Succinate dehydrogenase-deficient renal cell carcinoma:a clinicopathological, ultrastructural and molecular analysis / 中华病理学杂志

Objective: To investigate the clinicopathological features, immunophenotype, ultrastructure, genetic alterations and prognosis of succinate dehydrogenase-deficient renal cell carcinoma (SDH RCC). Methods: A total of 11 SDH RCCs, diagnosed from 2010 to 2019, were selected from the Department of Pathology of Nanjing Jingling Hospital, Nanjing University School of Medicine for clinicopathologic, immunohistochemical (IHC), ultrastructural investigation and follow-up. The molecular features of seven cases were analyzed by the panel-targeted DNA next generation sequencing (NGS). Results: There were seven males and four females, with ages ranging from 24 to 62 years (mean 41.4 years, median 41 years). Microscopically, SDH RCC was mainly composed of solid and tubular structures with local cystic change. Four cases showed nested or trabecular structure distributed in a loose hypocellular connective tissue or around scar, similar to oncocytoma. The neoplastic cells demonstrated flocculent eosinophilic cytoplasm with typical intracytoplasmic vacuoles. Immunohistochemically, eight cases were negative for SDHB; three cases showed focal and weak expression, whereas normal renal tubular and vascular endothelial cells demonstrated strong cytoplasmic staining. NGS of DNA targeted-panel detected pathogenic mutations of SDHB gene in seven cases (including three cases with equivocal IHC expression of SDHB), without any mutations in other SDH related genes. There were four cases of SDHB missense mutation, one case of frameshift mutation, one case of splicing mutation, and one case of acquired stop codon mutation. Conclusions: SDH RCC is a distinct variant of RCCs with genetic tendency or with hereditary cancer syndrome. NGS is recommended to detect the related gene mutations for a definitive diagnosis. The patients should be closely followed up.

Germline gene testing of the RET, VHL, SDHD and SDHB genes in patients with pheochromocytoma/paraganglioma / 北京大学学报(医学版)

OBJECTIVE@#To analyze the germline variations of genes RET, VHL, SDHD and SDHB in patients with pheochromocytoma and/or paraganglioma and to evaluate variations of these genes in Chinese patients.@*METHODS@#Patients who were treated in Peking University First Hospital from September 2012 to March 2014 and diagnosed with pheochromocytoma and/or paraganglioma by pathologists were included in this study. Twelve patients were included in total, of whom 11 had pheochromocytoma, and 1 had paraganglioma. Deoxyribonucleic acid (DNA) was extracted from the leukocytes of peripheral blood of the patients. The exons 10, 11, 13-16 of the RET gene, and all exons of VHL, SDHB and SDHD genes and their nearby introns (±20 bp) were amplified with polymerase chain reactions, and the products were sent to a biotechnology company for sequencing. The sequencing results were compared with wildtype sequences of these genes to identify variations. One of the patients was diagnosed with multiple endocrine neoplasia type 2A. A family analysis was performed in his kindred, and his family members received genetic tests for the related variations.@*RESULTS@#Three patients were found to have germline gene variations. A c.136C>T (p.R46X) variation of the SDHB gene was found in a patient with malignant pheochromocytoma. A c.1901G>A (C634Y) variation, as well as c.2071G>A (p.G691S) and c.2712C>G (p.S904S) variations of the RET gene were found in a patient with multiple endocrine neoplasia type 2A. After a family analysis, five family members of this patient were found to have the same variations. c.2071G>A (p.G691S) and c.2712C>G (p.S904S) variations of the RET gene were also found in a clinical sporadic patient without evidence of malignancy. A patient with congenital single ventricle malformation and pheochromocytoma was included in this study, and no variation with clinical significance was found in the four genes of this patient.@*CONCLUSION@#25% (3/12) patients with pheochromocytoma or paraganglioma were found to have missense or nonsense germline gene variations in this study, including the c.136C>T (p.R46X) variation of the SDHB gene, the c.1901G>A (C634Y) variation of the RET gene, and c.2071G>A (p.G691S) and c.2712C>G (p.S904S) variations of the RET gene. The former two variations have already been confirmed to be pathogenic. The existence of these variations in Chinese patients with pheochromocytoma and/or paraganglioma was validated in this study, which supports the conclusion that genetic testing is necessary to be generally performed in patients with pheochromocytoma and/or paraganglioma.

