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.
Objective: Although the succinate dehydrogenase (SDH)-related tumor spectrum has been recently expanded, there are only rare reports of non-pheochromocytoma/paraganglioma tumors in SDHx-mutated patients. Therefore, questions still remain unresolved concerning the aforementioned tumors with regard to their pathogenesis, clinicopathological phenotype, and even causal relatedness to SDHx mutations. Absence of SDHB expression in tumors derived from tissues susceptible to SDH deficiency is not fully elucidated. Design and methods: Three unrelated SDHD patients, two with pituitary adenoma (PA) and one with papillary thyroid carcinoma (PTC), and three SDHB patients affected by renal cell carcinomas (RCCs) were identified from four European centers. SDHA/SDHB immunohistochemistry (IHC), SDHx mutation analysis, and loss of heterozygosity analysis of the involved SDHx gene were performed on all tumors. A cohort of 348 tumors of unknown SDHx mutational status, including renal tumors, PTCs, PAs, neuroblastic tumors, seminomas, and adenomatoid tumors, was investigated by SDHB IHC. Printed in Great BritainPublished by Bioscientifica Ltd.Conclusions: These findings strengthen the etiological association of SDHx genes with pituitary neoplasia and provide evidence against a link between PTC and SDHx mutations. Somatic deletions seem to constitute the second hit in SDHB-related renal neoplasia, while SDHx alterations do not appear to be primary drivers in sporadic tumorigenesis from tissues affected by SDH deficiency.
Solitary and multiple myofibromas are benign tumours that predominantly occur in infancy and childhood. Myofibromas occur especially in the head and neck region, and are characterized by SMA and, to a lesser extent, MSA expression. The clinical course is self-limiting, and local excision appears to be sufficient.
Most gastrointestinal stromal tumors (GISTs) harbor oncogenic mutations in KIT or platelet-derived growth factor receptor-a. However, a small subset of GISTs lacks such mutations and is termed 'wild-type GISTs'. Germline mutation in any of the subunits of succinate dehydrogenase (SDH) predisposes individuals to hereditary paragangliomas and pheochromocytomas. However, germline mutations of the genes encoding SDH subunits A, B, C or D (SDHA, SDHB, SDHC or SDHD; collectively SDHx) are also identified in GISTs. SDHA and SDHB immunohistochemistry are reliable techniques to identify pheochromocytomas and paragangliomas with mutations in SDHA, SDHB, SDHC and SDHD. In this study, we investigated if SDHA immunohistochemistry could also identify SDHA-mutated GISTs. Twenty-four adult wild-type GISTs and nine pediatric/adolescent wild-type GISTs were analyzed with SDHB, and where this was negative, then with SDHA immunohistochemistry. If SDHA immunohistochemistry was negative, sequencing analysis of the entire SDHA coding sequence was performed. All nine pediatric/adolescent GISTs and seven adult wild-type GISTs were negative for SDHB immunohistochemistry. One pediatric GIST and three SDHB-immunonegative adult wild-type GISTs were negative for SDHA immunohistochemistry. In all four SDHA-negative GISTs, a germline SDHA c.91C4T transition was found leading to a nonsense p.Arg31X mutation. Our results demonstrate that SDHA immunohistochemistry on GISTs can identify the presence of an SDHA germline mutation. Identifying GISTs with deficient SDH activity warrants additional genetic testing, evaluation and follow-up for inherited disorders and paragangliomas.
This study strengthens the etiological association of SDH genes with pituitary neoplasia, renal tumorigenesis, and gastric gastrointestinal stromal tumors. Furthermore, our results indicate that pancreatic neuroendocrine tumor also falls within the SDH-related tumor spectrum.
Understanding of the genetic pathophysiology of endocrine tumors has advanced significantly and mutations in many causative genes are routinely sought. New syndromic associations among endocrine tumors have also been identified. These novel associations are important to recognize in order to direct screening appropriately. For instance, pheochromocytomas and pituitary adenomas can rarely occur together, usually due to germline SDHx mutations (Dénes et al. 2015, Xekouki et al. 2015, Guerrero Pérez et al. 2016). Despite a multitude of known genetic risk factors, many unexplained cases of multiple endocrine tumors exist (O'Toole et al. 2015). New causative genes and other genomic mechanisms affecting previously identified genes need to be considered during diagnostic workup. Copy number variations (CNV) are an important mechanism in inherited tumor genetics. CNV can affect large genetic regions or can be limited to deletions of single exons. Such exon-level intragenic deletions have been reported in connection with genes associated with isolated and syndromic endocrine neoplasia (Bayley et al. 2009, Ricketts et al. 2010, Zatelli et al. 2014). Identification of single exon deletions can be challenging. Techniques like multiplex ligation-dependent probe amplification (MLPA) and quantitative PCR are generally available and can identify CNV (e.g. deletions) of individual exons in cases where sequencing results are apparently normal. Mutations in the MAX gene are associated with a risk of sporadic and hereditary pheochromocytoma and are also implicated in kidney tumors (Comino-Méndez et al. 2011, Burnichon et al. 2012). Recently a large deletion including the MAX promoter and exons 1 and 2 was identified in a family with bilateral pheochromocytoma and renal oncocytoma (Korpershoek et al. 2016). Using MLPA we studied six sporadic cases with multiple endocrine tumors that were negative on NGS panels and Sanger sequencing for known risk genes. Patients provided their consent and the study was approved by the Ethics Committee
Our results demonstrate that a positive SDHD immunostaining predicts the presence of an SDHx gene mutation. Because SDHB negative immunostaining is sometimes difficult to interpret in the case of background, the addition of SDHD positive immunohistochemistry will be a very useful tool to predict or validate SDHx gene variants in PGL/PCC.
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