6533b870fe1ef96bd12d0640

RESEARCH PRODUCT

Non-pheochromocytoma (PCC)/paraganglioma (PGL) tumors in patients with succinate dehydrogenase-related PCC-PGL syndromes: a clinicopathological and molecular analysis

Hans MorreauLeo J. HoflandDavid F. RestucciaJohan M. KrosMarieke F. Van DoorenOzgur MeteGeert J.l.h. Van LeendersEsther KorpershoekJosé GaalTorsten HansenSylvia L. AsaLeendert H. J. LooijengaRonald R. De KrijgerKetil HeimdalJean-pierre BayleyFrancien H Van NederveenWolf J. MannIngrid Van KesselWinand N.m. DinjensLindsey OudijkEleonora P M CorssmitPer Arne AndresenThomas G. PapathomasThomas SchreinerKonstantinos Papaspyrou

subject

AdenomaAdultMalemedicine.medical_specialtyPathologySDHBEndocrinology Diabetes and MetabolismSDHALoss of HeterozygosityBiologyPheochromocytomaLoss of heterozygosityEndocrinologyParagangliomaInternal medicinemedicineHumansPituitary NeoplasmsThyroid NeoplasmsCarcinoma Renal CellGerm-Line MutationCarcinomaGeneral MedicineExonsMiddle Agedmedicine.diseaseNeuroblastic TumorCarcinoma Papillary3. Good healthNeoplasm ProteinsSuccinate DehydrogenaseEndocrinologyThyroid Cancer PapillaryMutationFemaleSDHDClear cellGene Deletion

description

ObjectiveAlthough 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 methodsThree 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.ResultsOf the six index patients, all RCCs and one PA displayed SDHB immunonegativity in contrast to the other PA and PTC. All immunonegative tumors demonstrated loss of the WT allele, indicating bi-allelic inactivation of the germline mutated gene. Of 348 tumors, one clear cell RCC exhibited partial loss of SDHB expression.ConclusionsThese 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.

10.1530/eje-13-0623https://doi.org/10.1530/eje-13-0623