Nephroblastoma – Causes, Symptoms, Diagnosis, Treatment

Nephroblastoma is the most common renal cancer in the pediatric age group.[rx][rx] It is also the most common pediatric abdominal cancer, and the fourth most common pediatric cancer overall.  Wilms tumor is typically found in children younger than five years old. The tumor is named after the German physician, Dr. Max Wilms, who first described it in 1899.

Wilms’ tumor (WT) is the most common pediatric renal tumor, which can present as a single nodule, as multifocal unilateral lesions or as bilateral tumors. Typically, WT comprises three histological components namely blastemal, epithelial and stromal. The proportion and the degree of maturation of these components vary significantly, making the histological appearance of each tumor unique. Classical triphasic WT rarely presents a diagnostic difficulty for pathologists, but when only one component is present, especially in a small biopsy specimen, the differential diagnosis may include renal cell carcinoma, metanephric adenoma and hyperplastic nephrogenic rest for epithelial elements and clear cell sarcoma of the kidney, mesoblastic nephroma and synovial sarcoma for stromal elements. Pure blastemal-type WT may be difficult to distinguish from other embryonal ‘small round blue cell tumors’, including neuroblastoma, primitive neuroectodermal tumor/Ewing sarcoma, desmoplastic small round cell tumor and lymphoma.

Synonyms of Nephroblastoma

• embryoma kidney
• nephroblastoma
• embryonal adenosarcoma
• embryonal nephroma
• kidney Wilms tumor
• kidney, adenomyosarcoma, embryonal
• kidney, carcinosarcoma, embryonal
• kidney, embryoma
• kidney, embryonal mixed tumor
• nephroblastoma
• nephroma
• renal adenosarcoma
• renal cancer, Wilms
• renal Wilms tumor
• tumor, Wilms
• Wilms’ tumor

Types of Nephroblastoma

Wilms’ tumors can also be classified by looking at the tumor cells under a microscope. This process is called histology.

• Unfavorable histology – Unfavorable histology means that the tumors have a nucleus in the cells that looks very large and distorted. This is referred to as anaplasia. The more anaplasia, the harder the tumor is to cure.
• Favorable histology – Favorable histology means that there is no anaplasia. Over 90 percent of Wilms’ tumors have favorable histology. This means most tumors are easier to cure.

Causes of Nephroblastoma

The cause of Wilms tumor is not precisely known, but it is believed to be due to genetic alterations that deal with the normal embryological development of the genitourinary tract. Some of the genetic markers that have been associated with Wilms tumor include WT1, CTNNB1, and WTX gene alterations that have been found in about 1/3 of all Wilms tumors.  Other genes associated with Wilms tumor include TP53 and MYNC.  A poorer prognosis has been linked to TP53 and with the loss of heterozygosity at chromosomes 1p, 1q, 11p15 and 16q.[rx][rx]

Only about 1% of Wilms patients have a relative with the disease who is typically not a parent.

Wilms is thought to develop from persistent metanephric tissue or nephrogenic rests. These may occur in 1% of infantile kidneys but typically regress during childhood. These abnormal metanephric cells are found in up to 100% of cases of bilateral Wilms but only 35% of unilateral tumors.[rx]

Hemihypertrophy and aniridia as well as a variety of urological disorders like cryptorchidism, horseshoe kidney, and hypospadias, are associated with the malignancy although it is unlikely they play any role in actual carcinogenesis. Bilateral disease represents only about 5% of all patients with Wilms tumor and is more commonly found in girls.

Diagnosis of Nephroblastoma

Histopathology

Grossly, Wilms tumors are usually well-circumscribed and have a pseudo-capsule. Histologically, Wilms is divided into “Favorable” and “Unfavorable” histologies.

• “Favorable” Histology – Ninety percent 90% of Wilms tumors will demonstrate “favorable” histology which generally has a better prognosis.  Classical histological features of a “favorable” Wilms tumor include a triphasic pattern of blastema, epithelial, and stromal tissues.  The blastema is the most undifferentiated and possibly the most malignant component.  It consists of collections of small, round blue cells with very active mitotic activity and overlapping nuclei.

