Long-term Functional and Oncologic Outcomes of Partial Adrenalectomy for Pheochromocytoma.

OBJECTIVE: To evaluate the recurrence and functional outcomes in a primarily hereditary cohort of patients undergoing partial adrenalectomy for pheochromocytoma. METHODS: A retrospective review from a prospectively managed database of patients undergoing partial adrenalectomy from 1995 to 2018 at the National Cancer Institute was performed. Local recurrence was defined as imaging evidence of a recurrent or de novo lesion on the operative side. Steroid dependency was defined as requiring daily steroid replacement at time of last follow-up. RESULTS: One hundred and twenty-four partial adrenalectomies, removing 162 tumors, were performed in 107 patients. Most patients had a known hereditary predisposition to develop bilateral, multifocal, and recurrent pheochromocytoma. Median tumor size was 2 cm (interquartile range (IQR) 1.5-2.8). Median follow-up was 60 months (IQR 13-131). Local recurrence occurred in 17 patients (15.8%) and were managed with active surveillance or surgery. A single patient (1/106, 0.9%) developed metastatic spread of pheochromocytoma approximately 14 years after his first of 2 partial adrenalectomies and remains alive under active surveillance. Median time to recurrence was 71 months (IQR 26-127) with 10 patients (9.3%) requiring daily steroid replacement at time of last follow-up. CONCLUSION: Partial adrenalectomy offers excellent oncologic and functional outcomes, sparing most patients from lifelong steroid replacement therapy. Recurrences can be easily managed with repeat surgery or active surveillance via functional work-up and imaging. Partial adrenalectomy remains the recommended surgical management for patients pre-disposed to development of bilateral, multifocal and recurrent pheochromocytoma.

Screening of mutations in genes that predispose to hereditary paragangliomas and pheochromocytomas.

Thirty per cent of the paragangliomas and pheochromocytomas reported are hereditary. Mutations in SDHB, SDHC, SDHD, and more recently SDHAF2 and TMEM127 genes have been described in these hereditary tumors. We looked for mutations in these 5 genes in a series of 269 patients with paragangliomas and/or pheochromocytomas. The SDHB, SDHC, and SDHD genes were analyzed in a series of 269 unrelated index patients with paragangliomas and/or pheochromocytomas using dHPLC screening of point mutations followed by direct sequencing and Multiplex PCR Liquid Chromatography to detect large rearrangements confirmed by quantitative PCR. In a second phase, we adapted Multiplex PCR Liquid Chromatography to the SDHAF2 and TMEM127 genes. This method and direct sequencing were applied to 230 patients without the SDHB, C, D mutations. Of the 269 patients, 44 carried a mutation (16.3%). Thirty-seven different mutations were identified: 18 in SDHB (including 2 large deletions), 8 in SDHD, 6 in SDHC, 5 in TMEM127, and no mutations in SDHAF2. Thirteen mutations have not been published so far. An exhaustive study of the different genes is needed to make possible a familial genetic diagnosis in paraganglioma and pheochromocytoma hereditary syndromes. Although mutations in SDHC and TMEM127 are less frequent than mutations in SDHB and SDHD, they also have less evident clinical feature indicators. Analyzing SDHAF2 must be restricted to familial extra-adrenal paragangliomas. Multiplex PCR Liquid Chromatography is a sensitive, fast, and inexpensive method for screening large rearrangements, which are infrequent in these syndromes.

An update on the genetics of paraganglioma, pheochromocytoma, and associated hereditary syndromes.

Pheochromocytomas (PCCs) and paragangliomas (PGLs) are catecholamine-secreting tumors of neural crest origin. Once collectively known as the '10% tumor', based on the frequency of inherited forms of the disease, they are now referred to as the '10-gene tumor', based on the number of susceptibility genes identified to date. Most familial cases of pheochromocytoma and/or paraganglioma and 10-20% sporadic cases carry germline mutations in VHL, RET, NF1, SDHA, SDHB, SDHC, SDHD, SDHAF2, TMEM127, or MAX. The finding of somatic mutations in VHL and RET in an additional 10-15% of tumors has brought the proportion of all patients with PCC and/or PGL due to a genetic disruption in these genes to approximately one half. These findings impact on the clinical management of patients. The diversity in the genetic etiology has transcription correlates, which are reflected in the 2 main transcription signatures underlying these mutations: a pseudohypoxic cluster (VHL and SDH gene mutation carriers) and a cluster rich in kinase receptor signaling and protein translation pathways (RET, NF1, TMEM127 and MAX mutation carriers). Recognition of these clusters offers clues to better understand tumor pathogenesis as well as a rationale for the development of targeted therapies. In this report we provide an overview of the transcription-based classification of PCCs and PGLs, an update on the more recently identified susceptibility genes and an outline of current gaps in this research field as well as challenges for the coming years.

Laparoscopic adrenal surgery for recurrent tumours in patients with hereditary phaeochromocytoma.

OBJECTIVE: To report our experience with Laparoscopic Partial Adrenalectomy (LPA) for recurrent tumours in patients with hereditary phaeochromocytoma. PATIENTS AND METHODS: Five patients with hereditary phaeochromocytoma (4 with von Hippel-Lindau disease and 1 with Multiple Endocrine Neoplasia 2B), who had undergone adrenal surgery previously, presented with recurrent adrenal tumours. One patient was pregnant at 20 weeks of gestation. All patients underwent hormonal evaluation, genetic screening and imaging with CT or MRI, metaiodobenzylguanidine (MIBG) scintigraphy. RESULTS: Of the 7 attempted LPA in five patients, five procedures (71%) were successfully completed and total adrenalectomy was needed on two occasions. The adrenal vein could be spared in all patients except one. There were no intra-operative complications. The adrenal function was adequate in all patients without need for steroid supplementation except one patient who lost both adrenals eventually. There was no correlation between the preservation of adrenal vein and adrenocortical function. CONCLUSION: Laparoscopic partial adrenalectomy is feasible, safe and effective in recurrent phaeochromocytoma, despite previous adrenal surgery and is technically easier if the previous approach had been laparoscopic as well. Patients with hereditary phaeochromocytoma are prone for recurrent tumours and may need repeated surgical procedures. Hence, minimally invasive approach is ideal for these patients.

Hereditary paraganglioma/pheochromocytoma and inherited succinate dehydrogenase deficiency.

Mitochondrial complex II, or succinate dehydrogenase, is a key enzymatic complex involved in both the tricarboxylic acid (TCA) cycle and oxidative phosphorylation as part of the mitochondrial respiratory chain. Germline succinate dehydrogenase subunit A (SDHA) mutations have been reported in a few patients with a classical mitochondrial neurodegenerative disease. Mutations in the genes encoding the three other succinate dehydrogenase subunits (SDHB, SDHC and SDHD) have been identified in patients affected by familial or 'apparently sporadic' paraganglioma and/or pheochromocytoma, an autosomal inherited cancer-susceptibility syndrome. These discoveries have dramatically changed the work-up and genetic counseling of patients and families with paragangliomas and/or pheochromocytomas. The subsequent identification of germline mutations in the gene encoding fumarase--another TCA cycle enzyme--in a new hereditary form of susceptibility to renal, uterine and cutaneous tumors has highlighted the potential role of the TCA cycle and, more generally, of the mitochondria in cancer.