Genetic studies in a coexistence of acromegaly, pheochromocytoma, gastrointestinal stromal tumor (GIST) and thyroid follicular adenoma

Abstract

SUMMARYWe report on an adult woman with rare coexistence of acromegaly, pheochromocytoma (PHEO), gastrointestinal stromal tumor (GIST), intestinal polyposis, and thyroid follicular adenoma. At the age of 56, she was diagnosed with acromegaly caused by a pituitary macroadenoma, treated by transsphenoidal surgery, radiotherapy, and octreotide. During routine colonoscopy, multiple polyps were identified as tubular adenomas with high-grade dysplasia on histology. Years later, an abdominal mass of 8.0 x 6.2 cm was detected by routine ultrasound. Surgical exploration revealed an adrenal mass and another tumor adhered to the lesser gastric curvature, which were removed. Pathology confirmed the diagnosis of PHEO and GIST. PHEO immunohistochemistry was negative for GHRH. During follow-up, nodular goiter was found with normal levels of calcitonin and inconclusive cytology. Near-total thyroidectomy was performed, revealing a follicular adenoma. Her family history was negative for all of these tumor types. Genetic analysis for PHEO/paraganglioma genes (SDH A-D, SDHAF2, RET, VHL, TMEM127, and MAX), and pituitary-related genes (AIP, MEN1, and p27) were negative. Though the finding of PHEO and acromegaly with multiple other tumors could be a fortuitous coexistence, we suggest that this case may represent a new variant of MEN syndrome with a de novo germline mutation in a not yet identified gene. Arq Bras Endocrinol Metab. 2012;56(8):507-12 SUMÁRIORelatamos o caso de uma mulher com rara coexistência de acromegalia, feocromocitoma (FEO), tumor do estroma gastrointestinal (GIST), polipose intestinal e adenoma folicular de tireoide. Aos 56 anos, ela foi diagnosticada com acromegalia por um macroadenoma hipofisário, tratado com cirurgia transesfenoidal, radioterapia e octreotide. Uma colonoscopia de rotina detectou múltiplos pólipos, que à histologia eram adenomas tubulares com alto grau de displasia. Anos mais tarde, uma ecografia detectou uma massa abdominal de 8.0 x 6.2 cm, que na exploração cirúrgica era uma lesão adrenal e outro tumor aderido à pequena curvatura gás-trica. A patologia confirmou os diagnósticos de FEO e GIST. A imuno-histoquímica do FEO foi negativa para GHRH. No seguimento, encontrou-se um bócio nodular com níveis normais de calcitonina e citologia inconclusiva. Após tireoidectomia total o diagnóstico histológico foi de adenoma folicular. A história familiar era negativa para todos esses tumores. As análises gené-ticas para genes de síndromes de FEO/paragangliomas (SDH A-D, SDHAF2, RET, VHL, TMEM127 e MAX) e para hipofisárias (AIP, MEN1 e p27) foram todas negativas. Embora a presença de FEO e acromegalia com múltiplos outros tumores possa ser uma coexistência fortuita, acreditamos na possibilidade de uma nova variante de NEM com uma mutação germinativa de novo em um gene ainda não identificado Arq Bras Endocrinol Metab. 2012;56(8):507-12

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

“…Haploinsufficient effects for the SDHx genes have been suggested in: i) bilateral adrenal medullary hyperplasia associated with a germline SDHB mutation showing retention of heterozygosity (38); ii) PCCs without loss of the WT SDHD allele arising in SDHD-mutated patients (39); and iii) somatic SDHD inactivation being accompanied by consistent reduction of transcript levels in various tumors (40,41). Albeit, in mouse models, no indications were obtained for an SDHB/SDHD haploinsufficient contribution to tumorigenesis (42,43) Table 1), with a further 31 PAs co-occurring with PCCs and/or PGLs pointing to a causative association with SDHx, MEN1, or other yet unidentified predisposing genes (44,45,46). SDHx-mutated patients appear to have a characteristic clinical phenotype with PRL-secreting macroadenomas, and to a lesser extent GH-secreting macroadenomas, usually accompanied with a personal history of PCC/PGL, implying that SDH deficiency might promote tumor growth with lactotrophs being more susceptible to this particular deficient state.…”

MANAGEMENT OF ENDOCRINE DISEASE: Acromegaly and cancer: an old debate revisited

“…Moreover, germline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene and X-chromosomal microduplication have been linked to pituitary adenomas (1). There are also reports on acromegaly patients harboring several different tumors where a genetic defect was suspected but not identified (63).…”

Familiar Papillary Thyroid Carcinoma in a Large Brazilian Family Is Not Associated with Succinate Dehydrogenase Defects

“…The coexistence of bilateral pheochromocytomas, abdominal paraganglioma, papillary thyroid carcinoma, and parathyroid adenoma has already been described in the literature [38,39,40]. GIST and thyroid cancer coexisted in 2.5% of the cases [38].…”