Malignant rhabdoid tumor

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Ifeoma Odukwe, M.D. [2], Sujit Routray, M.D. [3]

Synonyms and keywords: Malignant rhabdoid tumour; Malignant rhabdoid neoplasm; Atypical teratoid rhabdoid tumor

Overview

Malignant rhabdoid tumor is an aggressive tumor in the pediatric population. It commonly starts in the kidney (rhabdoid tumor of the kidney) but it can occur in other soft tissues (extrarenal malignant rhabdoid tumor) and the brain (atypical teratoid rhabdoid tumor). It was originally believed to be a rhabdomyosarcomatoid variant of Wilms' tumor because of the cells resemblance to rhabdomyoblasts. It was later determined to be its own distinct clinicopathologic entity because the cells could not demonstrate myogenic differentiation on immunohistochemical studies. Malignant rhabdoid tumor of the kidney accounts for about 2% of all pediatric renal malignancies. The exact cause is unknown but it has been shown to be associated with the mutation of SMARCB1/INI-1 which is a tumor suppressor gene. It may be associated with conditions such as ependymoma and astrocytoma. Some of the histological characteristics of malignant rhabdoid tumor include eosinophilic cytoplasmic inclusions, vesicular nucleus with prominent nucleoli, and moderate to abundant eosinophilic cytoplasm. The incidence of malignant rhabdoid tumor of the kidney is approximately 0.019 per 100,000 individuals per year in the US. Though the tumor is seen mostly in infants, some cases have been reported in adults. The prognosis is poor with the overall survival rate being low. Metastasis is a common cause of death in these patients and most of the tumors metastasize early. Patients experience symptoms based on the location of the tumor. Patients with tumors in the liver may experience abdominal pain, fever, irritability. Those with tumors in the brain present with headache, ataxia, nystagmus. Imaging modalities that may be used in the diagnosis of malignant rhabdoid tumor include CT scan and MRI. They have different findings depending on the tumor location. The treatment depends on the character of the tumor and the circumstances that surround it. Some may be treated with surgical excision and chemotherapy/radiotherapy. Some tumors cannot be treated surgically and may need to rely on chemotherapy. Some common chemotherapeutic agents used include vincristine, cyclophosphamide, doxorubicin, and ifosfamide.

Historical Perspective

• In 1978, Beckwith and Palmar first described malignant rhabdoid tumor of the kidney as a "rhabdomyosarcomatoid variant of wilms tumor" because the cells resembled rhabdomyoblasts. Although with further studies, it was recognized as a distinct clinicopathologic entity because of the inability to demonstrate myogenic differentiation.
• In 1982, Gonzalez-Crussi et al first described malignant rhabdoid tumor of the liver.
• In 1989, Rootman et al were the first to originally describe primary malignant tumor of the orbit.

Classification

There is no established system for the classification of malignant rhabdoid tumor.

Pathophysiology

• Malignant rhabdoid tumor is a rare and aggressive tumor commonly seen in young children. It commonly arises in the kidney but can be seen in various sites including the liver, pelvis, CNS, abdomen, heart and other soft tissues.
• Cytogenetic and molecular analyses have shown that the deletion of chromosome 22q11.2 may be associated with the development of malignant rhabdoid tumor. Through this deletion, which is bi-allelic, the SMARCB1/INI-1 (integrase interactor 1) tumor suppressor gene was discovered and its mutation is believed to contribute to the oncogenesis of renal and extrarenal malignant rhabdoid tumors.
• The tumors may emerge in different ways, either through tumor progression from other types of neoplasms or de novo from non-neoplastic cells. When it arises from other neoplasms with other nonrhabdoid tumor components discovered, the tumors are called composite malignant rhabdoid tumors.
• Rhabdoid tumors can arise in parts of the body outside the kidney such as the urinary bladder, gastrointestinal tract, mediastinum, liver, soft tissue, orbit, uterus, and central nervous system. When it arises in the CNS, it is called atypical teratoid rhabdoid tumor.
• Conditions associated with malignant rhabdoid tumor include pancreatic neuroendocrine tumors, ependymoma, and astrocytoma.
• On gross pathology, malignant rhabdoid tumor of the kidney is characterized by poorly circumscribed soft tan lesion with areas of necrosis. There may be numerous tan-gray nodules present within.
• On microscopic histopathological analysis, malignant rhabdoid tumor is characterized by:

