Case 4 -

Atypical Teratoid/Rhabdoid Tumor (AT/RT) Daniel Brat, Emory University Hospital, Atlanta, GA

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Clinical History This 10-month-old girl had a history of perinatal arrhythmia for which she recieved a cardiovascular work up and body CT at the age of 1 month. Body CT was negative at that time. She recently fell from the couch onto the floor and hit her head, resulting in a bruise, but without loss of consciousness. At the pediatric emergency department, aside from bruising on the scalp, the physical exam was normal. However, the head CT and subsequent MRI revealed a large, heterogenesously contrast-enhancing mass in the posterior fossa, centered in the cerebellum. One week later, she was taken to the operating room, where a near- total resection was achieved. Case 4 - Figure 1 Post-contrast MRI demonstrating a large mass in the posterior fossa with patchy contrast enhancement. Case 4 - Figure 2 The neoplastic population on the right has a "small round blue cell" morphology, typical of what is seen in medulloblastoma or PNET. There are scattered large eosinophilic neoplastic cells noted as well. Case 4 - Figure 3 Higher magnification of poorly differentiated, embyonal cells, with a high nuclear-cytoplasmic ratio, with only modest neuropil in the background. Case 4 - Figure 4 Highly malignant cells with large, atypical nuclei and abundant pink cytoplasm, occasionally with spherical cytoplasmic inclusions that displace the nucleus (rhabdoid inclusions). Case 4 - Figure 5 Higly atypical cells with abundant pink cytoplasm, epithelioid properties and occasional rhabdoid inclusions. Case 4 - Figure 6 Other regions show tumor cells growing as neuro-epithelial ribbons with clearly evident cell-cell borders. Case 4 - Figure 7 Immunohistochemistry for synanptophysin was strongly positive in cells with embryonal morphology. Case 4 - Figure 8 Strong patchy immunoreactivity for cytokeratin was noted. Case 4 - Figure 9 Strong patchy immunoreactivity for actin was present. Case 4 - Figure 10 Immunohistochemistry for INI1 revealed a lack of staining in neoplastic cells, while vascular endothelial cells showed retained expression. Introduction: Brain tumors are the most common solid tumor type in the pediatric population. Posterior fossa tumors, such as the one in the present case, account for approximately two- thirds of pediatric brain tumors. Pathological/Microscopic Findings and any Immunohistochemical or Other Studies: The tumor demonstrated in the present case grows in a solid, non-infiltrative pattern, and is composed of a heterogeneous population of highly malignant cells. There are regions that display an embryonal, "small round blue cell" morphology typical of medulloblastoma (or PNET). Other variably-sized regions show a spindled growth pattern, epitheliod differentiation, and a population of large eosinophilic cells with spherical (rhabdoid) cytoplasmic inclusions. Immunohistochemical stains demonstrate lineage heterogeneity as well, with foci of malignant cells staining strongly for synaptophysin, GFAP, cytokeratin, actin and neurofilament. Immunohistochemistry for INI1 reveals a lack of protein expression in neoplastic cells with a retention of expression in vascular endothelial cells. Differential Diagnoses: The differential diagnosis of a posterior fossa tumor in a child includes medulloblastoma, ependymoma, pilocytic astrocytoma and atypical teratoid/rhabdoid tumor (AT/RT). In the present case, where the tumor is clearly malignant and demonstrates embryonal characteristics, the main considerations would be medulloblastoma and AT/RT. Final Diagnosis: Atypical Teratoid/Rhabdoid Tumor (AT/RT) Case Discussion: The current case represents a highly malignant neoplasm in the posterior fossa of an infant. The primary differential diagnosis would include medulloblastoma, AT/RT and anaplastic ependymoma. Since the tumor lacks a high degree of fibrillarity and does not demonstrate any appreciable ependymal differentiation, such as pseudorosette or canal formation, the diagnosis of an ependymal neoplasm can be excluded. The distinction between medulloblastoma and AT/RT can be difficult, mostly because AT/RT often shows a component of primitive "small round