Context:

The A883F germline mutation of the REarranged during Transfection proto-oncogene causes multiple endocrine neoplasia 2B. In the revised American Thyroid Association (ATA) guidelines for the management of medullary thyroid carcinoma (MTC) the A883F mutation has been reclassified from the highest to high risk level, although no well-defined risk profile for this mutation exists.
Objective:

To create a risk profile for the A883F mutation for appropriate classification in the ATA risk levels.
Design:

Retrospective analysis.
Setting:

International collaboration.
Patients:
Included were 13 A883F carriers.
Intervention:

The intervention was thyroidectomy.
Main Outcome Measures:

Earliest age of MTC, regional lymph node metastases, distant metastases, age-related penetrance of MTC and pheochromocytoma (PHEO), overall and disease-specific survival and biochemical cure rate.
Results:

One and three carriers were diagnosed at age 7-9 years (median 7.5) with a normal thyroid and C-cell hyperplasia, respectively. Nine carriers had MTC diagnosed at age 10-39 years (median 19). The earliest age of MTC, regional lymph node and distant metastasis were 10, 20, 20 years, respectively. Fifty percent penetrance of MTC and PHEO was achieved by age 19 and 34 years, respectively. Five- and 10-year survival (both overall and disease-specific) were 88% and 88%, respectively. Biochemical cure for MTC at latest follow-up was achieved in 63% (5/8 carriers) with pertinent data.
Conclusions:

MTC of A883F carriers seems to have a more indolent natural course compared to that of M918T carriers. Our results support the classification of the A883F mutation in the ATA high risk level.