TSC/MTOR-associated Eosinophilic Renal Tumors Exhibit a Heterogeneous Clinicopathologic Spectrum

Abstract

Background: Several TSC1/2-or MTOR-mutated eosinophilic renal tumor subsets are emerging, including eosinophilic solid and cystic renal cell carcinoma (ESC RCC), eosinophilic vacuolated tumors (EVTs) and low-grade oncocytic tumors (LOTs). "Unclassified renal tumors with TSC/MTOR mutations" (TSC-mt RCC-NOS) do not meet the criteria for other histomolecular subtypes. Whether these tumors represent a continuum of 1 TSC/MTOR-mutation-associated disease is unknown.Design: We evaluated the clinicopathologic and IHC profiles of 39 eosinophilic renal tumors with targeted DNA sequencingconfirmed TSC/MTOR mutations. Twenty-eight of these, plus 6 ChRCC, 5 RO, 5 ccRCC, 7 MiT RCC and 6 normal renal tissues, were profiled transcriptionally by RNA-seq. Results:The 39 cases were reclassified based on morphological and IHC features as ESC RCC (12), EVT (9), LOT, (8) and TSC-mt RCC-NOS (10). The mutation profiles demonstrated consistency; ESC RCCs (12/12) had TSC mutations, and most LOTs (7/8) had MTOR mutations. Ten TSC-mt RCC-NOSs exhibited heterogeneous morphology, arising a differential diagnosis with other renal tumors, including MiT RCC, PRCC and epithelioid PEComa. RNA sequencing-based clustering segregated ESC RCC, EVT and LOT from each other and other renal tumors, indicating expression profile-level differences. Most TSC-mt RCC-NOSs (6/7) formed a mixed cluster with ESC RCC, indicating similar expression signatures; one TSC-mt RCC-NOS with unusual biphasic morphology clustered with EVT. Conclusions:We expanded the TSC/MTOR-associated eosinophilic renal tumor morphologic spectrum, identified gene mutation characteristics, and highlighted differential diagnosis challenges, especially with MiT RCC. ESC RCC, EVT, and LOT having distinct expression profiles. TSC-mt RCC-NOS may cluster with recognized TSC/MTOR-associated entities.

TSC/MTOR-associated Eosinophilic Renal Tumors Exhibit a Heterogeneous Clinicopathologic Spectrum

“…I would like to congratulate Xia Q and colleagues on their article “ TSC/MTOR -associated Eosinophilic Renal Tumors Exhibit a Heterogeneous Clinicopathologic Spectrum—A Targeted Next-generation Sequencing and Gene Expression Profiling Study.”1 I completely agree with their findings and conclusions that further validate the previous work showing that eosinophilic solid and cystic renal cell carcinoma (ESC RCC), eosinophilic vacuolated tumor (EVT), and low-grade oncocytic tumor (LOT) (reviewed in Trpkov et al2) represent novel and emerging renal entities that demonstrate consistent morphologic and immunohistochemical profiles, and mutation profiles associated with TSC/MTOR abnormalities. They also expand on the spectrum of the sporadic TSC/MTOR-associated eosinophilic renal tumors and show that such alterations are not specific for any single entity.…”

Low-grade oncocytic tumour (LOT) of the kidney is characterised by GATA3 positivity, FOXI1 negativity and mTOR pathway mutations

“…Low-grade oncocytic tumour (LOT) of the kidney has emerged as a new diagnostic entity in renal tumour pathology in recent years (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13). LOT is now enrolled in a new tumour subgroup called other oncocytic tumours of the kidney in the fifth edition of the WHO classification of urinary and male genital tumours (14), and is defined as a neoplasm with bland low-grade nuclei, diffuse strong CK7 labelling, and negative CD117 labelling.…”

“…CCND1 rearrangements were not found in LOT by using fluorescence in situ hybridization (FISH) ( 5 ). An increasing number of genetic tests have identified genetic mutations in LOT patients, including RHEB ( 8 ), MTOR ( 7 – 13 ), TSC1 ( 6 – 9 , 11 – 13 ), TSC2 ( 11 , 12 ), and PIK3CA ( 12 ), which are primarily involved in the mTOR pathway. The PI3K/AKT/mTOR signalling pathway plays a key role in cell survival and growth, mTOR is the master regulator of cell metabolism and growth, and acts through two different multiprotein complexes, namely, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2).…”

“…EVT demonstrates a solid growth architecture, large eosinophilic cells with distinct intracytoplasmic vacuoles, prominent cell membranes, large nuclei with prominent nucleoli, a CK7-/CD117+/CD10+/cathepsin K+ immunophenotype ( 23 ), and sporadic TSC/MTOR mutations ( 24 ). Recently, Xia et al ( 13 ) further explored the molecular characteristics of TSC/MTOR -associated eosinophilic renal tumours, which included ESC RCC, EVT, LOT and unclassified renal tumours with TSC/MTOR mutations ( TSC-mt RCC-NOS). They observed a specific trend in TSC/MTOR mutation in different tumours.…”

Update on classification of oncocytic neoplasms of the kidney

“…Mutations in tuberous sclerosis (TSC) 1/TSC2/mammalian target of rapamycin (MTOR) genes are common in both EVT and LOT, but also in the eosinophilic solid and cystic (ESC) RCC [13][14][15]17,[22][23][24]. All of these tumors are also more frequent in patients with pathogenic germline mutations in the MTOR regulators TSC1/TSC2 [25,26], some of which present with clinical features of tuberous sclerosis.…”