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Published on: January 22, 2013
Genetic validation of a TSC2 immunohistochemistry assay in TSC/mTOR-pathway altered renal tumors
Amir Akbari1, Clarence Rachel Villanueva2, Ondrej Hes3
1Department of Pathology, Johns Hopkins School of Medicine, USA; Department of Pathology, University of Southern California Keck School of Medicine, USA.
Abstract:
Pathogenic mutations in the genes associated with tuberous sclerosis complex (TSC)/mTOR pathway are linked to histologically diverse renal cell neoplasms, including eosinophilic solid and cystic renal cell carcinoma (ESC RCC), low grade oncocytic tumor (LOT), eosinophilic vacuolated tumor (EVT), and xanthomatous giant cell renal cell carcinoma (XGC RCC). Here, we validate a TSC2 immunohistochemistry (IHC) assay by comparison to genomic data in these neoplasms. Automated TSC2 IHC was performed on formalin-fixed paraffin embedded (FFPE) tissues from 38 genetically-confirmed TSC/mTOR-associated renal tumors (6 ESCs, 16 EVTs, 13 LOTs, 2 XGC and 1 clear cell RCC) and visually scored in a semi-dichotomous fashion compared to internal control tissue. The positive predictive value (PPV) of TSC2 protein loss for underlying pathogenic mutation in TSC2 was 92% (11/12), while the negative predictive value (NPV) of intact TSC2 by IHC for lack of underlying pathogenic mutation in TSC2 was 81% (21/26). Intact TSC2 by IHC was 95% (21/22) specific for absence of underlying pathogenic TSC2 mutation. All the cases lacking TSC2 mutation with intact TSC2 protein had an underlying mutation in TSC1, MTOR or PIK3CA. Loss of TSC2 was 77% (10/13) sensitive for underlying TSC2 truncation mutations and 33% (1/3) sensitive for underlying TSC2 missense mutations. Overall, 73% (8/11) tumors with TSC2 IHC loss and underlying pathogenic alterations in TSC2 showed heterogeneous protein loss, with rare interspersed positively staining tumor cells. These data support TSC2 IHC as a potentially useful assay for the diagnostic workup of renal tumors suspected to belong to the TSC/mTOR-associated subgroups.
Insights
Immunohistochemistry for TSC2 protein loss can help diagnose rare kidney cancers linked to the TSC/mTOR pathway. This assay shows promise in identifying specific tumor subtypes, aiding in accurate diagnosis and patient management.
Area of Science:
- Oncology
- Pathology
- Genetics
Background:
- Tuberous sclerosis complex (TSC)/mTOR pathway mutations are associated with diverse renal cell neoplasms.
- Specific subtypes include eosinophilic solid and cystic renal cell carcinoma (ESC RCC), low grade oncocytic tumor (LOT), eosinophilic vacuolated tumor (EVT), and xanthomatous giant cell renal cell carcinoma (XGC RCC).
Purpose of the Study:
- To validate a TSC2 immunohistochemistry (IHC) assay for diagnosing TSC/mTOR-associated renal tumors.
- To compare IHC results with genomic data in these specific neoplasms.
Main Methods:
- Automated TSC2 IHC performed on formalin-fixed paraffin-embedded (FFPE) tissues from 38 genetically-confirmed TSC/mTOR-associated renal tumors.
- Visual scoring of TSC2 IHC in comparison to internal control tissue.
- Analysis of positive and negative predictive values, specificity, and sensitivity of TSC2 IHC.
Main Results:
- TSC2 IHC demonstrated a 92% positive predictive value for pathogenic TSC2 mutations.
- Intact TSC2 by IHC was 95% specific for the absence of TSC2 mutations, with mutations found in TSC1, MTOR, or PIK3CA in these cases.
- TSC2 loss sensitivity varied for truncation (77%) versus missense (33%) mutations.
- Heterogeneous TSC2 protein loss was observed in 73% of tumors with TSC2 alterations.
Conclusions:
- TSC2 IHC is a potentially useful assay for the diagnostic workup of renal tumors.
- The assay can help identify TSC/mTOR-associated subgroups of renal neoplasms.
- IHC findings support the utility of TSC2 protein assessment in diagnosing specific kidney cancers.