• Round or polygonal cells
• Sheets of anaplastic, noncohesive tumor cells with eccentric nuclei
• Large, vesicular nucleus with prominent nucleoli and moderate to abundant eosinophilic cytoplasm
• Eosinophilic, fibrillar cytoplasmic inclusions
• Intravascular tumor within adjacent soft tissues

Histopathology specimen showing atypical teratoid rhabdoid tumor source: Jensflorian

• It has a similar superficial histological resemblance with rhabdomyosarcoma with tangles of vimentin filaments in the eosinophilic cytoplasm. The difference is the absence of actin and myosin in the cytoplasm which are present in tumors of myogenic origin.
• On immunohistochemical studies, malignant rhabdoid tumor cells are positive for vimentin and pancytokeratin (AE 1–3), but negative for desmin, myoglobin, and S100.
• According to the Children’s Oncology Group (COG) staging system, there are 5 stages of malignant rhabdoid tumor."Types of Children's Cancer".

Staging	Characteristic findings
Stage I	Tumor is involving single kidney and its completely resectable. behind. No tumor mass left behind. Renal capsule isn't breached by surgery. Blood vessels are not involved.
Stage II	Tumor invades beyond the renal capsule into the neighboring fatty tissue or blood vessels, but its completely resectable. No tumor mass left behind. Abdominal or pelvic lymph nodes are tumor-free.
Stage III	Tumor mass that is not completely resectable. Residual tumor is confined to the abdomen. One or more features that may be present that include: Tumor involves abdominal and pelvic lymph nodes Tumor invades the nearby vital structures Tumor implants deposited on the peritoneal surface Spillage of the tumor into th peritoneal cavity before or after surgery Separate excision of the tumor at multiple sites (e.g., kidney and adrenals) Pre-operative biopsy is done
Stage IV	Hematogenous spread of the tumor to distant organs such as lung, brain, bones, liver, or to the distant lymph node meetastasis
Stage V	Tumor observed in bilateral kidneys

Causes

There is no clear cause of malignant rhabdoid tumor but it is believed that the loss-of-function mutation of SMARCB1 tumor suppression gene contributes to the oncogenesis.

Differentiating Malignant Rhabdoid Tumor from Other Diseases

Malignant rhabdoid tumor of the kidney should be differentiated from other diseases that present with hemeturia, abdominal pain and abdominal mass. The following are the differentials:

