THE IDENTIFICATION OF FALSE-POSITIVE RESPONSES TO THE PENTAGASTRIN STIMULATION TEST IN RET MUTATION NEGATIVE MEMBERS OF MEN 2A FAMILIES

OBJECTIVE The pentagastrin stimulation test is the traditional test us ed for the identification of asymptomatic individuals in multiple endo crine neoplasia type 2A (MEN 2A) and familiar medullary thyroid carcin oma (FMTC). The identification of mutations in the RET proto-oncogene segregating with the disease phenotype in MEN 2A and FMTC families has made it possible to re-examine the validity of using this test for th e identification of affected family members. DESIGN Sequential and sin gle pentagastrin stimulation test data were collected following the id entification of RET mutation positive and RET mutation negative member s of families with MEN 2A or FMTC. PATIENTS RET mutations were identif ied in 16 Australian and New Zealand MEN 2A or FMTC families, An analy sis of 39 individuals from these families was included in this study, Thirty-two individuals (14 males, 18 females) had previously been dete rmined as RET mutation negative, Seven individuals (6 males, 1 female) had previously been determined as RET mutation positive. Two RET muta tion negative males had thyroidectomy based on prior pentagastrin test results. MEASUREMENTS Serum calcitonin levels in response to stimulat ion with pentagastrin were measured at 0, 1, 2, 5 and 10 minutes post injection, Mutation analysis of the RET proto-oncogene was performed i n all individuals. In two RET mutation negative individuals from two M EN 2A families, thyroidectomy was performed and C-cells were quantitat ed in order to determine the diagnosis of C-cell hyperplasia. RESULTS There was a statistically significant difference (P < 0.013) between R ET mutation negative male and female mean peak calcitonin responses of 282+/-236 and 96+/-62 (mean+/-SD)ng/l respectively. False positive re sponses to pentagastrin stimulation were identified in seven individua ls who were RET mutation negative in two of the 16 families. Histologi c examination of the thyroid glands in the two RET mutation negative i ndividuals who had thyroidectomy demonstrated C-cell hyperplasia in on e but not in the other. CONCLUSIONS There is considerable overlap betw een pentagastrin test results in individuals who are RET mutation posi tive and those who are RET mutation negative. These results indicate a need for routine performance of RET proto-oncogene analysis on all in dividuals at risk of developing MEN 2A or FMTC and a coupling of penta gastrin test results and RET protooncogene analysis in the decision to proceed with thyroidectomy.