A 15-month-old boy presents with vomiting and weight loss. A large, heterogeneous brain lesion is found by MRI (see Figure 1), and the patient undergoes resection. Representative cytopathologic (Figure 2) and histopathologic (Figure 3) photomicrographs of the tumor are shown.
The correct answer is ...
Loss of INI1 expression.
The lumbar puncture cytology shows tumor cells with a striking rhabdoid morphology, characterized by enlarged eccentrically located nuclei, and dense cytoplasm with intracytoplasmic globular inclusions. The histopathologic sections reveal a polymorphic tumor, including areas with clear cell and spindled morphologies, as well as few rhabdoid cells. A radiologically and histologically heterogeneous tumor, coupled with the presence of rhabdoid cells, in a child in the first three years of life raises concern for an atypical teratoid/rhabdoid tumor (AT/RT). The hallmark molecular feature of this entity is an inactivating mutation in either SMARCB1 (approximately 95% of AT/RTs) or, less frequently, SMARCA4. Both of these genes are part of the SWI/SNF complex which regulates chromatin remodeling and cellular differentiation. The immunohistochemical surrogates for inactivating SMARCB1 or SMARCA4 alterations are loss of expression of INI1 or BRG1, respectively. Interestingly, WHO diagnostic criteria do not require rhabdoid morphology for classification as AT/RT; an embryonal CNS tumor with SMARCB1/INI1 or SMARCA4/BRG1 loss is sufficient for diagnosis.
Reflective of the morphologic polymorphism, AT/RTs can display a wide range of immunoreactivity and mimic numerous other tumors.
AT/RTs may express GFAP and thereby resemble a high-grade glioma.
Positivity for synaptophysin can be suggestive of medulloblastoma (especially the anaplastic variant) or CNS Ewing sarcoma (if more monomorphic areas happen to be sampled).
AT/RTs can also entrap normal choroid plexus, and the juxtaposition of choroid plexus with a poorly-differentiated high-grade malignancy in a pediatric patient can lead to consideration of choroid plexus carcinoma. Both entities may show variable or absent expression of EMA, further confounding evaluation.
Above all, it is the absence of INI1 (or BRG1) staining that distinguishes AT/RT from nearly all other entities on the differential diagnosis. AT/RT should be at least considered when approaching a poorly-differentiated CNS tumor in a very young child, making evaluation of SMARCB1 and SMARCA4 critical in diagnosing this entity.
Ryan Kendziora, M.D.
Resident, Anatomic and Clinical Pathology
Aditya Raghunathan, M.D., M.P.H.
Consultant, Anatomic Pathology
Associate Professor of Laboratory Medicine and Pathology
Mayo Clinic College of Medicine and Science