The epithelial component can demonstrate wide variations in differentiation from an early tubular formation with primitive epithelial rosette-like structures to differentiating tubules or glomeruli-like structures, which represent nephrogenesis at different developmental stages.

The stromal component may include densely packed undifferentiated mesenchymal cells or loose cellular myxoid areas. The latter areas may be difficult to distinguish from non-tumorous stroma associated with chemotherapy-induced change. Heterologous differentiation of neoplastic stroma in the form of well-differentiated smooth or skeletal muscle cells, fat tissue, cartilage, bone, and even glial tissue is present in some cases, especially in tumors that have undergone preoperative chemotherapy.

Even with “Favorable” histology, the loss of heterozygosity at 1p and 16q loci tend to have a worse prognosis. For this reason, when Wilms tumor tissue is available, it should be checked cytogenetically for 1p and 16q deletions.

• “Unfavorable” Histology – Wilms tumors with “unfavorable” histology will demonstrate much higher degrees of anaplasia and are associated with a relatively poorer prognosis and survival.
• Anaplasia is histologically defined as hyperchromatic, pleomorphic nuclei that are three times larger than adjacent cells and have abnormal mitotic figures. Anaplasia is associated with a poor response to treatment.

History and Physical

Wilms tumor usually presents as an asymptomatic abdominal mass in the majority of children. The mother may have discovered the mass during bathing the infant. Other features include:

• Abdominal pain
• Gross hematuria
• Urinary tract infections
• Varicocele
• Hypertension or hypotension (Up to 1/3 of Wilms patients will demonstrate hypertension which normalizes after nephrectomy)
• Fever
• Anemia
• If the patient has lung metastases, dyspnea or tachypnea may occur.

Abdominal pain is the most common initial presenting symptom (30% to 40%) followed by hypertension (25%), and hematuria (12% to 25%).

Tests and procedures used to diagnose and stage Wilms tumor and other childhood kidney tumors include the following:

• Physical exam and history. Children with a renal mass are carefully assessed for signs of associated syndromes such as aniridia, developmental delay, hypospadias, cryptorchidism, pseudohermaphrodism, overgrowth, and hemihyperplasia.
• Complete blood count (CBC).
• Liver function test.
• Renal function test.
• Urinalysis.

• Abdominal imaging.

  • Abdominal x-ray.
  • Ultrasonography exam of the abdomen. Ultrasonography exam of the abdomen is often performed before a more definitive computed tomography (CT) scan with contrast or magnetic resonance imaging (MRI) with the contrast of the abdomen is done. This procedure is unnecessary after the definitive diagnostic study has been performed.
  • CT scan with contrast or MRI of the abdomen.[rx]

    -CT scan of the abdomen will confirm the renal origin of the mass and determine whether there are bilateral tumors.[rx] About 5% of renal masses thought to be Wilms tumor on the basis of clinical and radiological findings are diagnosed as another condition.[rx]

    -A review of children with bilateral Wilms tumor demonstrated that only 0.25% of bilateral tumors were missed with modern helical CT scans, all of which were small tumors.[rx]

    -Preoperative assessment by imaging of intravascular extension of Wilms tumor is essential to guide management. Four percent of Wilms tumor patients present with inferior vena cava or atrial involvement and 11% with renal vein involvement, which may lead to differences in management. Embolization of a caval thrombus to the pulmonary artery is rare but can be lethal, and the presence of a thrombus must be identified preoperatively to prevent this occurrence and guide treatment. A report from the COG shows that CT can accurately identify cavoatrial thrombus, obviating the need for ultrasonography if CT has already been performed.[rx]

    -Ascites beyond the cul-de-sac is most predictive of preoperative Wilms tumor rupture, regardless of attenuation. In the presence of ascites, fat stranding around the tumor and the presence of retroperitoneal fluid are highly predictive of rupture.[137]

