Heterogeneous Genetic Background of the Association of Pheochromocytoma/Paraganglioma and Pituitary Adenoma: Results From a Large Patient Cohort

Abstract

Context:Pituitary adenomas and pheochromocytomas/paragangliomas (pheo/PGL) can occur in the same patient or in the same family. Coexistence of the two diseases could be due to either a common pathogenic mechanism or a coincidence.Objective:The objective of the investigation was to study the possible coexistence of pituitary adenoma and pheo/PGL.Design:Thirty-nine cases of sporadic or familial pheo/PGL and pituitary adenomas were investigated. Known pheo/PGL genes (SDHA-D, SDHAF2, RET, VHL, TMEM127, MAX, FH) and pituitary adenoma genes (MEN1, AIP, CDKN1B) were sequenced using next generation or Sanger sequencing. Loss of heterozygosity study and pathological studies were performed on the available tumor samples.Setting:The study was conducted at university hospitals.Patients:Thirty-nine patients with sporadic of familial pituitary adenoma and pheo/PGL participated in the study.Outcome:Outcomes included genetic screening and clinical characteristics.Results:Eleven germline mutations (five SDHB, one SDHC, one SDHD, two VHL, and two MEN1) and four variants of unknown significance (two SDHA, one SDHB, and one SDHAF2) were identified in the studied genes in our patient cohort. Tumor tissue analysis identified LOH at the SDHB locus in three pituitary adenomas and loss of heterozygosity at the MEN1 locus in two pheochromocytomas. All the pituitary adenomas of patients affected by SDHX alterations have a unique histological feature not previously described in this context.Conclusions:Mutations in the genes known to cause pheo/PGL can rarely be associated with pituitary adenomas, whereas mutation in a gene predisposing to pituitary adenomas (MEN1) can be associated with pheo/PGL. Our findings suggest that genetic testing should be considered in all patients or families with the constellation of pheo/PGL and a pituitary adenoma.

The clinical genetics of phaeochromocytoma and paraganglioma

“…The VHL gene encodes two proteins, pVHL 30 , pVHL 19 . They are "substrate recognition components" which target HIF1α and HIF2α for proteasomal-mediated degradation.…”

“…SDHAF2 is encoded by SDHAF2 gene which, similar to genetic defects in other SDH gene defects can cause familial catecholamine-hypersecreting tumours. Apart from catecholamine secreting tumours, genetic defects in the SDH complex less frequently gives rise to renal cell carcinomas and gastro-intestinal stromal tumours (GISTs), and more recently to pituitary adenomas (28)(29)(30)(31).…”

15 YEARS OF PARAGANGLIOMA: The association of pituitary adenomas and phaeochromocytomas or paragangliomas

“…In the largest study to date to look at the co-existence of phaeo/PGL and PA, Dénes et al (2015) identified eight patients with SDHx mutations or variants and both phaeo/PGL and PA within an international cohort of 19 patients. They also demonstrated that SDHx related PAs have a unique and specific histological phenotype characterised by intracytoplasmic vacuoles (Fig.…”

“…Six cases of patients with an SDHB mutation who have both a PA and phaeo/PGL have been reported (Table 1; Dénes et al 2015. All but two patients had functional PAs, one of which was a macroadenoma.…”

“…Converting association into causality has only begun to occur in the last few years due to the identification of the seemingly ever increasing multiple phaeo/PGL and PA-predisposing genes. Using a combination of tumour DNA analysis to look for loss of heterozygosity (LOH) at specific loci and immunohistochemistry for their related gene products, it has been possible to begin to identify causal relationships (Xekouki et al 2012, Papathomas et al 2014, Dénes et al 2015. Indeed, the term '3Pas' representing the association of three tumour types -pituitary, phaeo and PGL -has been coined to identify this clinical scenario .…”