A case of Carney triad complicated by renal cell carcinoma and a germline 
      <i>SDHA</i> pathogenic variant

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Summary

Succinate dehydrogenase deficiency has been associated with several neoplasias, including renal cell carcinoma (RCC) and those associated with hereditary paraganglioma (PGL)/ pheochromocytoma (PHEO) syndromes, Carney dyad, and Carney triad. Carney triad is a rare multitumoral syndrome characterized by co-existing PGL, gastrointestinal stromal tumor (GIST), and pulmonary chondroma (CHO). We report a case of a 57-year-old male who presented with para-aortic and gastroesophogeal masses, and a right renal superior pole lesion, which were classified as multiple PGLs, a GIST, and a clear cell renal carcinoma, respectively, on pathology following surgical resection. Additionally, a CHO was diagnosed radiologically, although no biopsy was performed. A diagnosis of Carney triad was made. SDHB immunohistochemical staining was negative for the PGL and the GIST, indicating SDH-deficiency. Interestingly, the renal cell carcinoma (RCC) stained positive for both SDHB and SDHA. Subsequent genetic screening of SDH subunit genes revealed a germline inactivating heterozygous SDHA pathogenic variant (c.91 C>T, p.R31X). Loss of heterozygosity was not detected at the tumor level for the RCC, which likely indicated the SDHA variant would not be causative of the RCC, but could still predispose to the development of neoplasias. To the knowledge of the authors this is the first reported case of an SDHA pathogenic variant in a patient with Carney triad complicated by RCC.

Learning points

The succinate dehydrogenase enzyme is encoded by four subunit genes ( SDHA, SDHB, SDHC, and SDHD; collectively referred to as SDHx), which have been implicated in several neoplasias and are classified as tumor suppressor genes.
Carney triad is a rare multiple-neoplasia syndrome presenting as an association of PGLs, GISTs, and CHOs.
Carney triad is most commonly associated with hypermethylation of SDHC as demonstrated in tumor tissue, but approximately 10% of cases are due to pathogenic SDHx variants.
Although SDHB pathogenic variants are most commonly reported in SDH-deficient renal cell carcinoma, SDHA disease-causing variants have been reported in rare cases.

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Most cited references 19

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WHO/ISUP classification, grading and pathological staging of renal cell carcinoma: standards and controversies

Anne Warren, David Harrison (2018)

Purpose Pathological parameters assessed on biopsies and resection specimens have a pivotal role in the diagnosis, prognosis and management of patients with renal cell carcinoma (RCC). Methods A non-systematic literature search was performed, updated to January 2018, to identify key standards and controversies in the pathological classification, grading and staging of RCC. Results Although most RCCs exhibit characteristic morphology that enables easy categorisation, RCCs show considerable morphological heterogeneity and it is not uncommon for there to be difficulty in assigning a tumour type, especially with rarer tumour subtypes. The differentiation between benign and malignant oncocytic tumours remains a particular challenge. The development of additional immunohistochemical and molecular tests is needed to facilitate tumour typing, because of the prognostic and therapeutic implications, and to enable more reliable identification of poorly differentiated metastatic tumours as being of renal origin. Any new tests need to be applicable to small biopsy samples, to overcome the heterogeneity of renal tumours. There is also a need to facilitate identification of tumour types that have genetic implications, to allow referral and management at specialist centres. Digital pathology has a potential role in such referral practice. Conclusion Much has been done to standardise pathological assessment of renal cell carcinomas in recent years, but there still remain areas of difficulty in classification and grading of these heterogeneous tumours.

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SDHA immunohistochemistry detects germline SDHA gene mutations in apparently sporadic paragangliomas and pheochromocytomas.

