulation ranges from 55 to 70% as reported [rx]. [rx]MRI treated with laparoscopic bipolar coagulation, having significant reduction or the resolution of dysmenorrhea or heavy menstrual bleeding.
• GnRH Analogue Therapy before In Vitro Fertilization – Several studies have shown that pretreatment with GnRH analog before IVF treatment improved pregnancy outcome. Zhou et al. [rx] analyzed the clinical efficacy of leuprorelin acetate in the treatment of uterine adenomyosis with infertility. They found that, after 2–6 months of leuprorelin acetate therapy, the mean uterine volume was significantly reduced from 180 ± 73 cm³ to 86 ± 67 cm³, leading to an improvement in embryo implantation and clinical pregnancy rates.
• Stimulation Protocol – In women without pre-IVF GnRH analog therapy as described above, a long GnRH analog protocol should be considered as it helps to induce decidualization of the adenomyotic deposits rendering the disease inactive. Tao et al. [rx] showed that GnRH antagonist protocol appears to be inferior to GnRH agonist long protocol cycle, and the latter appeared to be associated with increased pregnancy and decreased miscarriage rates.
• Two-Staged In Vitro Fertilization – In women with adenomyosis, a two-staged in vitro fertilization could be considered. Patients can undergo ovarian stimulation, oocyte retrieval, and fertilization followed by frozen-thawed embryo transfer (FET) at a later stage. Prior to the FET, GnRH analog suppression therapy for 3 months or so leads to shrinkage of the adenomyosis. FET in the first HRT cycle following GnRH analog suppression therapy, before the adenomyosis lesion regrows to its pretreatment size and exerts its adverse impact on implantation, may improve the result.
• Mock Embryo Transfer – Performing a mock embryo transfer is desirable in women with adenomyosis, as it may help to assess the uterine cavity length and position, choose the correct transfer catheter, and alert the clinicians any extra precautions (e.g., use of tenaculum or cervical dilatation). Mock embryo transfer is particularly desirable in those with an enlarged uterus or distorted uterine cavity.
• Single Embryo Transfer – Adenomyosis has been reported to be associated with an increased incidence of preterm delivery, preeclampsia, and second-trimester miscarriage when compared with the control group [rx]. Consequently, multiple pregnancies should be avoided and so single embryo transfer should be advised. Women who had adenomyomectomy prior to IVF should also be advised to have SET to avoid multiple pregnancies with a view to minimizing the risk of scar rupture.
• HRT Protocol in Frozen-Thawed Embryo Transfer (FET) Cycle – GnRH agonist pretreatment to suppress the pituitary ovarian axis prior to hormone replacement therapy to prepare the endometrium in FET cycles appeared to improve the outcome compared with hormone replacement therapy without downregulation. In a study including 339 patients with adenomyosis, 194 received long-term GnRH agonist plus HRT (downregulation + HRT) and 145 with HRT alone. [rx].
• Uterine Contractility and Atosiban Therapy – Several functional studies showed that excessive uterine contractility (>5 contractions per minute) has been demonstrated in approximately 30% of patients undergoing embryo transfer and this may have a significant adverse impact on subsequent embryo implantation and clinical pregnancy rates [rx]. The incidence of abnormal contractility appeared to be higher in women with adenomyosis [rx] which may in part explain the higher incidence of reproductive failure observed in this group of women. Recurrent Implantation Failure – Recurrent implantation failure is diagnosed when there is a failure to achieve a clinical pregnancy after the transfer of at least four good-quality embryos in a minimum of three fresh or frozen cycles in a woman under the age of 40 years [rx]. It is known that adenomyosis is associated with recurrent implantation failure [rx]. Women with recurrent implantation failure should be offered a 3D scan or MRI to establish if there is adenomyosis; if adenomyosis is present, the above management strategies should be adopted to improve the outcome.

