1. Conclusions We conclude that early thyroidectomy and central lymph node dissection is effective treatment for hereditary MTC at this interim time point. However, the identification of recurrent calcitonin elevations in a child operated at 9 years of age underscores the importance of performing a thyroidectomy by age 5 years in children with a codon 634 RET proto-oncogene mutation, reflecting current American Thyroid Association guidelines for use of RET genetic testing information. References Methods Inclusion criteria for this IRB-approved study included clinically normal family members who underwent thyroidectomy and CND between the years 1972-1994 based upon newly acquired abnormal serum calcitonin (CTN ) values after provocative testing with pentagastrin (PG) whose gene carrier status was retrospectively confirmed by the presence of a germline RET C634G mutation in a peripheral blood sample. Evidence of persistent or recurrent MTC evaluated by: 1.Measurement of basal serum calcitonin 2.Evaluation of neck by comprehensive cervical ultrasound by one senior radiology blinded to clinical status of participant Serum calcium and albumin also measured Disease free status defined as no detectable serum calcitonin and a negative neck ultrasound The median follow-up duration for the 18 participants was 40 years (yrs)(range 21-43) with a mean current age of the family members of 52 yrs (range 34-65). Median age at thyroidectomy was 15.5 yrs (range 9-24). 7 patients had C-cell hyperplasia (CCH) at median age of 21 years (range 9-23) and 11 had microscopic MTC (mMTC) at median age of 15 years (range 9-24). Fifteen of 18 patients had no detectable serum CTN (<2 pg/ml); three had low level (<60 pg/ml) serum CTN values. Prophylactic Thyroidectomy for Hereditary Medullary Thyroid Carcinoma: A 40 Year Follow-up Study Elizabeth G Grubbs, MD 1, Ronald M Lechan, MD 2, Beth Edeiken-Monroe, MD 1, Gilbert J Cote, PhD 1, Chardria S Trotter, BA 1, Frances Nieves-Munoz, BS 1, Arthur S Tischler, MD 2 and Robert F Gagel, MD 1 1 The University of Texas MD Anderson Cancer Center, Houston, TX, 2 Tufts Medical Center, Boston, MA Summary 15 of 18 (83%) of children and young adults who underwent prophylactic thyroidectomy a median of 40-years ago are free of disease No long-term sequelae of thyroidectomy noted (no calcium supplementation needed or clinical evidence of RLN injury) The hypothesis tested was whether total thyroidectomy and central lymph node dissection (CND) would result in surgical cure with a normal life span in asymptomatic family members with an abnormal pentagastrin- stimulated serum calcitonin value. Figure 1: Pedigree of the J-kindred 29 patients with abnormal PG- stimulated calcitonin 4 RET+ declined participation (1 mMTC, 3 CCH) 11 RET+ with mMTC7 RET+ with CCH 7 false positive patients (negative germline RET) Introduction Forty years ago physicians and family members of the J-kindred, a 100+ member family with Multiple Endocrine Neoplasia type 2A (MEN2A), proposed a bold experiment – to test the hypothesis that total thyroidectomy and central lymph node dissection could cure medullary thyroid carcinoma (MTC) in children/young adults at risk for hereditary MTC. A prior report (1988) provided an optimistic assessment of outcomes at a mean of 11 years after thyroidectomy (1). Why is this family important? The J-kindred family has 40 years of follow-up, the longest longitudinal study available of prophylactic thyroidectomy for MEN2A. The J-Kindred has MEN2A and was the first kindred to be evaluated prospectively for hereditary MTC by annual serum calcitonin testing. This study focused on the cohort within the kindred screened as children and young adults at genetic risk for MTC annually who had normal pentagastrin-stimulated serum calcitonin values initially and converted to an abnormal value over time. Results Pedigree ID Gender Current age (years) Year (age) of first thyroid surgery Years of follow- up Pathology from first surgery Current serum CTN (pg/mL) Current serum calcium (corrected) Current neck ultrasound: Thyroid bed category Current neck ultrasound: Soft tissues of the neck category 112F61 1973 (21) 42CCH<2.09.4 No evidence of disease 1121M34 1994 (13) 21mMTC<2.09.4 No evidence of disease 133F58 1974 (17) 41CCH<2.010.0 No evidence of disease 221M54 1976 (15) 39mMTC15.09.0 No ultrasound performed 331F52 1975 (12) 40mMTC<2.09.6 No ultrasound performed 412M56 1975 (16) 40mMTC<2.09.2 Postoperative changes or normal anatomy No evidence of disease 413M55 1975 (15) 40mMTC<2.09.1 Postoperative changes or normal anatomy Benign appearing lymph nodes 415M49 1981 (15) 34mMTC10.29.5 No evidence of disease 431F52 1975 (12) 40mMTC<2.09.3 Postoperative changes or normal anatomy No evidence of disease 441F49 1975 (9) 40mMTC56.49.2 No evidence of disease 443F47 1987 (19) 28mMTC<2.09.6 Postoperative changes or normal anatomy No evidence of disease 811F53 1975 (13) 40mMTC<2.09.2 Postoperative changes or normal anatomy No evidence of disease 812M49 1975 (9) 40CCH<2.07.8 No evidence of disease 821F48 1991 (24) 24mMTC<2.09.3 No evidence of disease 822M47 1991 (23) 24CCH<2.09.6 Postoperative changes or normal anatomy No evidence of disease 823F45 1991 (21) 24CCH<2.09.3 Postoperative changes or normal anatomy No evidence of disease 84F65 1973 (23) 42CCH<2.010.1 No evidence of disease 85F60 1972 (17) 43CCH<2.08.8 No evidence of disease Demographics, pathology detail and current disease status of clinically normal members of the J- kindred who underwent thyroidectomy based on abnormal calcitonin values after provocative testing Figure 1. This figure shows individual serum calcitonin values in 18 family members who underwent thyroidectomy and central lymph node dissection between 1972-1994. Each cylinder shows the current serum calcitonin value on an individual patient originally found to have either C-cell hyperplasia (red) or microscopic medullary thyroid carcinoma (blue) at the indicated duration of follow-up after surgery (median 40 years). Values below the lower limit of sensitivity of the assay (2 pg/ml; indicated by dotted line) were assigned a value of 0.5 pg/ml to clarify the display. Figure 2. Three individuals (Pedigree #221, #415, and #441) who had mMTC at initial diagnosis have detectable current serum calcitonin values. Longitudinal measurements of their basal serum calcitonin values are depicted here. The data utilized predominately a 3rd generation assay. 1. Gagel RF, Tashjian AH, Jr., Cummings T, et al. The clinical outcome of prospective screening for multiple endocrine neoplasia type 2a. An 18-year experience. The New England journal of medicine. Feb 25 1988;318(8):478-484.