NQ-002 Answer: (E) Atypical teratoid rhabdoid tumor (AT/RT)

Pathology of the case:  

• There are some large egg-shaped cells with eccentrically located nuclei and prominent nucleoli (black arrow) with a large amount of cytoplasm at the “belly”. Some cells with large pleomorphic nucleoli but less cytoplasm are also present. For the most typical examples, the cytoplasm in the big belly would appear like an inclusion body. These are the rhabdoid cells. Cytologic preparation, in the opinion of the author, is extremely sensitive in picking up these cells.

• “Rhabdoid” refer to cytologic features mimicking rhabdomyoblastic differentiation but is not genuine rhabdomyoblastic changes as the cytoplasm is negative for skeletal muscle markers such as desmin. The typical feature include a large to very large egg-shaped, sometimes oval cells with a large, eccentric nuclei, prominent nucleoli and an inclusion body like eosinophilic cytoplasm, often but not always, in the fat end of the egg-shaped cell.

• It should also be noted that many of the cells present has enlarged nuclei, somewhat prominent nucleoli and lack the big belly of cytoplasm of a typical rhabdoid cells. One must note that the degree and extent of rhabdoid changes can vary from scant to occasional to widespread. A careful search is mandatory when the number of rhabdoid cells is low. It should be noted that any tumor arising from the brain of an infant with prominent nucleoli is encountered AT/RT must be taken into the differential diagnosis. Relying entirely on the rhabdoid features is not recommended as a few of these cases may totally lack rhabdoid cells. This would be particularly challenging when the sample is small at the time of intraoperative consultation.

• With the age taken into consideration, the most likely diagnosis is atypical teratoid/ rhabdoid tumor (AT/RT), WHO grade IV. AT/RT is essentially a primary rhaboid tumor of the central nervous system that may occur with or without non-rhabdoid element. The most common associated non-rhabdoid elements are medulloblastoma-like neoplastic component. They occur most commonly in infants under three years of age, they are highly aggressive.

• As per the 2016 WHO classification, it is defined as a tumor with alterations of either SMARCB1/INI1 (on chromosome 22q11.2) or, very rarely, BRG1 (Transcription activator BRG1 also known as ATP-dependent helicase SMARCA4 on chromosome 19p13.2).

•  Deletion of 22q is often, but not always, seen in AT/RT. Demonstration of this deletion by FISH was often used in the past. BAF47 is an antibody that detects the product of INI1. This protein is widely expressed in normal cells. Deletion or mutation of INI1 will lead to loss of expression and negative staining results in AT/RT and this is currently used in diagnosis. It should be noted that deletion or mutation of INI1 gene is not limited to AT/RT only. For example, loss of BAF47 expression is present in both conventional and proximal-type epithelioid sarcoma. Therfore, other pathologic considerations must be taken into consideration.

• Hornick JL, Dal Cin P, Fletcher CD. Loss of INI1 expression is characteristic of both conventional and proximal-type epithelioid sarcoma. Am J Surg Pathol. 2009 Apr;33(4):542-50.

 

Large cell/anaplastic medulloblastoma: These tumors are characterized by tumor cells similar to medulloblastoma cells but with large and prominent nucleoli. Also present are numerous apoptotic figures and often necrosis. Characteristic rhabdoid cells are usually not present and most of the tumor cells have naked nuclei or only a very thin rim of cytoplasm on squash preparation. Other than the presence of rhabdoid cells, it may be difficult to distinguish them from AT/RT at the time of intraoperative consultation. One must note that the nuclear details are usually not very well preserved in both AT/RT and in medulloblastoma (any variants) on frozen section. Cytologic preparation is often the best mean to view the nuclear features. Some times, the two entities cannot be confidently differentiated on intraoperative consultation. [click here to see a smear]

Pilocytic astrocytoma: The tumor cells on squash preparation will be elongated glial cells. Other features such as Rosenthal fibers and eosinophilic granular bodies may be present. Although it shares the features of being a common tumor in the posterior fossa with AT/RT, it should not be mistaken as AT/RT on histologic grounds. [click here to see a smear]

Germinoma: The tumor cells are typically composed of round to polygonal large cells with a large nuclei and prominent nucleoli. For these features, a suspicion of AT/RT is legitimate. Although large, germinoma cells do not have rhabdoid changes. However, germinoma often comes with a background of benign reactive astrocytes. In addition, germinomas typically arise from the pineal and, far less frequently, the pituitary. Barring from extension of a pineal tumor into the posterior fossa, germinoma does not arise from the posterior fossa. These features are helpful at the time of intraoperative consultation. [click here to see a smear]

Multiple myeloma: The egg-shaped cells with an eccentric nucleus can lead someone to think of a plasmacytoma/multiple myeloma. The clock face nuclei are missing and there is no cytoplasmic halo. In addition, variation among tumor cells on squash preparation in plasmacytoma/multiple myeloma is usually not prominent and tumor cells look more or less like a homogeneous population which is not true in this case. Also, the age is wrong. Plasmacytoma/multiple myeloma is usually a disease of adults. In addition, it is extremely rare to see a primary tumor or secondary involvement of the posterior fossa by a plasmacytoma/multiple myeloma. [click here to see a smear]