• A chest x-ray is unnecessary if a chest CT is performed initially.
• CT scan of the chest. The common sites of metastases for Wilms tumor are the lung and liver. Approximately 15% of patients will present with pulmonary metastases. CT scanning provides the most sensitive method of detecting metastatic lung nodules.
• Fluorine F 18-fludeoxyglucose (18F-FDG) positron emission tomography (PET)-CT. Wilms tumor is 18F-FDG avid, and 18F-FDG PET-CT imaging adds clinically applicable information to conventional CT scan imaging. PET-CT may be particularly helpful in patients with bilateral disease or those receiving preoperative chemotherapy. 18F-FDG PET-CT highlights FDG-avid areas in the tumor and metastases, which corresponds to histologically confirmed active disease.[rx]
• von Willebrand disease work-up. About 1% to 8% of patients presenting with Wilms tumor have an acquired form of von Willebrand disease, although many are asymptomatic. von Willebrand multimers bind to Wilms tumor, reducing the plasma concentration to low levels.[rx] Some clinicians recommend evaluation for von Willebrand disease before surgery.
• Biopsy or resection and the issue of bilateral Wilms. In children with a renal mass that clinically appears to be resectable Wilms tumor, biopsy is not performed so that tumor cells are not spread during the biopsy. A biopsy would upstage such a patient to stage III. In North America, the initial treatment in most cases is primary nephrectomy. If a primary nephrectomy cannot be performed, a biopsy, either open or with multiple cores, is required. The contraindications to primary nephrectomy are the following:

  • Extension of tumor thrombus to the level of the hepatic veins. These patients should be considered for tumor resection after neoadjuvant chemotherapy when there is evidence of regression of the vena caval thrombus regardless of the degree of response of the primary tumor.
  • The tumor involves contiguous structures whereby the only means of removing the kidney tumor requires removal of the other structure (e.g., spleen, pancreas, colon but excluding the adrenal gland and diaphragm). While Wilms tumors are frequently adherent to adjacent organs, in most cases, there is not frank invasion by the tumor and the organs can be dissected freely from the tumor. Radical en bloc resection (e.g., partial hepatectomy) is not generally warranted. If removal of a small section of diaphragm, psoas muscle, or tip of the pancreas allows the tumor to be removed intact, this is considered safe and appropriate.
  • The surgeon’s judgment that nephrectomy would result in significant or unnecessary morbidity/mortality, significant tumor spill, or residual tumor.[143]
  • If there is pulmonary compromise because of extensive pulmonary metastases or, in rare cases, hepatic disease.
• Lymph node sampling is required to locally stage all Wilms tumor patients. Lymph nodes have shown to be of major prognostic value for both short-term and long-term survival. Gross inspection is notoriously inaccurate, with a false-negative rate of 31.3% and a false-positive rate of 18.1%.[rx]

About 5% of renal masses thought to be Wilms tumor on the basis of clinical and radiological findings are diagnosed as another condition.[rx]

For patients with suspected Wilms tumor, additional preoperative staging studies are performed to assess intravascular extension or rupture of Wilms tumor.[rx]

• Intravascular extension of the Wilms tumor. Preoperative assessment of intravascular extension of Wilms tumor is essential to guide management. The presence of intravenous tumor thrombus in the lumen of the renal vein, inferior vena cava, and right atrium has been reported in up to 11.3% of Wilms tumor patients and may lead to differences in management.[rx]
• Wilms tumors can rupture before surgery. The term rupture is used to imply a break in the tumor capsule before surgery, whereas the term spill refers to a break in the tumor during surgery. Based on their similar diagnostic performances, either CT or MRI can be used to detect rupture. Although imaging findings of rupture have high specificity (88%), the diagnosis of rupture has to be confirmed at surgery. Imaging alone cannot be used for initial staging because of the low sensitivity and specificity for preoperative rupture and lymph node status.[rx]

Evaluation

The usual labs are not specific for Wilms tumor but need to be ordered to look for other pathologies. Routine blood work includes:[rx][rx][rx][rx]

• Complete blood count to look for anemia
• Chemistry profile
• Renal function
• Urinalysis
• Coagulation studies
• Cytogenetics studies to look for 1p and 16q deletion.

