Morphoproteomic Study on Cytology Specimen on Renal and Extra-Renal Rhabdoid Tumor: One Monster, Two Faces

Abstract

Malignant rhabdoid tumors (MRT) are rare, aggressive, high-grade malignant tumors diagnosed mainly in infants and children; they arise in the kidneys, soft tissues, and central nervous system. MRTs at all sites are recognized as the same entity due to their similar morphology, aggressive behavior, and a common genetic abnormality, an inactivating mutation of the INI-1/hSNF5 gene. Despite multimodal therapy, outcome in rhabdoid tumors remains poor with only 31% of patients surviving to 1 year. Currently there is no optimal standard of treatment, due to a lack of studies defining the biological properties of such tumor. We analyzed morphoproteomic profiles of one malignant rhabdoid tumor of kidney and one case of malignant extrarenal rhabdoid tumor (MERT). Immunohistochemical analysis of paraffin embedded cell block was used to detect the following protein analytes:IGF-1R (Tyr 1165/1166), p-cMet (Tyr 1234/1235), pERK1/2 (Thr202/Tyr204), pAkt (Ser473), p-mTOR (Ser2448), INI-1, cyclinD1, topoisomerase II alpha, Ki-67, Nestin, Gli 2, p-STAT3 (Tyr 705), Sirt1, c-Myc, FASN, and EZH2. Morphoproteomic tumor analyses revealed constitutive activation of 1) the insulin growth factor pathway in the form of phosphorylated (p)-insulin growth factor receptor 1 (Tyr 1165/1166); 2) mTOR pathway as evidenced by variable expression of phosphorylated (p)-mTOR and to a lesser extent of pAKT; 3) the hedgehog and/or TGF-beta (Smad3) pathway demonstrated by nuclear positivity of Gli2, albeit with weaker staining in MERT; 4) expression of a dedifferentiation associated molecular, Sirt-1. Interestingly, the 2 different tumors have different expression patterns on Nestin, p-STAT3 (Tyr 705), c-Myc, FASN, and p-cMet. MERT is negative for c-Myc and FASN whereas rhabdoid tumor of kidney is negative for p-STAT3. This is the first morphoproteomic study of such pathways in this rare entity that provides insight into the biology of this malignant rhabdoid tumor and raises therapeutic options that could complement standard therapies. We hypothesized that although MRTs are indeed the same tumor, independent of the site of origin, the morphoproteomic expression profile differences could reflect the influence of microenvironment over tumor development. Morphoproteomic studies on FNA specimens could provide the necessarily tools that would enable individualized therapy.