	S.No.			Disease	Symptoms			Signs		Diagnosis			Comments
Abdominal Pain		Hematuria	Headache		Abdominal mass	Abdominal tenderness	Ultrasonography	CT scan	Histology
1.	Wilms tumor	+	+	-	+	+	It is the best initial diagnostic study used in cases suspected with Wilms tumor. Ultrasonography can help identify the mass as a kidney mass. It can distinguish tumor mass from other causes of renal swelling like hydronephrosis. Doppler ultrasonography can help to detect invasion of renal vein and IVC by the tumor.	Findings on CT scan which can be suggestive of Wilms tumor include: Heterogeneous soft-tissue density masses These masses have frequent areas of calcification (~10%) and fat-density regions Lymph node metastasis CT scan of the renal mass can further reveal: Invasion of surrounding organs Thrombus in or occlusion of the renal vein and/or the inferior vena cava Abdominal lymph nodes and contralateral involvement	Wilms tumor has a triphasic appearance. It is comprised of 3 types of cells: Stromal Epithelial Blastemal All the 3 types are not required for the diagnosis of Wilms tumor. Primitive tubules and glomeruli are often seen comprised of neoplastic cells. Beckwith and Palmer reported in NWTS the different histopathologic types of Wilms tumor to categorize them based on prognosis. Spindled cell stroma surrounding abortive tubules and glomeruli is characteristic. The stroma may include: Striated muscle cartilage bone Fat tissue Fibrous tissue.
2.	Renal cell carcinoma	+	+	+/-	+	-	Ultrasound (US) may be helpful when CT scan results are equivocal. It is noteworthy to mention that not all renal cell carcinomas are detectable on ultrasound.	Both CT and MRI may be used to detect neoplastic masses that may define renal cell carcinoma or metastasis of the primary cancer. CT scan and use of intravenous (IV) contrast is generally used for work-up and follow-up of patients with renal cell carcinoma.	The histological pattern of renal cell carcinoma depends whether it is papillary, chromophobe or collecting duct renal cell carcinoma.
3.	Rhabdoid kidney disease	+	+	-	+	-	Ultrasound shows a complex cystic mass.	CT scan may be diagnostic of malignant rhabdoid tumor. Findings on CT scan suggestive of malignant rhabdoid tumor include a large, heterogenous, centrally located mass, which is lobulated with individual lobules separated by intervening areas of decreased attenuation, relating to either previous hemorrhage or necrosis. Enhancement is similarly heterogeneous. Calcification is relatively common, observed in 20-50% of cases and is typically linear and tends to outline tumor lobules.	Malignant rhabdoid tumor is characterized by the round blue tumor cells of high cellularity composed of atypical cells with eccentric nuclei, small nucleoli, and abundant amounts of eosinophilic cytoplasm with frequent mitotic figures.
4.	Polycystic kidney disease	+	+	+ (from hypertension)	+	-	Ultrasound may be helpful in the diagnosis of polycystic kidney disease. Findings on an ultrasound diagnostic of polycystic kidney disease include: At least three unilateral or bilateral cysts in patients 15 - 39 years old Atleast two cysts in each kidney in patients 40 - 59 years old Atleast four cysts in each kidney in patients 60 years of age or older	Renal CT scan may be helpful in the diagnosis of polycystic kidney disease. Findings on CT scan diagnostic of ADPKD include: Numerous renal cysts of varying size and shape with little intervening parenchyma with water attenuation and very thin wall. Reduction in sinus fat due to expansion of the cortex Occasional complex cysts with hyperdense appearance, with possible septations or calcifications Multiple homogeneous and hypoattenuating cystic lesions in the liver in patients with liver involvement	On microscopic histopathological analysis, interstitial fibrosis, tubular atrophy, thickening and lamellation of tubular basement membranes, microcysts and negative immunofluorescence for complement and immunoglobulin are characteristic findings of ADPKD.
5.	Pheochromocytoma	-	-	+ (as a part of the hypertension paroxysm)	-	-	CT is the preferred imaging modality for the diagnosis of pheochromocytoma.	The following findings may be observed on CT scan: Most common extra-adrenal locations are superior and inferior abdominal paraaortic areas, the urinary bladder, thorax, head, neck and pelvis. In sporadic pheochromocytoma, CT and MRI are good choices. The choice depends on availability and cost. In patients with the multiple endocrine neoplasia type 2 (MEN2) syndrome, CT may miss the tumors.	On microscopic pathology, Pheochromocytoma typically demonstrates a nesting (Zellballen) pattern on microscopy. This pattern is composed of well-defined clusters of tumor cells containing eosinophilic cytoplasm separated by fibrovascular stroma.