Sunitinib in the therapy of malignant paragangliomas: report on the efficacy in a SDHB mutation carrier and review of the literature

SUMMARY Metastatic pheochromocytomas (PHEOs) and paragangliomas (sPGLs) are rare neural crest-derived tumors with a poor prognosis. About 50% of them are due to germ-line mutations of the SDHB gene. At present, there is no cure for these tumors. Their therapy is palliative and represented by different options among which antiangiogenic drugs, like sunitinib, have been hypothesized to be effective especially in malignant SDHB mutated tumors. We report the effects of sunitinib therapy in a SDHB mutation carrier affected by a malignant sPGL. During 101 weeks of therapy at different doses, sunitinib was able to cause a partial response and then a stable disease for a total of 78 weeks. This favorable response is the longest, out of the 35 so far reported in the literature, registered in a patient treated exclusively with sunitinib but, similarly to the other responses, the effect was limited in time. From our analysis of the scanty data present in the literature, the effect of sunitinib does not seem to be different among wild-type patients and those carrying a cluster 1 germ-line mutation. Sunitinib seems able to slow the disease progression in some patients with malignant PHEO/PGL and therefore may represent a therapeutic option, although randomized controlled studies are needed to assess its efficacy definitively in the treatment of these aggressive tumors.

Over-representation of the G12S polymorphism of the SDHD gene in patients with MEN2A syndrome

OBJECTIVE: To evaluate whether germline variants of the succinate dehydrogenase genes might be phenotypic modifiers in patients with multiple endocrine neoplasia type 2. Mutations of genes encoding subunits of the succinate dehydrogenase are associated with hereditary paraganglioma/pheochromocytoma syndrome. Pheochromocytoma is one of the main manifestations of multiple endocrine neoplasia type 2 caused by germline mutation of the rearranged during transfection proto-oncogene. METHODS: Polymorphisms of the succinate dehydrogenase genes were analyzed in 77 rearranged during transfection mutation carriers, 47 patients with sporadic medullary thyroid cancer, 48 patients with sporadic Pheo, and 100 healthy individuals. Exons 10-16 of the rearranged during transfection proto-oncogene were analyzed by direct DNA sequencing, and all exons of the von Hippel-Lindau, succinate dehydrogenase B, and succinate dehydrogenase subunit D genes were tested by direct DNA sequencing and multiple ligation probe analysis. The G12S polymorphism of the succinate dehydrogenase subunit D gene was determined by restriction fragment length polymorphism. RESULTS: Of the 77 rearranged during transfection mutation carriers, 55 from 16 families had multiple endocrine neoplasia type 2A, three from three families had multiple endocrine neoplasia type 2B, and 19 from two families had familial medullary thyroid carcinoma. Eight of 55 (14.5%) patients with multiple endocrine neoplasia type 2A had this variant whereas it was absent in multiple endocrine neoplasia type 2B, familial medullary thyroid carcinoma, sporadic medullary thyroid carcinoma, and sporadic pheochromocytoma groups, and its prevalence in controls was 1% (p<0.002 multiple endocrine neoplasia type 2A versus controls). No associations between G12S and age of manifestation, incidence of pheochromocytoma or hyperparathyroidism, or level of serum calcitonin were observed. CONCLUSION: The high prevalence of the G12S variant in patients with multiple endocrine neoplasia type 2A raises questions about its role as a genetic modifier, but this proposal remains to be established.

