Atypical teratoid rhabdoid tumor (AT/RT)
This case highlights the value and challenge of formulating a concise list of differential diagnoses in neuropathology. First characterized in 1985, atypical teratoid rhabdoid tumor (AT/RT) of the CNS is a highly malignant tumor most commonly found in children less than 2 years of age, with the median age at diagnosis in one series being 16.5 months (1). In children, AT/RT has a predilection for infratentorial structures and arises in this location in a majority of cases (1). The neoplasm is rare, accounting for approximately 2% of childhood CNS tumors. Even more unusual is the adult-onset variant, which typically involves the supratentorial region (2). Based on the location of the lesion seen in this case, the differential diagnosis invariably includes pituitary adenoma, meningioma, lymphoma, germ cell tumor, chordoid glioma, or a metastasis. Imaging features, however, can be helpful in narrowing the list of possible diagnoses. On imaging, AT/RT in adults usually appears as a well-demarcated mass with heterogeneous enhancement on T1-weighted images (2), features that make a pituitary etiology less likely. Also described, but not seen in this case, is a band-like wavy rim of enhancement surrounding a cystic or necrotic focus. Peritumoral edema has also been frequently reported. Glioblastoma and gliosarcoma can present with similar features on imaging (e.g. bony destruction and calcifications). The heterogeneous enhancement seen in AT/RT can be useful in distinguishing it from meningioma, which typically appears homogeneous on T1-weighted images (2). Age, distribution, and history of malignancy are useful in the work-up of metastatic disease.
While the occurrence of AT/RT in the sellar region is rare, increasing reports of adults with tumors in this location should lower the threshold of suspicion for the pathologist or clinician. To date, ten cases of adult onset sellar/suprasellar AT/RT have been reported in the literature (2, 3, 4). In contrast to a male predominance seen in pediatric AT/RT (1), reports of adult AT/RT in the sellar region have exclusively been in females. The name lends itself to the morphology seen on histology (rhabdoid) and the multiple germ cell layers from which the tumor cells are thought to derive (teratoid); however, the cell of origin has yet to be identified (5). Histologic features of both age groups include large atypical cells with eccentric nuclei, prominent nucleoli, and copious amounts of cytoplasm (rhabdoid cells). The presence of the classic rhabdoid morphology, however, can be variable (as seen in our case) and primitive elements commonly found on AT/RT histology can often lead to misdiagnosis (6, 7). Entities to consider when presented with this morphology alone include medulloblastoma, anaplastic ependymoma, epithelial peripheral malignant nerve sheath tumor, and primitive neuroectodermal tumor (PNET). Indeed, there may be small foci of PNET present in up to 70% of AT/RTs (1). A useful distinguishing feature is the high cellularity usually seen in AT/RTs. The so-called "essential" immunohistochemical stains that should be performed when suspecting AT/RT include glial fibrillary acidic protein (GFAP) and epithelial membrane antigen (EMA) (8). The tumors typically demonstrate positive staining with antibodies to epithelial/myoepithelial antigens such as EMA or SMA, in addition to GFAP, synaptophysin, and vimentin. Staining for cytokeratins is also typically positive.
The hallmark genetic event identified in AT/RT tumors is inactivation or deletion of the INI1/hSNF5 gene on chromosome 22q11.2; this aberration results in loss of staining for INI1 on immunohistochemistry (IHC). First described in 1998, this genetic feature has been shown to be a consistent finding in malignant rhabdoid tumors (9). The protein product of the INI1 gene is part of the SWI/SNF chromatin remodeling complex. It should be noted, however, that loss of INI1 staining on IHC can be seen in other neoplasms such as epithelioid sarcomas, epithelioid MPNST, medulloblastomas, and supratentorial PNET (10, 11). Furthermore, the pathologist should account for nonspecific staining of INI1. Most native cells, including endothelial cells and lymphocytes, are positive for INI1 (Figure 1h); this scattered positivity can be misleading and evaluation of immunoreactivity should focus on identifying the morphologic features of tumor cells on counterstaining. Confirmation of the diagnosis can be made with molecular analysis (9) or the detection of cytogenetic alterations with FISH (1).
An emerging difference between pediatric and adult-onset AT/RT is prognosis and treatment modalities. Established treatment for childhood AT/RT includes complete resection and systemic/intrathecal chemotherapy (3, 12). While the typical age of onset in pediatric AT/RTs commonly precludes the use of radiotherapy, it has shown benefit in adult patients. Inclusion of chemotherapy in the treatment regimen is crucial and commonly includes etoposide, ifosfamide, and carboplatin. Overall survival (OS) in children diagnosed with AT/RT remains dismal, ranging 8.5 to 13 months. In adults, OS of over 48 months has been reported with the use of multidisciplinary approaches, including radiation, chemotherapy, and aggressive surgical resection (3).
This research was supported by the Intramural Research Programs of the National Cancer Institute, and the National Institute of Neurological Disorders and Stroke.
Contributed by Drew Pratt, MD; Gautam U. Mehta, MD; Hao-Wei Wang, MD, PhD; Prashant Chittiboina, MD; Martha Quezado, MD