Imaging studies utilized include the following:

• Renal ultrasonography (often the initial study) but is operator dependent
• Chest x-ray to look for lung metastases
• Abdominal and chest CT with sedation
• Abdominal MRI is an optional study.

Imaging is particularly important in surgical planning. Surgical risk factors include larger tumor size, contralateral tumor extension and displacement of the great vessels which typically result in longer surgical times, increased blood loss and higher complications rates.

The most common site of metastases are the lungs, so chest imaging is recommended. Abdominal CT and MRI appear to be about equal in diagnosing Wilms so either can be used. Metastases to bones are uncommon but ominous and typically develop later as a relapse or recurrence.

Recently, MRI diffusion studies have possibly made it easier to differentiate Wilms tumor from neuroblastoma, the other common abdominal malignancy in children. It was found that the apparent diffusion coefficient (ADC) was substantially higher for Wilms. This differentiation is critical as the treatments for these two tumors are different. It was suggested that a cutoff ADC value of greater than or equal to 0.645 × 10 – 3 mm2 per second be used with higher values suggesting Wilms and lower values indicating neuroblastoma. While useful, this will need to be confirmed with additional studies before it can be considered a reliable indicator.

Treatment of Nephroblastoma

Treatment of Wilms tumor/ nephroblastoma is usually nephrectomy followed by systemic chemotherapy, but some protocols initiate chemotherapy first and do the nephrectomy later. The opposite kidney may be explored to ensure that cancer has not spread although this is not necessary for low-stage tumors with favorable histology if imaging is negative. Lymph nodes around the aorta are sampled for staging and to improve survival.[rx][rx][rx][rx]

There is no apparent significant difference in short-term morbidity, mortality out to three years, hospital readmission rate, or surgical margin status between traditional open surgery or minimally invasive techniques.  Open surgery, however, typically provides more lymph nodes in the surgical specimen.

Routine biopsies are not recommended except in unusual circumstances as a biopsy automatically increases tumor staging to Stage III.  This stage requires radiation and chemotherapy.

Postoperative radiation may or may not be administered depending on tumor histology and the extent of spread. For patients without metastases who will be receiving radiation, initiation of therapy within 14 days of surgery appears to improve overall survival.

Combination chemotherapy is usually administered for more aggressive disease. Initial chemotherapy most typically includes vincristine and dactinomycin. Doxorubicin, cyclophosphamide, etoposide, and carboplatin are also used.[14]

In children with bilateral disease, immediate nephrectomy is not performed. Some experts attempt high-dose chemotherapy to kill the tumor cells and hopefully salvage the kidney. Bilateral nephrectomy immediately mandates dialysis, and so all efforts are made to salvage the kidneys. Repeat biopsies are required to determine if the tumor is responding to therapy.  Nephron sparing surgery can be performed in select cases. bilatera[rx]

Patients who relapse after initial combined therapy tend to have a worse prognosis than newly discovered Wilms patients.

The hepatic veno-occlusive disease can occur in patients receiving therapy for Wilms.  It is characterized by right upper quadrant pain associated with jaundice, ascites, weight gain, and/or hepatomegaly. Treatment for the hepatic veno-occlusive disease is mainly supportive.[rx]

Surgery for Wilms’ tumor may include

• Removing part of the affected kidney – Partial nephrectomy involves removal of the tumor and a small part of the kidney tissue surrounding it. A partial nephrectomy may be an option if the cancer is very small or if your child has only one functioning kidney.
• Removing the affected kidney and surrounding tissue – In a radical nephrectomy, doctors remove the kidney and surrounding tissues, including part of the ureter and sometimes the adrenal gland. Nearby lymph nodes also are removed. The remaining kidney can increase its capacity and take over the job of filtering the blood.
• Removing all or part of both kidneys – If cancer affects both kidneys, the surgeon removes as much cancer as possible from both kidneys. In a small number of cases, this may mean removing both kidneys, and your child would then need kidney dialysis. If a kidney transplant is an option, your child would no longer need dialysis.