Hormones and hormone modulators

• Levonorgestrel-releasing intrauterine devices or hormonal IUDs – such as the Mirena, are an effective treatment for adenomyosis.^[rx] They reduce symptoms by causing decidualization of the endometrium, reducing or eliminating menstrual flow.^[rx] Additionally, by helping downregulate estrogen receptors, hormonal IUDs shrink the clusters of endometrial tissue within the myometrium. This leads to reduced menstrual blood flow, helps the uterus contract more properly, and helps to reduce menstrual pain. The use of hormonal IUDs in patients with adenomyosis has been proven to reduce menstrual bleeding, improve anemia and iron levels, reduce pain, and even result in an improvement of adenomyosis with a smaller uterus on medical imaging.^[rx][rx] 
• Oral contraceptives  – reduce the menstrual pain and bleeding associated with adenomyosis. This may require taking continuous hormone therapy to reduce or eliminating menstrual flow. Oral contraceptives may even lead to short-term regression of adenomyosis.
• Progesterone or Progestins – Progesterone counteracts estrogen and inhibits the growth of endometrial tissue. Such therapy can reduce or eliminate menstruation in a controlled and reversible fashion. Progestins are chemical variants of natural progesterone.
• Gonadotropin-releasing hormone (GnRH) – agonists and danazol have been tried in order to relieve adenomyosis related symptoms and show some effect, but the studies are few, mainly with a retrospective study design and have small sample sizes.^[rx] Long-time use of GnRH-analogues is often associated with heavy side effects, loss of bone density and increased risk of cardiovascular events, and therefore not feasible for young women. Furthermore, all present treatment options are irrelevant options for women trying to conceive. Exogenous progestogenic treatments have been found to be ineffective.^[rx] In IVF-settings long down-regulation prior to IVF might have a positive effect on pregnancy rates.^[rx]

Surgery

Uterine-sparing procedures

• Uterine artery embolization (UAE) – In this minimally-invasive procedure, doctors intentionally block two large arteries that supply the uterus, called the uterine arteries. This is performed in order to dramatically reduce the blood supply to the uterus. By doing so, there is insufficient blood and thus oxygen present for the adenomyosis to develop and spread.  57-75% of women who undergo UAE for adenomyosis typically report long-term improvement in their menstrual pain and bleeding. However, there is a recurrence rate of symptoms in 35% of women following a UAE. 
• Myometrium or adenomyoma resection – In this procedure, surgeons remove a focal consolidation of adenomyosis known as an adenomyoma. To be successful this procedure requires that the adenomyosis is relatively focally isolated and with a minimal diffuse spread. Unfortunately, adenomyosis is commonly diffuse and the operation is successful only 50% of the time. The procedure is performed with either a laparoscope or hysteroscope.^[rx]
• Myometrial electrocoagulation^[rx]
• Myometrial reduction^[tx]
• MRI-guided focused ultrasound surgery^[rx]

Endometrial ablation and resection

• Endometrial ablation techniques –  are only for women who have completed their childbearing. The techniques either include physical resection and removal of the endometrium through a hysteroscope or focus on ablating or killing the endometrial layer of the uterus without its immediate removal. Endometrial ablation and resection techniques are most appropriate for shallow adenomyosis. The efficacy of the procedures is reduced if the adenomyosis is too widespread or deep. Furthermore, deep adenomyosis may become trapped behind a scarred region that was ablated, leading to further bleeding and pain. Endometrial resection is also limited to relatively shallow adenomyosis as significant bleeding may result from damage to large arteries that are present 5 mm deep within the myometrium.^[rx]
• Non-hysteroscopic procedures – These techniques do not require a hysteroscope are relatively fast, and many can be performed as an outpatient procedure.
• Thermal balloon – Using a thin expanding balloon placed within the uterus, providers can introduce heated fluid and ablate the endometrium. This procedure has been shown to result in amenorrhea or complete cessation of menstrual bleeding for 12 months in 23% of patients. 16% of patients eventually experience treatment failure with pain or bleeding requiring additional treatments or a hysterectomy. ^[9]
• Cryo-endometrial ablation (CEA) – A form of cryotherapy whereby using a small probe, providers can directly apply sub-zero temperatures within the uterus to freeze and ablate the endometrium.
• Circulating Hot Water – Heated water directly introduced into the uterus is used to thermally ablate the endometrium.
• Microwave ablation – Using a small probe introduced into the uterus, a provider uses microwave energy to ablate the endometrium.
• High-energy radiofrequency ablation – Using a small expandable mesh placed within the uterus, providers use high-energy radio waves to ablate the endometrium.
• Hysteroscopic procedures: These techniques all require the use of a hysteroscope to perform.
  • Wire-loop resection – Under direct visualization through a hysteroscope, a wire loop instrument charged with an electric current permits a provider to carefully remove the endometrium in strips.
  • Laser ablation – Under direct visualization through a hysteroscope, lasers are used to vaporize and ablate the endometrium.
  • Rollerball ablation – Under direct visualization through a hysteroscope, a metallic ball on the end of a probe is charged with electricity and rolled across the surface of the endometrium. This has been shown to have a coagulative effect to the depth of 2–3 mm into the myometrium. This destroys the endometrium and the nearby growth of dysfunctional smooth muscle. Deeper adenomyosis escapes this coagulative effect.^[9]

References

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