TSC/mTOR Pathway Mutation Associated Eosinophilic/Oncocytic Renal Neoplasms: A Heterogeneous Group of Tumors with Distinct Morphology, Immunohistochemical Profile, and Similar Genetic Background

Abstract

A number of recently described renal tumor entities share an eosinophilic/oncocytic morphology, somewhat solid architectural growth pattern, and tendency to present as low-stage tumors. The vast majority of such tumors follow a non-aggressive clinical behavior. In this review, we discuss the morphological, immunohistochemical, and molecular genetic profiles of the three most recent novel/emerging renal entities associated with TSC/mTOR pathway mutations. These are eosinophilic solid and cystic renal cell carcinoma, eosinophilic vacuolated tumors, and low-grade oncocytic tumors, which belong to a heterogeneous group of renal tumors, demonstrating mostly solid architecture, eosinophilic/oncocytic cytoplasm, and overlapping morphological and immunohistochemical features between renal oncocytoma and chromophobe renal cell carcinoma. All three tumors also share a molecular genetic background with mutations in the mTORC1 pathway (TSC1/TSC2/mTOR/RHEB). Despite the common genetic background, it appears that the tumors with TSC/mTOR mutations represent a diverse group of distinct renal neoplasms.

WHO 2022 landscape of papillary and chromophobe renal cell carcinoma

“…These would include SDH-deficient RCC associated with hereditary paraganglioma/pheochromocytoma syndrome, [97][98][99] hybrid oncocytic/chromophobe tumour (HOCT) associated with BHD syndrome, 94 fumarate hydratase-deficient RCC, 26 epithelioid angiomyolipoma ('oncocytoma-like'), 7 TFE3/TFEB-rearranged RCC, 28 so-called 'unclassified' RCC, 100,101 and a heterogeneous group of tumours associated with TSC/mTOR pathway mutation, including eosinophilic solid and cystic (ESC)-RCC, eosinophilic vacuolated tumour (EVT), and so-called 'low-grade' oncocytic tumour (LOT). 102 The SDH-deficient RCC is typically composed of eosinophilic cells with bubbly cytoplasmic appearance and/or intracytoplasmic inclusions containing eosinophilic or pale flocculent material. The tumour cells lack prominent cell borders that are present in chromophobe RCC.…”

“…Currently, three subtypes, ESC-RCC, EVT, and so-called LOT, with distinct morphological and immunohistochemical features, have been proposed. 102,107,108 108 and were recognised as an its own tumour entity by the 2022 WHO classification. 109 The majority of tumours occurred sporadically without germline TSC1/2 mutation and a small subset of tumours are found in tuberous sclerosis complex patients.…”

“…These characteristic histomorphological patterns on haematoxylin and eosin (H&E) staining and immunohistochemical profile with a combination of CK7, CK20, CD117, and vimentin can support distinctly separate histological subtypes from chRCC. 102,[107][108][109][110] EVT was initially described in two different studies as 'high-grade oncocytic tumour/HOT' by He et al 111 and 'sporadic RCC with eosinophilic and vacuolated cytoplasm' by Chen et al 112 Subsequently, the Genitourinary Pathology Society proposed the current nomenclature. 107 Typically, EVT comprises large eosinophilic cells with voluminous intracytoplasmic vacuoles, prominent cell membranes, and oval nuclei with enlarged nucleoli (corresponding to nuclear grade WHO/ISUP 3), arranged in solid to nested architecture, focally with tubulocystic areas (Figure 2F).…”

“…101,107,109 In contrast, chRCC is cathepsin K-negative and lacks marked cytoplasmic vacuoles and 'atypical' nuclear features with very prominent nucleoli. 102 The third category, so-called LOT, was first proposed by Trpkov et al in 2019 as an emerging entity for the oncocytic tumours with indolent behaviour and characterized by a CD117-negative/CK7-positive immunoprofile. 114 This tumour does not fit entirely into either oncocytoma or eosinophilic chRCC.…”

Oncocytic Carcinoma of the Cranio-Orbital Area: A Case Report

“…The skin on the surface of the oncocytic carcinoma may change colour and shrink (2). Oncocytic tumours may have a history of rapid growth from recent long-standing oncocytic carcinomas (3)(4)(5). There are also reports of oncocytic carcinomas in the nasal cavity, the paranasal sinuses (i.e.…”