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

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.