The clinical patterns and RET proto-oncogene identification of pheochromocytoma in 13 multiple endocrine neoplasia type 2A pedigrees

Abstract

To explore the clinical patterns and clinical significance for RET screening in adrenal pheochromocytoma (PHEO) associated with multiple endocrine neoplasia type 2A (MEN2A). The clinical data of 32 PHEO patients with MEN2A from 13 unrelated MEN2A pedigrees from August 1989 to January 2013 were analyzed. The comprehensive medical data included systemic examinations and germline RET gene screening. Among 68 patients belonging to 13 MEN2A families, 32 (47.1%) presented with PHEO. There were 19 males and 13 females with a mean age of (41 ± 12) years. And the mean maximum diameter of PHEO was (4.6 ± 2.2) cm. The diagnosis of PHEO was made after medullary thyroid carcinoma (n = 12, 37.5%), simultaneously (n = 12, 37.5%), initially (n = 7, 21.9%) and death during appendectomy for PHEO-induced hypertensive crisis (n = 1, 3.1%). The diagnosis of PHEO was made before (n = 22) or after (n = 10) clinical screening. The former had 12 symptomatic cases while the latter only 1 case (12/22 vs 1/10, P = 0.024).Except for 5 asymtomatic fatal cases during non-PHEO operations, bilateral PHEO was found in 17 cases including 3 unilaterally treated cases developing another PHEO in contralateral adrenal with a lag period of 5, 10 and 17 years. There were 7 symptomatic patients in bilateral cases versus 6 in unilateral cases (7/17 vs 6/10, P = 0.440). Twenty-five patients underwent PHEO surgery: laparascopic approach in 14 cases (8 with bilateral simultaneous adrenalectomy) and open approach in 11 (2 with bilateral simultaneous adrenalectomy). And 10 patients undergoing bilateral adrenal-sparing operations or adrenalectomy required hormonal replacement therapy. During a mean observation period of 72 (1-282) months, no local recurrence, distant metastasis or Addisonian crisis were noted in 25 cases (contralateral relapse in 3 cases). Among them, 2 cases developed adrenocortical insufficiency unresponsive to an adjustment of hormonal doses.RET screening showed 4 recurrent missense substitutions in 32 MEN2A-PHEO patients: p. C634Y exon 11 (n = 27, 84.4%), p. C634R exon 11 (n = 3, 9.4%), p. C634F exon 11 (n = 1, 3.1%) and p. C618R exon 10 (n = 1, 3.1%). The mutations of RET proto-oncognene of PHEO in MEN2A are frequently located at codon 634. A combination of pedigree examination and RET gene screening may facilitate an early diagnosis and early treatment of asymptomatic PHEO patients in MEN2A.Laparoscopic cortical-sparing adrenalectomy for preserving adrenocortical function is a preferred surgical approach.