Esther Korpershoek, Judith Favier, José Gaal … (2011)

Pheochromocytoma-paraganglioma syndrome is caused by mutations in SDHB, SDHC, and SDHD, encoding subunits of succinate dehydrogenase (SDH), and in SDHAF2, required for flavination of SDHA. A recent report described a patient with an abdominal paraganglioma, immunohistochemically negative for SDHA, and identified a causal germline mutation in SDHA. In this study, we evaluated the significance of SDHA immunohistochemistry in the identification of new patients with SDHA mutations. This study was performed in the Erasmus Medical Center in Rotterdam (The Netherlands) and the Université Paris Descartes in Paris (France). We investigated 316 pheochromocytomas and paragangliomas for SDHA expression. Sequence analysis of SDHA was performed on all tumors that were immunohistochemically negative for SDHA and on a subset of tumors immunohistochemically positive for SDHA. Six tumors were immunohistochemically negative for SDHA. Four tumors from Dutch patients showed a germline c.91C → T SDHA gene mutation (p.Arg31X). Another tumor (from France) carried a germline SDHA missense mutation c.1753C → T (p.Arg585Trp). Loss of the wild-type SDHA allele was confirmed by loss of heterozygosity analysis. Sequence analysis of 35 SDHA immunohistochemically positive tumors did not reveal additional SDHA mutations. Our results demonstrate that SDHA immunohistochemistry on paraffin-embedded tumors can reveal the presence of SDHA germline mutations and allowed the identification of SDHA-related tumors in at least 3% of patients affected by apparently sporadic (para)sympathetic paragangliomas and pheochromocytomas.

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Recurrent epimutation of SDHC in gastrointestinal stromal tumors.

J Killian, Markku Miettinen, Robert Walker … (2014)

Succinate dehydrogenase (SDH) is a conserved effector of cellular metabolism and energy production, and loss of SDH function is a driver mechanism in several cancers. SDH-deficient gastrointestinal stromal tumors (dSDH GISTs) collectively manifest similar phenotypes, including hypermethylated epigenomic signatures, tendency to occur in pediatric patients, and lack of KIT/PDGFRA mutations. dSDH GISTs often harbor deleterious mutations in SDH subunit genes (SDHA, SDHB, SDHC, and SDHD, termed SDHx), but some are SDHx wild type (WT). To further elucidate mechanisms of SDH deactivation in SDHx-WT GIST, we performed targeted exome sequencing on 59 dSDH GISTs to identify 43 SDHx-mutant and 16 SDHx-WT cases. Genome-wide DNA methylation and expression profiling exposed SDHC promoter-specific CpG island hypermethylation and gene silencing in SDHx-WT dSDH GISTs [15 of 16 cases (94%)]. Six of 15 SDHC-epimutant GISTs occurred in the setting of the multitumor syndrome Carney triad. We observed neither SDHB promoter hypermethylation nor large deletions on chromosome 1q in any SDHx-WT cases. Deep genome sequencing of a 130-kbp (kilo-base pair) window around SDHC revealed no recognizable sequence anomalies in SDHC-epimutant tumors. More than 2000 benign and tumor reference tissues, including stem cells and malignancies with a hypermethylator epigenotype, exhibit solely a non-epimutant SDHC promoter. Mosaic constitutional SDHC promoter hypermethylation in blood and saliva from patients with SDHC-epimutant GIST implicates a postzygotic mechanism in the establishment and maintenance of SDHC epimutation. The discovery of SDHC epimutation provides a unifying explanation for the pathogenesis of dSDH GIST, whereby loss of SDH function stems from either SDHx mutation or SDHC epimutation.

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Author and article information

Journal

Journal ID (nlm-ta): Endocrinol Diabetes Metab Case Rep

Journal ID (iso-abbrev): Endocrinol Diabetes Metab Case Rep

Journal ID (hwp): EDM

Title: Endocrinology, Diabetes & Metabolism Case Reports

Publisher: Bioscientifica Ltd (Bristol )

ISSN (Electronic): 2052-0573

Publication date (Electronic): 02 March 2021

Publication date Collection: 2021

Volume: 2021

Electronic Location Identifier: 20-0170

Affiliations

[1 ]Section on Endocrinology and Genetics , National Institutes of Health, Bethesda, Maryland, USA

[2 ]Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development , National Institutes of Health, Bethesda, Maryland, USA

[3 ]Cancer Diagnosis and Pathology Group , Kolling Institute of Medical Research, Royal North Shore Hospital St Leonards NSW 2065 Australian and Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia

[4 ]Adult Genetics Unit , Royal Adelaide Hospital

[5 ]Adelaide Medical School , University of Adelaide, Adelaide, South Australia, Australia

[6 ]Laboratory of Pathology Center for Cancer Research , National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA