Maternal embryonal leucine zipper kinase immunoreactivity in atypical teratoid/rhabdoid tumors: a study of 50 cases

Atypical teratoid/rhabdoid tumors (AT/RTs) are aggressive embryonal neoplasms of the central nervous system that correspond to WHO grade IV and have a dismal prognosis. The latest Central Brain Tumor Registry of the United States data shows that AT/RT constitutes 16.6% of all embryonal tumors in children. The molecular hallmark of this tumor is pathogenic SMARCB1 genetic alterations resulting in the loss of INI-1 immunopositivity, with fewer tumors harboring SMARCA4 (BRG1) variants. Maternal embryonal leucine zipper kinase (MELK) is a member of the Snf1/AMPK family of serine/threonine-protein kinases involved in various processes such as cell cycle regulation, self-renewal of stem cells, apoptosis, and splicing regulation. Recent studies have highlighted the involvement of MELK in AT/RT and its possible therapeutic role. The purpose of this study was to review the histological and immunohistochemical profile of AT/RT with special reference to MELK staining. In this retrospective study conducted over 6 years, all diagnosed cases of AT/RT, defined by loss of INI-1 immunopositivity, were retrieved and studied. Demographic details of patients and microscopic findings were analyzed, with special attention to histological patterns and immunohistochemistry profile including MELK immunoreactivity. There were 50 cases of AT/RT diagnosed in the specified period. Of the cases operated at our institute during this period, embryonal tumors constituted 20.6% of all pediatric brain tumors with AT/RT representing 12.6% of this subset. The median age at presentation was 3.5 years (range: 8 months-22 years) and there were three adult cases. Males outnumbered females by a ratio of 1.94:1. Tumor location was distributed equally between the supratentorial and infratentorial compartments. Characteristic rhabdoid cells were identified in 70% of cases. Areas with epithelial, mesenchymal, and undifferentiated tumor cells were seen in 8%, 20%, and 52% of cases, respectively. Cells with vacuolated cytoplasm were noted in 28% of cases. Immunohistochemistry (IHC) showed a polyimmunophenotypic profile with immunopositivity for GFAP in 70%, Vimentin in 100%, SMA in 68%, and EMA in 88% of cases, indicating the remarkable heterogeneity of the tumor cells. MELK immunopositivity was noted in 83.33% of cases. Thus, atypical teratoid/rhabdoid tumors are rare neoplasms. In line with other studies, we show that these tumors occur predominantly in very young children and display marked variability on histology and IHC with loss of INI-1. MELK is presumed to be an important molecule involved in cell cycle regulation, proliferation, and other critical functions. High expression of MELK in AT/RT may suggest its plausible role in neoplastic transformation of embryonic and postnatal multipotent neural progenitors which in turn could explain the diverse morphological and immunohistochemical characteristics observed in these tumors.