Biphasic squamoid alveolar papillary renal cell carcinoma (BSA-PRCC) is a recently studied lesion considered a morphologic variant of papillary renal cell carcinoma (RCC), more closely related to type 1. Considering the role of proto-oncogene MET in both sporadic type 1 papillary RCC and hereditary papillary RCC, we aimed to explore the role of MET activation in the oncogenesis of BSA-PRCC. We identified 17 patients with either unique (n = 14) or multiple (n = 3) BSA-PRCC, all localized, and performed an integrative analysis of MET status in 18 formalin-fixed paraffin-embedded tumors combining next-generation sequencing analysis, fluorescent in situ hybridization and immunohistochemistry. Trisomy 7 was found in 86% of tumors (14/16) without MET amplification at 7q31 (15/15). A pathogenic MET genetic variant was identified in 60% (9/15) of cases, at the germline level in 57% (4/7) of tested patients or at the somatic level (5/11). MET expression was observed in all tumors with a higher value of combined score in large cells (mean 97%, range 80-100%) than in small cells (mean 74%, range 10-100%) and was lower in two cases without MET copy number gain. In conclusion, our study provides additional evidence to consider biphasic squamoid alveolar papillary RCC as a morphological variant of type 1 papillary renal RCC. Our data strongly suggest that MET represents a major oncogenic driver gene in BSA-PRCC, harboring a higher frequency of MET mutation that encourages to further explore the benefice of anti-MET targeted therapies for aggressive BSA-PRCC.
Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc. 2020 Aug 07 [Epub ahead of print]
Thomas Denize, Pierre Alexandre Just, Mathilde Sibony, Hélène Blons, Marc Olivier Timsit, Tom Drossart, Deborah Jakubowicz, Chloé Broudin, Aurélien Morini, Thierry Molina, Yann Vano, Marie Auvray-Kuentz, Stéphane Richard, Arnaud Mejean, Anne Paule Gimenez Roqueplo, Nelly Burnichon, Virginie Verkarre
Assistance Publique-Hôpitaux de Paris (AP-HP) Paris-Centre, Hôpital Européen Georges Pompidou, Service de Pathologie, F-75015, Paris, France., Université de Paris, F-75006, Paris, France., Assistance Publique-Hôpitaux de Paris (AP-HP) Paris-Centre, Hôpital Européen Georges Pompidou, Département de Biochimie, UF de Pharmacogénétique et Oncologie Moléculaire, F-75015, Paris, France., Assistance Publique-Hôpitaux de Paris (AP-HP) Paris-Centre, Hôpital Européen Georges Pompidou, Service d'Urologie, F-75015, Paris, France., Université de Paris, PARCC, INSERM, Equipe Labellisée par la Ligue contre le Cancer, F-75015, Paris, France., Réseau national de référence pour cancers rares de l'adulte PREDIR (Maladie de von Hippel-Lindau et prédispositions héréditaires au cancer rénal) labellisée par l'Institut national du cancer, Université Paris Saclay, Assistance Publique-Hôpitaux de Paris, Le Kremlin-Bicêtre, France., Université de Paris, PARCC, INSERM, Equipe Labellisée par la Ligue contre le Cancer, F-75015, Paris, France. ., Assistance Publique-Hôpitaux de Paris (AP-HP) Paris-Centre, Hôpital Européen Georges Pompidou, Service de Pathologie, F-75015, Paris, France. .