6.	Burkitt lymphoma	+/- (in non-endemic or sporadic form of the disease)	-	-	-	-	Abdominal ultrasonography may show splenomegaly and ascites.	Chest, abdomen, and pelvis CT scan may be helpful in the diagnosis of Burkitt's lymphoma but it is not done routinely.	On microscopic histopathological analysis, characteristic findings of Burkitt's lymphoma include: Medium-sized (~1.5-2x the size of a RBC) with uniform size ("monotonous") -- key feature (i.e. tumor nuclei size similar to that of histiocytes or endothelial cells) Round nucleus Small nucleoli Relatively abundant cytoplasm (basophilic) Brisk mitotic rate and apoptotic activity Cellular outline usually appears squared off "Starry-sky pattern": The stars in the pattern are tingible-body macrophages (macrophages containing apoptotic tumor cells. The tumour cells are the sky
7.	Intussusception	+	-	-	+/-	+	Ultrasound is the gold standard imaging modality used to diagnose intussusception Target or doughnut sign Edematous intussuscipien forms an external ring around the centrally located intussusceptum Target sign is usually seen in right lower quadrant Layers of intussusception forms pseudo-kidney appearance on the transverse view	CT scan may be helpful in the diagnosis of intussusception. CT scan maybe used when other image modalities like x-ray and ultrasound have not given positive results but suspicion of intussusception is high.	Intussusception occurs if there is an imbalance between the longitudinal and radial smooth muscle forces of intestine that maintain its normal structure. This imbalance leads to a segment of intestine to invaginate into another segment and cause entero-enteral intussusception. Etiology of intussusception is either idiopathic or pathologic (lead point).
8.	Hydronephrosis	+	+/-	-	-	+ (CVA tenderness in case of pyelonephritis)	Ultrasound allows for visualization of the ureters and kidneys and can be used to assess the presence of hydronephrosis and/or hydroureter.	In the case of renal colic (one sided loin pain usually accompanied by a trace of blood in the urine) the initial investigation is usually an intravenous urogram. This has the advantage of showing whether there is any obstruction of flow of urine causing hydronephrosis as well as demonstrating the function of the other kidney. Many stones are not visible on plain x ray or IVU but 99% of stones are visible on CT and therefore CT is becoming a common choice of initial investigation.	The kidney undergoes extensive dilation with atrophy and thinning of the renal cortex.
9.	Dysplastic kidney	N/A	N/A	N/A	N/A	N/A	MCDK is usually diagnosed by ultrasound examination before birth. Mass of non-communicating cysts of variable size. Unlike severe hydronephrosis, in which the largest cystic structure (the renal pelvis) lies in a central location and is surrounded by dilated calices, in multicystic dysplastic kidney the cyst distribution shows no recognizable pattern. Dysplastic, echogenic parenchyma may be visible between the cysts, but no normal renal parenchyma is seen.	MCKD can be discovered accidentally on CT scan. CT scan shows myltiple cysts with absence of renal parenchyma.	MCKD is the result of abnormal differentiation of the renal parenchyma.
10.	Pediatric Neuroblastoma	+	-	-	+/-	+/-	On ultrasound, neuroblastoma is characterized by a heterogeneous echogenicity due to the vascular, necrotic, and calcified content of the mass.	CT scan is the investigation of choice for the diagnosis of neuroblastoma. On CT scan, neuroblastoma is characterized by: Heterogeneous mass Calcification Necrosis Compression of the surrounding vessels Invasion of the psoas muscle or kidneys Swollen lymph nodes	On microscopic histopathological analysis the presence of round blue cells separated by thin fibrous septa are characteristic findings of neuroblastoma. Other findings of neuroblastoma on light microscopy may include: Homer-Wright rosettes (rosettes with a small meshwork of fibers at the center) Neuropil-like stroma (paucicellular stroma with a cotton candy-like appearance) On electron microscopy neuroblastoma is characterized by: Dendritic processes with longitudinally oriented microtubules Membrane bound electron-dense granules that contain catecholamines Presence of desmosomes Absence of glycogen
11.	Pediatric Rhabdomyosarcoma	+	+/-	+/-	-	+/-		On CT scan, rhabdomyosarocma is characterized by: Soft tissue density Some enhancement with contrast Adjacent bony destruction (over 20% of cases)	Rhadbomyosarcoma has an appearance similar to the other round blue cell tumors such as Ewing sarcoma and small cell osteoblastoma.
12.	Mesoblastic nephroma	+	+	-	+	-	Ultrasound may be helpful in the diagnosis of mesoblastic nephroma. Mesoblastic nephroma may presents as a well-defined mass with low-level homogeneous echoes. The presence of concentric echogenic and hypoechoic rings can be a helpful diagnostic feature of mesoblastic nephroma.	CT scan may be helpful in the diagnosis of mesoblastic nephroma. Findings on CT scan suggestive of mesoblastic nephroma include: Solid hypoattenuating renal lesion Variable contrast enhancement No calcification	Classic mesoblastic nephroma Spindle cells in fascicles Infiltrative border Cellular mesoblastic nephroma Plump cells with vesicular nuclei Well-defined border Mitotically active Mixed mesoblastic nephroma Both classic pattern and cellular pattern areas are present	Most common renal tumor that occurs in 1st month of life

