NF2-mutated Renal Carcinomas Have Common Morphologic Features Which Overlap With Biphasic Hyalinizing Psammomatous Renal Cell Carcinoma

Abstract

Genetic alterations involving NF2 occur at low frequencies in renal cell carcinoma across all of the major histologic subtypes and have been associated with adverse outcomes. To better characterize tumors harboring these alterations, we identified 14 cases with NF2 mutations that had been previously diagnosed as papillary renal cell carcinoma; renal cell carcinoma, unclassified; or translocation associated renal cell carcinoma. These tumors were characterized by a tubulopapillary architecture, sclerotic stroma, microscopic coagulative necrosis, and psammomatous calcifications. All the cases displayed eosinophilic cytology as well as a high nuclear grade (World Health Organization/International Society of Urological Pathology [WHO/ISUP] grade 3 to 4) in all but 1 case. A subset of cases shared features with the recently described biphasic hyalinizing psammomatous renal cell carcinoma. Next-generation sequencing demonstrated mutations involving NF2 gene in all cases. In 10 cases, this was paired with the loss of chromosome 22. Additional mutations involving PBRM1 were found in 5 cases that were associated with a more solid growth pattern. Eight patients presented with metastatic disease including all 5 with PBRM1 mutations. Despite the aggressive disease course seen in many of the patients in our series, 2 patients exhibited a dramatic response to immunotherapy. Our results support the existence of a distinct group of cases of renal cell carcinoma characterized by distinct although admittedly nonspecific morphology, an aggressive disease course, and NF2 mutations, often paired with the loss of chromosome 22.

Merlin immunohistochemistry is useful in diagnosis of tumours within the spectrum of biphasic hyalinizing psammomatous renal cell carcinoma

“…Tumours within the spectrum of RCC purportedly driven by NF2 inactivation described in prior studies (henceforth referred to as 'BHP RCC') [7][8][9][10] were retrieved from the personal files of the authors, including tumours previously reported by Argani et al, 7 Paintal et al, 8 and Gopinath et al, 10 as well as newly identified tumours. Additionally, pathology databases and personal consultation files were queried for tumours diagnosed as papillary RCC, TFE3-rearranged RCC, TFEB-altered RCC (TFEB-rearranged RCC and TFEB-amplified RCC), and MTSCC (NF2 mutation status unknown) with archival formalin-fixed paraffinembedded (FFPE) tissue available for IHC.…”

“…Testing for NF2 was assessed using the solid tumour panels by the University of Chicago, Memorial Sloan Kettering Cancer Center, UT Southwestern, University of Florida Health Jacksonville Molecular Pathology Laboratory, and Nanjing Geneseeq Technology (Nanjing, China) as described in the corresponding publications. [7][8][9][10] Results…”

“…The series included 13 BHP RCC, including 11 tumours (85%) with known biallelic loss of NF2, as demonstrated by next-generation sequencing in prior series (patients 1-11, all published in prior studies), 7,8,10 one tumour (8%) with monosomy 22 detected by single-nucleotide polymorphism array (case #12), and one tumour (8%) with fitting morphology but no molecular studies available (case #13). All patients were adults, with a median age of 59 years (range 43-88 years) and an M:F ratio of 11:2 (Table 1).…”

“…Subsequent studies of renal tumours purportedly driven by NF2 inactivation have suggested that the morphologic spectrum of this entity may be somewhat wider than initially thought. 8,9 In a study by Wang et al, 9 the diagnostic utility of merlin immunohistochemistry (IHC) was suggested for identification of BHP RCC; however, its diagnostic utility has not yet been systemically investigated and identification of these tumours has relied on high-complexity massively parallel sequencing assays. In this study we evaluated the utility of merlin IHC in tumours within the spectrum of BHP RCC, including reported tumours in the original descriptions of this entity.…”

“…In this study we evaluated the utility of merlin IHC in tumours within the spectrum of BHP RCC, including reported tumours in the original descriptions of this entity. [7][8][9][10]…”