4.5 Malignant Rhabdoid Tumor of the Kidney

4.5Malignant Rhabdoid Tumor of the Kidney

4.5.1Introduction

•Malignant rhabdoid tumor (MRT) is a rare and very aggressive renal tumor that occurs mainly in children.

•The term rhabdoid was used due to its similarity with rhabdomyosarcoma. The tumor cells resemble muscle cells under the light microscope.

•It was originally described as a variant of Wilms’ tumor.

•Malignant rhabdoid tumor was initially described in 1978 as a rhabdomyosarcomatoid variant of a Wilms tumor because of its occurrence in the kidney and because of the resemblance of its cells to rhabdomyoblasts.

•The absence of muscular differentiation led Haas and colleagues to coin the term rhabdoid tumor of the kidney in 1981.

•It is now recognized as an entity separate from a Wilms tumor.

•In contrast to a Wilms tumor, a malignant rhabdoid tumor of the kidney is characterized by the early onset of local and distant metastases and resistance to chemotherapy.

•Malignant rhabdoid tumor of the kidney is a highly aggressive, has a poor prognosis, and tend to occur in children less than 2 years of age.

•Malignant rhabdoid tumor of the kidney is a rare, highly aggressive malignancy of early childhood and accounts for approximately 2 % of pediatric renal malignancies.

•Malignant rhabdoid tumors of the kidneys are more common in infants.

•Most patients with malignant rhabdoid tumor of the kidney are younger than 2 years of age at presentation.

•The median age at diagnosis is 10.6 months, with a mean age of 15 months.

•The majority are diagnosed between 6 and 12 months of age.

•It occurs exclusively in children, with 60 % occurring before the age of 1 year of age, and 80 % before the age of 2 years.

•The age at presentation of malignant rhabdoid tumor of the kidney overlaps with that noted for congenital mesoblastic nephroma.

•It is more common in males with a male to female ratio of 1.5:1.

•Clinically, patients may develop hypercalcemia secondary to elevated parathormone levels.

•Rhabdoid tumor has the worst prognosis of all renal tumors. It is highly aggressive and metastasizes early, with most patients presenting with advanced disease.

•Eighty percent develop metastases, most commonly to the lungs and less often to the liver, abdomen, brain, lymph nodes, or skeleton.

•Survival is poor, with an 18-month survival rate of only 20 %.

•A key to the diagnosis is negativity of immunohistochemistry for SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, sub-family B, member 1 INI1 (SMARCB1).

•There is no standard treatment for MRT and prognosis is very poor with published overall survivals of 15–36%, however more recent treatment regimens including surgery, radiotherapy, high dose chemotherapy and autologous stem cell rescue (HDCT/ASCR) may improve survival.

•Malignant rhabdoid tumors occur at other sites outside the kidney including:

–The liver

–Soft tissues

–Lung

–Skin

–Heart

–The central nervous system

–The cerebellum is the most common location for primary intracerebral MRT

•Abnormalities in chromosome 22 (commonly deletions of the INI1 gene in chromosome 22) are commonly seen in patients with MRT.

•About 10–15 % of patients with MRTs have synchronous or metachronous brain tumors, many of which are second primary malignant rhabdoid tumors.

•The brain tumors may precede or appear several years after the detection of malignant rhabdoid tumor of the kidney.

•For this reason, brain MRI is part of the workup of these patients and a close follow-up is also important in these patients.

•Malignant rhabdoid tumor of the kidney can be diagnosed in utero.

•The presentation of these patients include:

–An abdominal mass

–Hypertension

–Hypercalcemia

–Fever

–Hematuria

•The clinical and radiological images characteristics of malignant rhabdoid tumors of the kidney are similar to those of congenital mesoblastic nephroma, clear cell sarcoma of the kidney, and Wilms’ tumor.

•Whereas the overall survival rate for Wilms tumors exceeds 85 %, the survival rate for renal malignant rhabdoid tumors is only 20–25 %.

4.5.2Etiology and Pathophysiology

•Malignant rhabdoid tumors frequently contain deletions at chromosome locus 22q11.1.

•This locus contains the SWI/SNF related, matrix-associated, actin-dependent regulator of chromatin, subfamily B, member 1 (SMARCB1) gene.

•SMARCB1 encodes a member of the human SWI/SNF complex.

•SMARCB1 is presumed to function as a classic tumor suppressor and the primary gene responsible for malignant rhabdoid tumor development.