Epidemiology and Demographics

• The incidence of malignant rhabdoid tumor of the kidney is approximately 0.019 per 100,000 individuals per year in the US. That of atypical teratoid/rhabdoid tumor is 0.089 per 100,000 per year, and 0.032 per 1000,000 yearly for the tumors found in other sites.
• Malignant rhabdoid tumor of the kidney accounts for about 2% of all pediatric renal malignancies.
• The mortality rate of malignant rhabdoid tumor is approximately 80%.
• It mostly occur in infants. The median reported age is about 22.5 months.
• Although malignant rhabdoid tumors usually affect children, some cases in adults have been reported with the age at diagnosis ranging from 32 to 60 years.
• It affects females and males equally.

Risk Factors

There are no established risk factors for malignant rhabdoid tumor.

Screening

There is insufficient evidence to recommend routine screening for malignant rhabdoid tumor.

Natural History, Complications, and Prognosis

• Malignant rhabdoid tumors are prone to metastasize early with metastasis being the most common cause of death among patients. Most cases may have already metastasized before the diagnosis is made.
• In most cases, patients die at an average of 6 months after diagnosis.
• Common complications of malignant rhabdoid tumor include spontaneous tumor rupture and thrombotic pulmonary microangiopathy (pulmonary tumor embolism syndrome) which may be seen in adult patients with metastasis to the lungs.
• The 5-year survival rate of malignant rhabdoid tumor is 33%.
• The overall survival rate ranges from between 22% to 42%.
• In adults, the prognosis is poor with the survival time after diagnosis being only a few months.
• Factors associated with significantly reduced survival include metastases/multifocal disease, younger age, infratentorial location, and less than complete remission at the end of chemotherapy.
• Neither tumor volume at diagnosis nor pre-operative chemosensitivity affects the outcome.

Diagnosis

Diagnostic Study of Choice

• The diagnosis of malignant rhabdoid tumor is based on characteristic histopathological features, which include large oval to polygonal cells with abundant eosinophilic cytoplasm, large vesicular nuclei with prominent nucleoli, and conspicuous filamentous cytoplasmic inclusions.
• Immunohistochemistry is important in the diagnosis of malignant rhabdoid tumor. The tumor has a positive immunoreactivity for vimentin, cytokeratin and epithelial membrane antigen. The tumor is usually positive for vimentin with that of cytokeratin and epithelial membrane antigen being variable. it's negative immunoreactivity for muscle markers, histiocytic markers, HMB-45, and S100 protein helps to exclude myogenic and histiocytic neoplasms and malignant melanoma.

History and Symptoms

• Patients with malignant rhabdoid tumor of the kidney may have a positive history of fatigue and abdominal distension.
• A positive history of fever and abdominal distension is suggestive of malignant rhabdoid tumor of the liver.
• Common symptoms of malignant rhabdoid tumor of the kidney include:

• Vomiting

• Common symptoms of malignant rhabdoid tumor of the liver include:

• Irritability
• Reluctance to eat
• Fever
• Abdominal pain

• Common symptoms of malignant rhabdoid tumor of the orbit include proptosis.
• Common symptoms of malignant rhabdoid tumor of the bladder include:

• Blood in urine
• Weight loss
• Decreased appetite

• Common symptoms of malignant rhabdoid tumor of the head (atypical teratoid/rhabdoid tumor) include:

• Headache
• Vomiting
• Lethargy
• Failure to thrive
• Regression of developmental milestones
• Irritability
• Macrocephaly
• Ataxia
• Nystagmus
• Cranial nerve palsies

Physical Examination

• The physical examination findings according to the location of the tumor include:

• Malignant rhabdoid tumor of the orbit: Dilated pupils and proptosis.
• Malignant rhabdoid tumor of the liver: Right upper quadrant tenderness and hepatomegaly.
• Malignant rhabdoid tumor of the kidney: Palpable abdominal mass and hypertension.
• Atypical teratoid/rhabdoid tumor: Ataxia, nystagmus, cranial nerve palsies.