blue cell" morphology similar to medulloblastoma. Moreover, medulloblastoma can, albeit less commonly, demonstrate regions of divergent differentiation. The differential diagnosis is most challenging in the setting of a highly anaplastic neoplasm, where the differental diagnosis consists of the large cell/anaplastic variant of medulloblastoma and AT/RT. AT/RT should be strongly considered when there is a high degree of both morphologic and immunohistochemical diversity within the neoplasm. Most AT/RTs will demonstrate regions with morphologies distinct from the primitive neuro-epithelial appearance of medulloblastoma and also include epitheliod, stellate, myxoid, or spidled regions. The presence of large, highly atypical cells with rhabdoid inclusions strongly favors the diagnosis of AT/RT. There rhabdoid inclusions are not present in all AT/RTs, however, and are not required to establish the diagnosis. Importantly, there are many malignant neoplasms of the CNS that can have "rhabdoid" morphology, including glioblastoma, meningioma and carcinomas. These tumors do not show the same clinical, morphologic and molecular features as AT/RT and are not considered to be related. The immuophenotype of AT/RT displays a similar diversity, with foci of cells demonstrating strong immunoreactivity for synaptophysin, GFAP, actin, neurofilament and cytokeratin. Immunohistochemical evaluation of AT/RT for the INI1 protein (using the BAF47 antibody) shows a loss of labeling in tumor cell nuclei, but retention of nuclear labeling in nonneoplastic cells, such as endothelial cells. Review of the Literature/Treatment Options (if applicable): The 2007 version of the WHO Classification of Tumours of the Central Nervous System, 4th Edition, includes a description of the recently recognized rhabdoid tumor predisposition syndrome (RTPS). This syndrome is characterized by germline mutations of the INI1 gene (22q11.2) and is manifested by a marked predisposition to the development of malignant rhabdoid tumors of infancy and early childhood. The atypical teratoid/rhabdoid tumor (AT/RT) is the most common CNS malignancy associated with this syndrome. Up to one-third of AT/RTs are thought to arise in the setting of RTPS and the majority of these occur within the first year of life. The most common non-CNS malignancy of RTPS is the malignant rhabdoid tumor of the kidney, also noted in infancy. The RTPS is highly suggested in those clinical scenarios that involve the synchronous occurrence of renal malignant rhabdoid tumor and AT/RT, the finding of bilateral malignant rhabdoid tumors of the kidney or the occurrence of malignant rhabdoid tumors in two or more siblings. The diagnosis of RTPS is established with certainty by sequencing of the INI1 gene on tissue representing the patient's germline Because of the risk associated with the RTPS, it is recommended that the germline status of the INI1 allele be investigated in each new case of AT/RT. The sporadic form of AT/RT is characterized by the same spectrum of INI1 mutations that are seen in the germline of RTPS. In either case, the second INI1 allele is believed to be lost by deletion as the second tumorigenic step. Conclusion(s): AT/RT is a highly malignant neoplasm that occurs in the posterior fossa and supratentorial compartment of young children. In the posterior fossa, the primary differential diagnosis includes large cell/anaplastic medulloblastoma. The morphologic and immunophenotypic diversity of AT/RT and its loss of INI1 protein expression lead to its correct classification. References: Louis DN, Ohgaki H, Weistler OD, Cavenee WK. (2007) WHO Classification of Tumours of the Central Nervous System. 4th ed. Lyon: Intl. Agency for Research. Yachnis AT, Perry A. (2010) Embryonal (Primitive) Neoplasms of the Central Nervous System. In Perry A, Brat DJ, eds. Practical Surgical Neuropathology: A Diagnostic Approach. Philadelphia: Churchill-Livingstone. Biegel JA, Zhou JY, Rorke LB, Stenstrom C, Wainwright LM, Fogelgren B. (1999). Germ-line and acquired mutations of INI1 in atypical teratoid and rhabdoid tumors. Cancer Res. 59:74-79. Judkins AR, Mauger J, Ht A, Rorke LB, Biegel JA. (2004) Immunohistochemical analysis of hSNF5/INI1 in pediatric CNS neoplasms. Am J Surg Pathol. 28:644-650.