SDHC phaeochromocytoma and paraganglioma: A UK‐wide case series

Abstract

Objective Phaeochromocytomas and paragangliomas (PPGL) are rare, but strongly heritable tumours. Variants in succinate dehydrogenase (SDH) subunits are identified in approximately 25% of cases. However, clinical and genetic information of patients with SDHC variants are underreported. Design This retrospective case series collated data from 18 UK Genetics and Endocrinology departments. Patients Both asymptomatic and disease‐affected patients with confirmed SDHC germline variants are included. Measurements Clinical data including tumour type and location, surveillance outcomes and interventions, SDHC genetic variant assessment, interpretation, and tumour risk calculation. Results We report 91 SDHC cases, 46 probands and 45 non‐probands. Fifty‐one cases were disease‐affected. Median age at genetic diagnosis was 43 years (range: 11–79). Twenty‐four SDHC germline variants were identified including six novel variants. Head and neck paraganglioma (HNPGL, n = 30, 65.2%), extra‐adrenal paraganglioma (EAPGL, n = 13, 28.2%) and phaeochromocytomas (PCC) (n = 3, 6.5%) were present. One case had multiple PPGLs. Malignant disease was reported in 19.6% (9/46). Eight cases had non‐PPGL SDHC‐associated tumours, six gastrointestinal stromal tumours (GIST) and two renal cell cancers (RCC). Cumulative tumour risk (95% CI) at age 60 years was 0.94 (CI: 0.79–0.99) in probands, and 0.16 (CI: 0–0.31) in non‐probands, respectively. Conclusions This study describes the largest cohort of 91 SDHC patients worldwide. We confirm disease‐affected SDHC variant cases develop isolated HNPGL disease in nearly 2/3 of patients, EAPGL and PCC in 1/3, with an increased risk of GIST and RCC. One fifth developed malignant disease, requiring comprehensive lifelong tumour screening and surveillance.

Clear Cell Renal Cancer, a Tumour with Neuroendocrine Features Originating from the Erythropoietin-Producing Cell

“…Moreover, clinically ccRCCs have as outlined above, many similarities to neuroendocrine tumours in general. Furthermore, polycythaemia due to EPO production has been reported together with somatostatinoma, paraganglioma, and phaeochromocytoma [75,76]. We found not only EPO but also NSE expression in virtually all ccRCCs, but both markers, were mostly negative in the other types of renal cell carcinomas [2].…”

Head and Neck Cancer: United Kingdom National Multidisciplinary Guidelines, Sixth Edition

“…A UK-wide series of SDHC cases demonstrated that 65 per cent presented with head and neck paraganglioma. 1202 Around 20 per cent of head and neck paragangliomas and 30 per cent of phaeochromocytomas were metastatic. As with the other genes, penetrance is difficult to estimate.…”

Succinate dehydrogenase complex subunit C: Role in cellular physiology and disease

“…48,49 A case series of patients with SDHC mutations from the United Kingdom revealed SDHC mutations in head and neck paraganglioma, extra-adrenal paraganglioma, and pheochromocytoma. 50 Head and neck paragangliomas associated with SDHC mutations are almost always benign and mostly solitary. 51 A case of catecholamine-producing malignant paraganglioma due to SDHC mutation showed G→T transversion in intron 5 + 1 of SDHC , resulting in exon 5 deletion, reading frameshift, 52 and aberrant splicing.…”