•CNS atypical teratoid/rhabdoid tumors (AT/ RT) have deletions of the SMARCB1 gene.

•This suggests that rhabdoid tumors of the kidney and brain are identical or closely related entities.

•Moreover, 10–15 % of patients with malignant rhabdoid tumors have synchronous or metachronous brain tumors, many of which are second primary malignant rhabdoid tumors.

•Germline SMARCB1 mutations were detected in some of these patients.

•This is estimated to occur in approximately 15–30 % of patients with malignant rhabdoid

tumor.

•Although mutations or deletions of the SMARCB1/INI1 gene play a role in the development of malignant rhabdoid tumor, the triggering mechanisms for these genetic alterations are unknown.

•Several cases of familial malignant rhabdoid tumor were also reported.

•No environmental or infectious associations with malignant rhabdoid tumor have been established.

4.5.3Histologic Findings

•Grossly, malignant rhabdoid tumor of the kidney are heterogeneous, bulky, lobulated, friable, solid, gray-tan masses with areas of necrosis and hemorrhage (Figs. 4.79, 4.80, and 4.81).

•On microscopic examination, malignant rhabdoid tumors are characterized by the followings:

–Sheets or solid trabeculae of tumor cells.

–The tumor cells are large with vesicular nuclei, prominent cherry-red nucleoli.

–The tumor cells are characterized by an abundant eosinophilic cytoplasm.

–Many tumor cells have a distinct, pale or hyaline pink intracytoplasmic rhabdoid inclusion in the cytoplasm.

–Mitoses are frequent and necrosis is common.

–A subset of tumors may be composed predominantly of primitive undifferentiated small round blue cells.

–Other patterns described as sclerosing (including chondroid), epithelioid, spindled, lymphomatoid or histiocytoid, and vascular may coexist with the classic pattern.

–Malignant rhabdoid tumor of the kidney typically has an infiltrative border with the surrounding nonneoplastic cortex and renal medulla.

•The most useful ultrastructural findings include:

–A large whorl of intermediate filaments in the cytoplasm with a diameter of 8–10 nm.

–Dilated rough endoplasmic reticulum

–Rudimentary cell junctions

–Cytoplasmic tonofilamentlike bundles

–Immunohistochemical examination: The tumor cells are polyphenotypic with consistent staining for vimentin.

–The tumor cells are positive for epithelial membrane antigen and/or cytokeratin.

–The tumor cells are positive for glial fibrillary acidic protein, neuron-specific enolase, smooth muscle actin, desmin, and CD99.

–Malignant rhabdoid tumor lacks INI1 immunohistochemical staining.

4.5.4Clinical Features

•Malignant rhabdoid tumor is a rare tumor.

•It accounts for about 1.6 % of all childhood renal tumors.

•Malignant rhabdoid tumor occurs slightly more frequently in males than in females, with male-to-female ratio of 1.4:1.

•The median age at presentation is 10.6 months, with a mean age of 15 months.

•Most patients are younger than 2 years at presentation.

•The usual presentation is an abdominal mass but the initial manifestation may be due to metastatic disease.

•It is highly aggressive and metastasizes early, with up to 80 % of patients presenting with metastatic disease, typically to the lungs and less often to the liver, abdomen, brain, lymph nodes, or skeleton.

•The mass may be noticed by the parents usually during clothing or while giving a bath to the child.

•Sometimes, the mass is discovered by the primary care physician or pediatrician.

•The mass may reach a large in size.

•Sometimes they present with pain or more commonly fussiness.

•Gross hematuria is a presenting feature in approximately 60 % of patients.

•This is in contrast to patients with Wilms tumor where only 20 % of patients have gross hematuria.

•Fever is a presenting symptom in 50 % of patients

•This is in contrast to patients with Wilms tumor where only 25 % of patients have fever.

•As many as 20 % of patients with a rhabdoid tumor of the kidney have synchronous or metachronous CNS tumors, including both metastases and second primary cancers.

•Hypertension is observed in up to 70 % of patients.

•There may be evidence of focal neurologic signs or increased intracranial pressure in light of the prevalence of synchronous CNS tumors.

4.5.5Investigations and Diagnosis

•The definitive diagnosis of malignant rhabdoid tumor (MRT) is by means of histologic analysis.

•CBC count:

–Approximately 55 % of patients with malignant rhabdoid tumor present with a hemoglobin level of less than 9 g/dL.

