Peak incidence of pheochromocytoma and primary hyperparathyroidism in multiple endocrine neoplasia 2: Need for age-adjusted biochemical screening

Abstract

Context: In multiple endocrine neoplasia type 2, American Thyroid Association (ATA) management guidelines recommend continuous biochemical screening for pheochromocytoma and/or primary hyperparathyroidism. This implicit assumption of linear tumor development is difficult to reconcile with current thinking that cells accrue somatic mutations stochastically, yielding a bell-shaped distribution. Objective: This investigation aimed at evaluating the age distribution of pheochromocytoma and primary hyperparathyroidism in gene carriers at risk of developing multiple endocrine neoplasia type 2. Design: ATA class D, C, B, and A mutations, with or without pheochromocytoma and/or primary hyperparathyroidism, were plotted against carrier age at the time of diagnosis or last follow-up. Setting: The setting was a surgical referral center. Patients: Included were 474 carriers of ATA class D (37 patients), C (170 patients), B (112 patients), and A (155 patients) mutations. Eighty-four carriers (17.8%) developed pheochromocytoma (bilateral in 42 patients) and 20 carriers (4.2%) primary hyperparathyroidism. Interventions: Interventions were adrenalectomy and/or parathyroidectomy. Main Outcome Measures: Main outcome measures were multiple endocrine neoplasia type 2-associated tumors. Results: Bell-shaped age distribution curves were obtained for unilateral and bilateral pheochromocytoma (ATA class D, C, and B) and primary hyperparathyroidism (ATA class C and B). Owing to the rarity of events, the bell shape of the distribution curve was faint but consistent with a random distribution for ATA class A mutations (unilateral pheochromocytoma and primary hyperparathyroidism). With decreasing penetrance, the bell-shaped distribution curve, becoming narrower and flatter, shifted to the right toward higher age groups. Conclusions: These data, revealing phases of greater amidst phases of lower penetrance, support adjustment of biochemical screening to carrier age and ATA class. Copyright © 2013 by The Endocrine Society.