Malignant rhabdoid tumor
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
- 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 13), but negative for desmin, myoglobin, and S100.
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# 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:

# 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

## 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.