Laboratory Findings

• Depending on the location of the tumor, there may be different lab findings in patients. The lab findings that may be seen according to the location of the tumor include:

• Malignant rhabdoid tumor of the kidney: Microscopic hematuria, leukocytosis, decreased hemoglobin and hematocrit, elevated BUN and creatinine, and hypercalcemia (due to elevated parathormone levels).
• Malignant rhadoid tumor of the liver: elevated lactose dehydrogenase.

Electrocardiogram

• There are no ECG findings associated with malignant rhabdoid tumor.

X-ray

There are no x-ray findings associated with malignant rhabdoid tumor.

Echocardiography or Ultrasound

• Ultrasound may be helpful in the diagnosis of malignant rhabdoid tumor. Findings on an ultrasound suggestive of/diagnostic of malignant rhabdoid tumor include:

• A lobulated mass with heterogeneous echogenicity that may be due to hemorrhage, necrosis, fat, or calcification.

CT Scan

• CT scan may be helpful in the diagnosis of malignant rhabdoid tumor. Findings on CT scan suggestive of/diagnostic of malignant rhabdoid tumor include:

• Homogenously hypodense lesion/lesions in the liver
• Ill-defined homogeneous mass filling the intraconal space (MRT of the orbit)
• Soft tissue mass that may compress the underlying normal renal parenchyma
• Fluid accumulation and peripheral nodules in the subcapsular space

• After the diagnosis of malignant rhabdoid tumor in a patient, further imaging of other parts of the chest, liver, brain, and other parts of the body is recommended in order to search for distant metastasis.

MRI

• Abdominal MRI may be helpful in the diagnosis of malignant rhabdoid tumor. Findings on MRI suggestive of/diagnostic of malignant rhabdoid tumor include:

• A lobulated mass with hypointense lesions on T1-weighted (W) and hyperintense on T2-W images

MRI showing supratentorial atypical teratoid/rhabdoid tumor (ATRT) in a young child source:Marvin 101

Other Imaging Findings

There are no other imaging findings associated with malignant rhabdoid tumor.

Other Diagnostic Findings

There are no other diagnostic studies associated with malignant rhabdoid tumor.

Treatment

Medical Therapy

• There is no precise/exact treatment for malignant rhabdoid tumor.
• The chemotherapeutic agents used in the treatment of malignant rhabdoid tumor of the liver could be ifosfamide alone or in combination with carboplatin and etoposide alternating with vincristine, adriamycin, and cyclophosphamide at three weeks interval. MRT of the liver is known to be fatal and resistant to multimodal therapy.
• Malignant rhabdoid tumor of the orbit may be treated with chemotherapeutic agents such as ifosfamide, carboplatin, and etoposide. This may be combined with surgical resection or used to reduce the tumor size before the use of gamma knife radiation.
• The children's oncology group developed a protocol for the treatment of malignant rhabdoid tumor which has also been used to treat tumors in different locations. The chemotherapy protocol includes the use of vincristine, cyclophosphamide, and doxorubicin (VDCPM1) at weeks 1, 7, 13, 19, and 25, and cyclophosphamide, carboplatin, and etoposide (CPM5+CE) at weeks 4, 10, 16, 22, and 28.
• Patients may experience side effects such as anemia, neutropenia, thrombocytopenia, and infections.

Surgery

• Malignant rhabdoid tumor can be treated surgically.
• Depending on the location and character of the tumor, complete tumor resection can be pursued as in cases of malignant rhabdoid tumor of the liver. In cases where the tumor is not resectable, a liver transplant may be done. When located in the kidney, a nephrectomy may be done, and may be followed by chemotherapy and/or radiation therapy.
• Some tumors cannot be operated on due to the location. These tumors may be treated with chemotherapy and/or radiotherapy.
• Malignant rhabdoid tumor is an aggressive tumor that can recur even after surgical excision and chemotherapy. Most patients die from tumor invasion and metastasis.

Primary Prevention

There are no established measures for the primary prevention of malignant rhabdoid tumor.

Secondary Prevention

There are no established measures for the secondary prevention of malignant rhabdoid tumor.