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Extrarenal Rhabdoid Tumor

Extrarenal rhabdoid tumor is a highly malignant soft tissue tumor, mainly affecting infants and children, that consists of characteristic rounded or polygonal neoplastic cells with glassy eosinophilic cytoplasm containing hyaline-like inclusion bodies, eccentric nuclei, and macronucleoli. Morphologically and genetically identical tumors also arise in the kidney and brain. The majority of tumors are characterized by biallelic alterations of the SMARCB1 gene leading to loss of expression of SMARCB1 (INI1).

Symptoms & Causes

Introduction

Extrarenal rhabdoid tumor is a rare and aggressive soft tissue cancer in children, characterized by rhabdoid cells and often involving SMARCB1 gene alterations.

Reference
WHO Classification of Tumours Editorial Board. Soft tissue and bone tumours [Internet]. Lyon (France): International Agency for Research on Cancer; 2020 [cited 2024 09 11]. (WHO classification of tumours series, 5th ed.; vol. 3). Available from: https://tumourclassification.iarc.who.int/chapters/33.

Related Terminology
Acceptable: rhabdoid tumor of soft tissue; malignant rhabdoid tumor.

Subtype(s)
None

Symptoms

Most cases present as a rapidly enlarging soft tissue mass—the associated clinical symptoms depend on the primary organ involvement. Occasional cases present with multiple cutaneous nodules. Particularly in infants, some cases present with disseminated disease without an obvious primary tumor—such cases are often associated with rhabdoid tumor predisposition.

Localization

This rare tumor seems to arise most often in deep, axial locations such as the neck, paraspinal region, perineal region, abdominal cavity or retroperitoneum, and pelvic cavity. Lesions in the extremities (especially the thigh) and cutaneous lesions are also well documented. This tumor also often affects visceral organs such as the liver, thymus, genitourinary tracts, and gastrointestinal system. The liver appears to be the single most common visceral location (73% of all cases).

Epidemiology

Extrarenal rhabdoid tumor is exceedingly rare and is largely confined to infants and children. Among fetal and neonatal rhabdoid tumors, the extrarenal rhabdoid tumor is more common than those in the kidney or brain. Conversely, on average, patients with extrarenal, extracranial rhabdoid tumors tend to be older than patients with renal rhabdoid tumors.

Etiology

Familial cases are typically associated with germline mutations in SMARCB1 (INI1, hSNF5, BAF47) in 22q11.23. Germline mutations or deletions in SMARCB1 (rhabdoid tumor predisposition syndrome 1) are present in approximately 13% of patients with extrarenal rhabdoid tumors. Patients with germline alterations in SMARCB1 typically present in early childhood, but they are at increased risk for other soft tissue tumors, notably schwannomas, in later decades. A very small percentage of rhabdoid tumors are associated with SMARCA4 mutations, which may be present in the germline (rhabdoid tumor predisposition syndrome 2).

Diagnosis & Treatment

Staging

Not clinically relevant

Pathogenesis

Extrarenal rhabdoid tumors arise as a consequence of homozygous inactivation of the SMARCB1 gene in chromosome band 22q11.2. Approximately 98% of extrarenal rhabdoid tumors, malignant rhabdoid tumors of kidney, and atypical teratoid/rhabdoid tumors demonstrate genomic alterations of both copies of the gene, including coding-sequence mutations, partial- or whole-gene deletions, and copy-neutral loss-of-heterozygosity events that unmask a recessive allele on the remaining homologue. There is some genotype–phenotype correlation, with rhabdoid tumors demonstrating truncating mutations or deletions throughout the coding sequence. Extrarenal rhabdoid tumors have a particularly high incidence of homozygous deletions of the SMARCB1 gene. This is often a consequence of a chromosomal translocation between chromosome band 22q11.2 and a variety of different partner chromosomes. The translocation is unbalanced at the molecular level, resulting in deletion of SMARCB1. The second allele is usually lost as a result of an interstitial 22q11.2 deletion. Consistent with the function of SMARCB1 as a classic tumor suppressor gene, initiating germline mutations or deletions in SMARCB1 function as the first hit in patients who have a genetic predisposition to the development of rhabdoid tumors. Such patients are also at risk for malignant rhabdoid tumor of kidney and atypical teratoid/rhabdoid tumor. In rare rhabdoid tumors with retained SMARCB1 expression, mutation and/or loss of the SMARCA4 gene in 19p13.2 has been reported. Inactivation of the SWI/SNF complex by targeting either SMARCB1 or SMARCA4 gives rise to both intracranial and extracranial rhabdoid tumors. The loss of this epigenetic remodeler leads to silencing of a variety of tumor suppressor and differentiation genes and pathways that are considered hallmarks in the pathogenesis of these tumors.

Macroscopic Appearance

Most tumors are unencapsulated and measure > 5 cm in maximum diameter. The tumors are usually soft and grey to tan in color on cut surface, and they are frequently accompanied by foci of coagulative and hemorrhagic necrosis.

Histopathology

The tumor is characterized by rhabdoid cells with large vesicular rounded to bean-shaped nuclei, prominent nucleoli, and abundant cytoplasm, arranged in sheets or in a solid trabecular pattern. Many tumor cells have juxtanuclear eosinophilic, PAS-positive, diastase-resistant hyaline inclusions or globules. At the periphery, tumor cells infiltrate surrounding tissue. Nuclear pleomorphism is not evident, whereas mitotic figures are frequently observed. The tumor often shows loss of cellular cohesion. Some cases demonstrate predominant proliferation of undifferentiated small round cells, with only a small number of typical rhabdoid cells. Immunohistochemically, most of these tumors show expression of epithelial markers such as keratins and EMA. The expression of neural or neuroectodermal markers such as CD99 and synaptophysin is also frequently observed in soft tissue tumors. Less commonly, the cells express MSA and focal S100. SALL4 and glypican-3 (GPC3) immunoexpression is frequently observed. Characteristically, rhabdoid tumors show loss of SMARCB1 (INI1, BAF47) expression.

Cytology

Not clinically relevant

Prognosis and Prediction

Regardless of tumor location, patient outcome is dismal. Because of the entity’s rarity, there are no large studies of survival analysis in uniformly treated patients with extrarenal tumors. The median age was 28 months, and the overall 5-year survival rate was < 15%. Patients with rhabdoid tumors of the liver have a worse survival than patients with other extracranial and extrarenal sites.

Clinical Features

Diagnostic Molecular Pathology

Not clinically relevant

Essential and Desirable Diagnostic Criteria

Essential: primitive undifferentiated or rhabdoid cell morphology; loss of expression of SMARCB1 (INI1).

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