Prognosis

The prognosis varies by tumor stage and histology. Favorable histology has survival rates of 99% to 86% while unfavorable histology survival ranges from 84% to 38% depending on the stage.[rx][rx][rx][rx]

End-stage renal failure occurs in about 1% of patients; usually due to metachronous bilateral tumors.

A poorer prognosis is associated with the following characteristics:

• Anaplastic histology in stage II to IV tumors
• Diffuse anaplasia is worse than focal
• Loss of heterozygosity at chromosomes 1p, 1q, 11p15 and 16q or presence of TP53
• Higher stage (most epithelial predominant tumors are stage I; most blastema predominant tumors are stage III and IV)
• Age older than two years
• Higher positive lymph node density
• Large tumor size
• Even small tumor foci can be associated with a poorer prognosis due to resistance to chemotherapy

Complications

Radiation and chemotherapy are effective in improving survival in higher stage Wilms tumor patients, but they may also be responsible for an increased risk of secondary malignancies years later. [rx]

It is well established that radiation therapy will increase the risk for bone, breast, colon and thyroid cancers later on in life.  It will also increase the risk of osteoporosis.

Chemotherapy with dactinomycin, doxorubicin and vincristine contributes to a higher risk of secondary malignancies as well as specific toxicities such as hearing (carboplatin), cardiac function (adriamycin) and peripheral neuropathy (vincristine). [rx]

About 5% to 10% of Wilms patients will present with Von Willebrand’s disease which can complicate treatment.  Initial therapy for this should be DDAVP. If not successful, cryoprecipitate (concentrated Von Willebrand Factor) can be used. [rx]

Depending on the drugs used for chemotherapy, your child may also experience unpleasant side effects. These vary from child to child but may include:

• hair loss
• nausea and vomiting
• fatigue
• diarrhea
• anemia
• loss of appetite
• weight loss
• pain
• neutropenia
• mouth sores
• bruising
• sleep problems
• bladder issues
• skin and nail changes
• increased risk of infection

Postoperative and Rehabilitation Care of Wilms tumor/nephroblastoma

Follow-up visits for Wilms tumor are usually scheduled:[rx]

• every 3 months for 2 years after diagnosis
• then every 6 months for another 2 years
• then once every 2 years

Follow-up visits for Wilms tumor may include:

• feeling the abdomen for signs of any local recurrence or a liver tumor
• listening to the lungs for any signs of metastasis
• feeling the thyroid for any growths (if the child had radiation therapy to the chest)
• breast examination in female patients who received radiation therapy to the chest
• check for peripheral neuropathy (a complication of Vincristine therapy)
• check for liver/veno-occlusive disease in patients with right-sided tumors who received radiation therapy

Tests are part of follow-up care. These will include:

• Abdominal ultrasound (yearly is recommended)
• CT scan
• MRI
• Chest x-ray
• Liver function testing
• Renal function blood tests
• Early screening for infertility
• Hearing tests for patients who received carboplatin
• Cardiac function tests, such as an echocardiogram or electrocardiogram at least every 3 years for patients who received doxorubicin (Adriamycin)
• Early screening for colon cancer in patients who received abdominal radiation (should start 10 years after radiotherapy treatment or by age 35, whichever is later)

After lung or chest radiation, the following is added:

• Thyroid-stimulating hormone (TSH) and free thyroxine (T4), to monitor thyroid function
• Thyroid US is recommended every 3 years to screen for thyroid nodules and masses
• Bone density testing should be started 10 years before it would normally be done due to early osteoporosis
• Early screening for breast cancer in women

REferences