2020 NPB-10

This case was originally published in 2020. The information provided in this case was accurate and correct at the time of initial program release. Any changes in terminology since the time of initial publication may not be reflected in this case.

A 5-month-old girl presented with a two-day history of persistent emesis. She had a normal delivery and development history. Brain CT showed hydrocephalus and a possible posterior fossa mass. Brain MRI showed a mass in the anterior-most aspect of the right cerebellum in the foramen of Luschka with mass effect on the medulla and narrowing of the fourth ventricle. The mass was isointense on T1-weighted images, heterogeneously hyperintense on T2-weighted images, and heterogeneously enhancing postcontrast with foci of diffusion restriction. Spine MRI showed no evidence of drop metastases. After emergent placement of a ventriculostomy catheter, the patient underwent a posterior fossa craniotomy and tumor resection.

Tissue Site
Brain, posterior fossa

The whole slide image provided is an H&E-stained section of the posterior fossa mass resection specimen.

Additional IHC performed on this resection specimen included INI1, which showed loss of positivity in tumor cells with retained endothelial cell positivity (Image J). Molecular testing confirmed the presence of an inactivating mutation in the SMARCB1 gene. The tumor was diagnosed as atypical teratoid/rhabdoid tumor (AT/RT), WHO grade IV.

AT/RT is a rare malignant pediatric brain tumor most commonly seen in infancy and early childhood before two to three years of age. AT/RTs account for greater than 10% of infantile CNS neoplasms; however, rare adult onset cases have also been described. They can occur anywhere in the CNS including the cerebral hemispheres, cerebellar hemispheres, cerebellopontine angle, brainstem, or spinal cord. Infratentorial AT/RTs are most common in children under the age of 2 and are very rare in adults. MRI often shows variable fluid-attenuated inversion recovery (FLAIR) hyperintensity, postcontrast enhancement, and restricted diffusion (Image A). Leptomeningeal dissemination and/or seeding of cerebrospinal fluid is common in AT/RTs, and, therefore, regular whole axis CNS surveillance is necessary.

AT/RT received its definitive name from Drs. Jaclyn Biegel and Lucy Rorke and colleagues in the mid-1990s after studying a varied group of neoplasms with the same IHC profile. This new entity included tumors formerly known as primary CNS rhabdoid tumor and primitive neuroectodermal tumor-medulloblastoma (PNET-MB), which were found to have a similar immunoprofile, despite variable histomorphology, including expression of epithelial, mesenchymal, neuroectodermal, and sometimes glial proteins. The combination of rhabdoid, epithelial, mesenchymal, and primitive neuroectodermal features similar to, but not diagnostic of, a teratoma gave rise to the “teratoid” nomenclature. Cytogenetic studies at the time showed alterations in chromosome 22, specifically 22q11. By the late 1990s, homozygous deletions or inactivating mutations in the INI1/SMARCB1 gene (located at 22q11.2) were identified in AT/RTs as well as in renal and extrarenal rhabdoid tumors. The INI1 protein product is a member of the ATP-dependent SWI/SNF chromatin-remodeling complex and is a regulator of cell proliferation and differentiation. Following this exciting discovery, antibodies were made against the INI1 protein, and loss of expression was found to be a highly-sensitive and specific marker for AT/RTs. More recently, another member of the same chromatin-remodeling complex was discovered to be mutated in a very small subset of AT/RTs: the SMARCA4 gene that encodes the Brahma-related gene 1 (BRG1) protein product.

Histologically, AT/RTs are highly heterogeneous. Collections of rhabdoid cells with eccentric nuclei, prominent nucleoli, and abundant eosinophilic cytoplasm, sometimes containing a globular inclusion, are most characteristic, but classic rhabdoid forms can be focal and difficult to identify (Image B, Image C, and Image D). A small round blue cell component is commonly encountered (Image C), and areas with mesenchymal and/or epithelial differentiation, if present, are often focal. Classic high-grade features are frequently seen including increased mitotic activity and necrosis (Image E).

The immunophenotype of AT/RTs is as heterogeneous as the histologic appearance. Most commonly, the tumor cells show EMA, smooth muscle actin (SMA), and vimentin positivity (Image F and Image G). Vimentin can nicely highlight the eosinophilic inclusions in rhabdoid cells. In addition, scattered tumor cells may show expression of glial fibrillary acidic protein (GFAP) (Image H), synaptophysin (Image I), S100, neurofilament, chromogranin, and cytokeratins. Germ cell markers such as CD117, OCT4, and PLAP are negative, but SALL4 can be positive. As described above, loss of nuclear INI1 immunopositivity is a sensitive and specific marker for AT/RTs (Image J), and INI1 loss is diagnostic even in cases lacking rhabdoid cells. In the rarer AT/RT cases with inactivating SMARCA4 mutations, loss of BRG1 immunopositivity is diagnostic. While other CNS tumors including meningiomas, gliomas, and carcinomas can contain rhabdoid cells and be considered in the differential diagnosis, these so-called “composite rhabdoid tumors” retain INI1 and BRG1 nuclear positivity and are not thought to be true malignant rhabdoid tumors. Loss of INI1 or BRG1 immunopositivity also assists with ruling out other small round blue cell entities such as medulloblastoma or embryonal tumor with multilayered rosettes.

While the majority of SMARCB1 or SMARCA4 alterations in AT/RTs are somatic, germ-line mutations have also been detected as part of the rhabdoid tumor predisposition syndrome 1 (SMARCB1) or 2 (SMARCA4). It is estimated that more than 30% of children with AT/RTs have germline mutations in SMARCB1; therefore, genetic counseling/testing is recommended when patients are diagnosed with these tumors. In addition to AT/RTs, patients with rhabdoid tumor predisposition syndrome can present with synchronous renal or extrarenal malignant rhabdoid tumors.

Classically, patients with AT/RT have had poor prognoses with a three-year overall survival rate of only 22%, but newer data suggests that a small subset of patients can show long-term and event-free survival. Treatment involves surgical resection followed by combination high-dose chemotherapy and radiation; studies with chemotherapy alone have reported worse survival rates. Research using methylation profiling and transcriptomic analysis is ongoing in an effort to better characterize these tumors molecularly and assist with improved prognostication and treatment.

• AT/RTs are most commonly found in children under the age of three in the posterior fossa, but they can occur anywhere in the CNS, and rare adult cases have been reported.
• AT/RTs show a heterogeneous histomorphology and immunophenotype that can include rhabdoid, embryonal, mesenchymal, and epithelial features.
• The majority of AT/RTs harbor biallelic inactivation of the SMARCB1 gene resulting in loss of INI1 protein expression, but rare cases show inactivating mutations in SMARCA4 resulting in loss of BRG1 protein expression.
• A proportion of patients with AT/RTs harbor germline mutations in SMARCB1 or SMARCA4, characterized as rhabdoid tumor predisposition syndrome, and are at risk for malignant rhabdoid tumors outside the CNS.

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