Paraganglioma of seminal vesicle and chromophobe renal cell carcinoma: a case report and literature review / Paraganglioma da vesícula seminal e carcinoma de células renais cromófobo: um relato de caso e revisão da literatura

CONTEXT: Extra-adrenal paragangliomas are rare tumors that have been reported in many locations, including the kidney, urethra, urinary bladder, prostate, spermatic cord, gallbladder, uterus and vagina. CASE REPORT: This report describes, for the first time to the best of our knowledge, a primary paraganglioma of the seminal vesicle occurring in a 61-year-old male. The patient presented persistent arterial hypertension and a previous diagnosis of chromophobe renal cell carcinoma. It was hypothesized that the seminal vesicle tumor could be a metastasis from the chromophobe renal cell carcinoma. Immunohistochemical characterization revealed expression of synaptophysin and chromogranin in tumor cell nests and peripheral S100 protein expression in sustentacular cells. Succinate dehydrogenase A and B-related (SDHA and SDHB) expression was present in both tumors. CONCLUSIONS: No genetic alterations to the VHL and SDHB genes were detected in either the tumor tissue or tissues adjacent to the tumor, which led us to rule out a hereditary syndrome that could explain the association between paraganglioma and chromophobe renal cell carcinoma in a patient with arterial hypertension.

CONTEXTO: Paragangliomas extra-adrenais são tumores raros que têm sido relatados em muitas localizações, incluindo rim, uretra, bexiga, próstata, cordão espermático, vesícula biliar, útero e vagina. RELATO DE CASO: Este relato descreve, pela primeira vez em nosso conhecimento, um paraganglioma primário da vesícula seminal ocorrendo em um paciente do sexo masculino de 61 anos de idade. O paciente apresentou hipertensão arterial persistente e um diagnóstico prévio de carcinoma de células renais cromófobo (CCRC). Foi pensado que o tumor de vesícula seminal poderia ser uma metástase do CCRC. A caracterização imunoistoquímica revelou expressão de sinaptofisina e cromogranina nos ninhos de células tumorais e expressão de proteína S100 nas células sustentaculares. Expressão de succinato de-hidrogenase A e B relacionada (SDHA e SDHB) estiveram presentes em ambos os tumores CONCLUSÕES: Nenhuma alteração genética dos genes VHL e SDHB foi detectada nos tecidos tumorais e adjacentes ao tumor, o que nos levou a afastar uma síndrome hereditária que poderia explicar a associação entre o paraganglioma e o CCRC em um paciente com hipertensão arterial.

Paragangliomas múltiples asociados a mutación del gen SDHB: Caso clínico / Multiple paragangliomas associated to a SDHB gene mutation: Report of one case

Paragangliomas are tumors arising from sympathetic and parasympathetic tissues. The classic associated syndromes are neurofibromatosis type 1, multiple endocrine neoplasia type 2 and von Hippel-Lindau. Germline mutations of succinate dehydroge-nase subunits genes, are associated with familial paraganglioma syndromes 1,2,3 and 4. We report a 29-year-old woman with a family background of pheochromocytoma and history of paroxysmal headache, nausea, sweating, palpitations, associated with severe hypertension. The patient had elevated plasma noradrenalin and urinary normetanephrines. Imaging studies revealed three retroperitoneal extra-adrenal masses. The clinical and laboratory study of classic syndromes associated with para-ganglioma was negative. The patient was operated and the pathological study of the surgical specimen was consistent with paragangliomas. The genetic study showed a mutation in the SDHB succinate dehydrogenase gen, Exon 2 of CCTCA c.300_304 (p.P56delYfsX5).

No association of an SDHC gene polymorphism with gastric cancer.

It is widely reported that reactive oxygen species (ROS) cause apotosis and carcinogenesis. Marked infiltration of activated leukocyte and enhanced production of ROS appear to occur in the gastric mucosa infected with Helicobacter pylori (H. pylori). The previous studies reported that the mutation of the succinate dehydrogenase subunit C (SDHC) gene caused the increase in superoxide anion (O(2)(-)) and oxidative stress. To extend these findings, we epidemiologically investigated the association of a SDHC polymorphism at 3'-untranslated region of exon 6 (JST173800) with H. pylori infection, gastric atrophy and gastric cancer risk in Japan. The subjects consisted of 454 health checkup examinees without a history of cancer and 202 gastric cancer patients. The SDHC polymorphism was not associated with H. pylori infection seropositivity, gastric atrophy, and cancer risk in this study. Although the polymorphism at the 3'-untranslated region could be hypothesized to be functional, this study did not demonstrate any significant association of the SDHC gene polymorphism with gastric atrophy and cancer.