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Heterogeneity Mapping of Protein Expression in Tumors using Quantitative Immunofluorescence
Published on: October 25, 2011
TSC/MTOR -associated Eosinophilic Renal Tumors Exhibit a Heterogeneous Clinicopathologic Spectrum : A Targeted
Qiu-Yuan Xia1, Xiao-Tong Wang1, Ming Zhao2
1Department of Pathology, Affiliated Jinling Hospital, Medical School of Nanjing University, Jiangsu.
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 TS C/ MTOR -mutation-associated disease is unknown.
Design:
We evaluated the clinicopathologic and IHC profiles of 39 eosinophilic renal tumors with targeted DNA sequencing-confirmed 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.
Insights
New eosinophilic renal tumors with TSC/MTOR mutations are emerging, including eosinophilic solid and cystic renal cell carcinoma (ESC RCC), eosinophilic vacuolated tumors (EVTs), and low-grade oncocytic tumors (LOTs). These subtypes show distinct expression profiles, with unclassified tumors potentially representing a continuum of TSC/MTOR-associated disease.
Area of Science:
- Oncology
- Genetics
- Pathology
Background:
- Emerging subsets of eosinophilic renal tumors are associated with TSC1/2 or MTOR mutations.
- These include 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) present diagnostic challenges, and their relationship to other subtypes is unclear.
Purpose of the Study:
- To evaluate the clinicopathologic and immunohistochemical (IHC) profiles of eosinophilic renal tumors with TSC/MTOR mutations.
- To characterize the mutation profiles and transcriptional landscape of these tumors.
- To clarify the diagnostic boundaries and potential continuum among TSC/MTOR-associated eosinophilic renal tumors.
Main Methods:
- Clinicopathologic and IHC analysis of 39 eosinophilic renal tumors with confirmed TSC/MTOR mutations.
- Targeted DNA sequencing for mutation profiling.
- RNA sequencing (RNA-seq) for transcriptional profiling of selected cases and comparison with other renal tumor types.
Main Results:
- The 39 cases were reclassified into ESC RCC (12), EVT (9), LOT (8), and TSC-mt RCC-NOS (10) based on morphology and IHC.
- ESC RCCs predominantly harbored TSC mutations, while LOTs mostly had MTOR mutations.
- RNA-seq revealed distinct expression profiles for ESC RCC, EVT, and LOT, with TSC-mt RCC-NOS cases often clustering with ESC RCC or EVT, suggesting overlap.
Conclusions:
- The study expands the morphologic spectrum of TSC/MTOR-associated eosinophilic renal tumors.
- Distinct gene mutation characteristics and expression profiles were identified for ESC RCC, EVT, and LOT.
- TSC-mt RCC-NOS may represent a continuum within TSC/MTOR-mutation-associated entities, highlighting diagnostic challenges, particularly with MiT RCC.
