Dataset Information

Somatic Bi-allelic Loss of TSC Genes in Eosinophilic Solid and Cystic Renal Cell Carcinoma.

ABSTRACT: Renal cell carcinomas (RCC) with overlapping histomorphologic features poses diagnostic challenges. This is exemplified in RCCs with eosinophilic cytoplasm that include eosinophilic solid and cystic RCC (ESC RCC), RCCs in germline aberrations of tuberous sclerosis complex (TSC) genes mutated (TSC RCC) individuals, and other RCC subtypes. We used next-generation sequencing (NGS) technology to molecularly profile seven ESC RCC tumors. Mutational and copy number analysis of NGS data revealed mutually exclusively somatic bi-allelic loss of TSC1 or TSC2 genes-both negative regulators of the mammalian target of rapamycin (mTOR) pathway in 85% (6/7) of evaluated cases. Thus, lack of germline TSC aberration in matched non-neoplastic renal parenchyma distinguishes ESC RCC from TSC RCC. Immunohistochemistry data shows mTOR pathway activation in all tumors, thus supporting a pathognomonic role for TSC aberrations in ESC RCC. Our study clarifies the molecular identity of ESC RCC, provides basis for the revision of current RCC classification, and may guide future therapeutic strategies. PATIENT SUMMARY:Molecular characterization of eosinophilic solid and cystic renal cell carcinomas (ESC RCC) revealed recurrent and mutually exclusive somatic homozygous loss of tuberous sclerosis complex family genes. This observation provides greater insight into the unique biology of this novel type of tumor and potentially expands the therapeutic options for ESC RCC patients.

SUBMITTER: Mehra R

PROVIDER: S-EPMC6390848 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Somatic Bi-allelic Loss of TSC Genes in Eosinophilic Solid and Cystic Renal Cell Carcinoma.

Mehra Rohit R Vats Pankaj P Cao Xuhong X Su Fengyun F Lee Nicole D ND Lonigro Robert R Premkumar Kumpati K Trpkov Kiril K McKenney Jesse K JK Dhanasekaran Saravana M SM Chinnaiyan Arul M AM

European urology 20180623 4

Renal cell carcinomas (RCC) with overlapping histomorphologic features poses diagnostic challenges. This is exemplified in RCCs with eosinophilic cytoplasm that include eosinophilic solid and cystic RCC (ESC RCC), RCCs in germline aberrations of tuberous sclerosis complex (TSC) genes mutated (TSC RCC) individuals, and other RCC subtypes. We used next-generation sequencing (NGS) technology to molecularly profile seven ESC RCC tumors. Mutational and copy number analysis of NGS data revealed mutual ...[more]

PMID: 29941307

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Project description:Eosinophilic solid and cystic (ESC) renal cell carcinoma (RCC) has recently been described as a potentially new subtype of RCC based upon morphologic and immunohistochemical features. These neoplasms typically demonstrate solid and cystic architecture, and the neoplastic cells contain voluminous eosinophilic cytoplasm with granular cytoplasmic stippling. There is frequently focal immunoreactivity for cytokeratin 20. Although the initial cases all occurred in adult females and had benign outcome, we recently expanded the proposed spectrum of this neoplasm to include pediatric cases, multifocal neoplasms, and a case with hematogenous metastasis. ESC has been postulated to be analogous to a subtype of RCC consistently identified in tuberous sclerosis complex patients, and while previous work has demonstrated loss of heterozygosity at the TSC1 locus and copy number gains at TSC2 in ESC RCC, these genes have not been sequenced in ESC RCC. Using capture-based and amplicon-based next-generation sequencing, we now demonstrate the consistent presence of either TSC1 or TSC2 gene mutations in pediatric ESC RCC (8/9 cases) and adult ESC RCC (6/6 cases). These included a metastatic ESC RCC which had a complete response to mTOR targeted therapy. We also found these mutations in some neoplasms with variant morphology and thus potentially expand the spectrum of ESC RCC. These include one of our adult cases which demonstrated dominant "type 2" papillary RCC morphology and 2 of 3 previously unclassified pediatric RCC with features of ESC RCC minus granular cytoplasmic stippling. We also demonstrate TSC mutations in a case of so-called "oncocytoid RCC after neuroblastoma" with identical morphology and immunoprofile, providing a molecular link between the latter and ESC RCC. In summary, ESC RCC consistently harbors actionable TSC1 or TSC2 mutations, which are infrequently seen in established subtypes of RCC. These findings support TSC1/2 mutation as a molecular marker of ESC RCC, and suggest expansion of the clinicopathologic spectrum to include neoplasms with papillary architecture, occasional cases lacking well-developed granular cytoplasmic stippling, and a subset of RCC with oncocytic features in patients who have survived neuroblastoma.

Project description:The differential diagnosis of renal cell neoplasms with solid or nested architecture and eosinophilic cytoplasm has become increasingly complex. Despite recent advances in classifying a number of entities exhibiting this morphology, some tumors remain in the unclassified category. Here we describe a morphologically distinct group of sporadic renal cell carcinoma (RCC) with predominantly nested architecture, eosinophilic, and remarkably vacuolated cytoplasm retrospectively identified from a cohort of previously unclassified tumors. We examined the clinicopathologic and immunohistochemical features of these tumors and investigated their mutational and copy number alterations using a targeted next-generation sequencing platform. The study included 7 patients with a mean age of 54 years (range: 40 to 68 y) and a male to female ratio of 3:4. All patients presented with a solitary renal mass and had no prior medical or family history raising concern for syndromic conditions. Tumors were well-circumscribed, unencapsulated, and comprised of nests of eosinophilic cells in a hypocellular and often edematous stroma. Tumor cells had round nuclei with prominent nucleoli and granular cytoplasm with striking vacuolization. Thick-walled vessels and calcifications were also frequently present, whereas increased mitotic activity, necrosis, foamy histiocytes or lymphocytic infiltrates were not identified. All cases were positive for PAX8, had retained expression of SDHB and FH, and exhibited a CK7-/CK20- phenotype. While cathepsin-K was positive in 5 cases, none exhibited immunoreactivity to HMB45 or Melan A, or TFE3 immunostaining. Next-generation sequencing identified somatic inactivating mutations of TSC2 (3/5 tumors tested) or activating mutations of MTOR (2/5) as the primary molecular alterations, consistent with hyperactive mTOR complex 1 signaling which was further demonstrated by phospho-S6 and phospho-4E-BP1 immunostaining. Copy number analysis revealed a loss of chromosome 1 in both cases with MTOR mutation. These tumors represent a novel subset of sporadic RCC characterized by alterations in TSC1-TSC2 complex or the mTOR complex 1 pathway. Recognition of their characteristic morphologic and immunophenotypic features will allow them to be readily identified and separated from the unclassified RCC category.

Dataset Information

Somatic Bi-allelic Loss of TSC Genes in Eosinophilic Solid and Cystic Renal Cell Carcinoma.

Publications

Somatic Bi-allelic Loss of TSC Genes in Eosinophilic Solid and Cystic Renal Cell Carcinoma.

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