–Only 25 % of patients with Wilms tumor are anemic at presentation.

•Urinalysis:

–Microscopic hematuria is seen in 75 % of patients with malignant rhabdoid tumor.

–Approximately 25 % of patients with malignant rhabdoid tumors have proteinuria.

•Serum calcium measurement:

–As many as 25 % of patients with malignant rhabdoid tumor present with hypercalcemia.

–This finding is attributed to the ectopic production of parathyroid hormone-related protein by the tumor.

–Hypercalcemia is uncommon in Wilms

tumor but is associated with congenital mesoblastic nephroma.

•Liver function test:

–These may be abnormal in infants and children with metastases from a renal malignant rhabdoid tumor.

•No pathognomonic radiological features help distinguishing malignant rhabdoid tumor from the other renal tumors of childhood.

•There are however several features that may raise the suspicion for malignant rhabdoid tumor.

•Abdominal CT-scan and MRI (Figs. 4.82, 4.83, 4.84, 4.85, 4.86, and 4.87):

–Malignant rhabdoid tumor typically appears as a large, lobulated mass in the center or periphery of the kidney.

–The margins of the tumor may be sharply defined from the adjacent renal parenchyma, or they may be indistinct.

–Tumoral lobules are often separated by hypoattenuating areas of hemorrhage or necrosis.

–Calcification occurs frequently in malignant rhabdoid tumor.

–Malignant rhabdoid tumor–associated calcifications are often linear or curvilinear, and they may outline tumor lobules

–This is in contrast to Wilms tumor where calcification is seen in about 10 % only.

–Calcification is rarely seen in children with clear cell sarcoma or congenital mesoblastic nephroma.

–A peripheral, subcapsular, crescent-shaped fluid collection is often seen in association with malignant rhabdoid tumor.

–These subcapsular fluid collections may be due either to hemorrhage or tumor necrosis.

–Subcapsular fluid collections are more common in patients with malignant rhabdoid tumor of the kidney than with the other renal neoplasms that occur in children.

–The relative frequency of subcapsular fluid collection in different pediatric renal tumors of the kidney is as follows:

•Malignant rhabdoid tumor of the kidney (70 %)

•Wilms tumor (9 %)

•Mesoblastic nephroma (14 %)

•Clear cell sarcoma of the kidney (25 %)

•Chest CT-scan:

– The lungs remain the most common site of metastases from malignant rhabdoid tumor of the kidney.

– Lungs metastases are seen in 83 % of patients with metastatic malignant rhabdoid tumor at diagnosis.

– The metastases is usually bilateral.

•Abdominal ultrasonography:

– This is important to demonstrate invasion of the renal vein and/or the inferior vena cava in patients with malignant rhabdoid tumor.

•Radiological evaluation of the brain is indicated to exclude the possibility of a synchronous primary or metastatic brain tumor.

•Bone Scan:

– Bone metastases are present in 5 % of infants and children with metastatic malignant rhabdoid tumor at diagnosis.

– A bone scan is important to exclude bone metastases.

•Tissue biopsy is required to make a definitive diagnosis of malignant rhabdoid tumor.

•Bone marrow aspiration and biopsy are not routinely necessary because malignant rhabdoid tumor rarely metastasizes to the bone marrow.

•Lumbar puncture is not routinely indicated

unless a CNS tumor is diagnosed.

•Rhabdoid tumors of the kidney appear as large, centrally located, heterogeneous softtissue masses, involving the renal hilum with indistinct margins.

•Rhabdoid tumors are large and heterogeneous, usually located centrally within the kidney.

•They are lobulated with individual lobules separated by intervening areas of decreased attenuation, relating to either previous hemorrhage or necrosis.

•The histologic diagnosis of malignant rhabdoid tumor depends on identification of characteristic rhabdoid cells:

–These are large cells with eccentrically located nuclei and abundant, eosinophilic cytoplasm.

•Calcification is relatively common, seen in 20–50 % of cases and is typically linear and tends to outline tumor lobules.

•Subcapsular fluid accumulation is said to be a relatively characteristic feature, not often seen in other pediatric renal tumors.

•The INI1 gene (SMARCB1) on chromosome 22q functions as a classic tumor suppressor gene.

•Deletions or LOH of 22q in 49/51 was also found in rhabdoid tumors.

•There have been reported cases of a child having both atypical teratoid rhabdoid tumors in the brain as well as rhabdoid tumors of the