Tuberous sclerosis complex: Hamartin and tuberin expression in renal cysts and its discordant expression in renal neoplasms

Stephen M Bonsib,Christie Boils,Neriman Gokden,David Grignon,Xin Gu,John P.T Higgins,Xavier Leroy,Jesse K Mckenney,Samih H Nasr,Carrie Phillips,Ankur R Sangoi,Jon Wilson,Ping L Zhang

doi:10.1016/j.prp.2016.04.005

Abstract

Tuberous sclerosis complex (TSC) results from mutation of TSC1 or TSC2 that encode for hamartin and tuberin. It affects the kidneys often in advance of extra-renal stigmata. We studied 14 TSC cases, and 4 possible TSC cases with multiple angiomyolipomas (AMLs) for hamartin and tuberin protein expression to determine if the staining profile could predict mutation status or likelihood of TSC with renal-limited disease. The 18 cases included 15 nephrectomies and 1 section of 6 TSC-associated renal cell carcinomas (RCC). Controls included the non-neoplastic kidney in 5 tumor nephrectomies, 4 sporadic cases of AML and 6 clear cell RCCs. In the 14 TSC cases, 9 had AMLs, 9 had RCCs, 5 had polycystic kidney disease and 8 had eosinophilic cysts (EC) lined by large eosinophilic cells. The controls and study cases showed luminal staining of proximal tubules (PT) and peripheral membrane staining in distal tubules/collecting ducts for hamartin and cytoplasmic staining for tuberin. Eosinophilic cysts had a luminal PT-like stain with hamartin and a cytoplasmic reaction for tuberin. Hamartin stained myoid cells in all AMLs. Tuberin was negative in all but 1AML, an epithelioid AML. All but 1 RCC were positive for tuberin; 13 RCCs (7 TSC/6 non-TSC) were negative for hamartin and 4 showed a weak reaction. We conclude that the ECs of TSC are proximal tubule-derived. The hamartin and tuberin staining profiles of AMLs and most RCCs are reciprocal precluding prediction of the mutation in TSC, and fail to predict if a patient with multifocal AML has TSC.

Highlights

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder that affects 1 in 6000 people [1,2]
Of 1of 2 genes, TSC1 or TSC2, that encode for hamartin and tuberin, respectively, and has 95% penetrance but highly variable clinical expression and severity [1,2,3,4]
This study evaluates the immunohistochemical staining profiles for hamartin and tuberin in TSC to determine their utility as a surrogate marker for the underlying genetic mutation, especially relevant in the cases of possible TSC where multifocal renal AMLs are present as the sole clinical finding

Summary

Introduction

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder that affects 1 in 6000 people [1,2]. It results from mutation of 1of 2 genes, TSC1 or TSC2, that encode for hamartin and tuberin, respectively, and has 95% penetrance but highly variable clinical expression and severity [1,2,3,4]. With the Gomez Criteria, the presence of multiple AMLs in a single kidney was regarded as definitive of TSC. A definitive diagnosis of TSC requires 2 different major lesions, or 1 major and 2 minor lesions, rather than multiple lesions of the same type [14]. Even with 2 major features to support a clinical diagnosis of TSC, genetic testing will only identify a mutation in 85% of patients [2]

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Conclusion