Similar stage-dependent survival and outcome in sporadic and hereditary medullary thyroid carcinoma

Context Long-term data are scarce on large cohorts with sporadic (sMTC) and hereditary medullary thyroid carcinoma (hMTC). Objectives To compare long-term disease-specific survival (DSS) and outcomes between sMTC and hMTC groups. Design Retrospective analysis Setting German tertiary referral center Patients 673 patients with MTC that underwent surgery from January 1974 to July 2019 Intervention None (observational study) Main Outcome Measure Differences between sMTC and hMTC in long-term, stage-dependent survival and outcomes Results Surgery was performed at median ages of 49 years for sMTC (n=477, 44% male) and 29 years for hMTC (n=196, 43% male; p<0.0001). The mean follow-up times were 9.2±8.0 (sMTC) and 14.6±10.3 years (hMTC). Age and tumor stage at diagnosis were significantly different between the two groups (p<0.0001). The sMTC and hMTC groups had different overall DSS (log rank, p=0.0183), but similar stage-dependent DSS (log rank, p=0.1242 to 0.8981). In a multivariate analysis, sMTC and hMTC did not differ in DSS (HR=1.56, 95%CI=0.94-2.57), but in both groups, a worse DSS was significantly associated with age at diagnosis (HR=1.04, 95%CI=1.02-1.05), male sex (HR=0.49, 95%CI=0.32-0.76), and stages III and IV at diagnosis (HR=20.00, 95%CI=2.74-145.91 and HR=97.47, 95%CI=13.07-726.67, respectively). The groups had significantly different (p<0.0001) outcomes (i.e., cured, minimal residual disease, structural detectable disease, and death), but similar stage-dependent outcomes (p=0.9449 to 0.0511), except for stage III (p=0.0489). Conclusion Patients with sMTC and hMTC had different ages of onset, but similar stagedependent DSS and outcomes after the MTC diagnosis. This finding suggested that tumor behavior was similar in sMTC and hMTC. Précis This observational study of 673 patients with sporadic (n=477) and hereditary MTC (n=196) revealed similar disease-specific survival rates and outcomes, which suggested similar tumor behavior.

Kinetic analysis of the growth rate of sporadic and hereditary medullary thyroid carcinoma: Comparing the postoperative calcitonin-doubling rate with the hypothetical preoperative tumor volume-doubling rate

Background Our previous kinetic analyses of changes in the tumor volume (TV) of papillary thyroid microcarcinomas during active surveillance revealed that the tumors' growth varied over time from rather rapid growth to shrinkage and that the hypothetical TV-doubling rates (DRs) before the patients' presentation were much larger than their observed TV-DRs, indicating that rapid growth phases preceded their presentation. Whether this phenomenon also occurs in medullary thyroid carcinoma (MTC) was unknown. Methods We retrospectively analyzed the cases of 46 MTC patients (18 hereditary, 28 sporadic; 9–80 years old at surgery, median 53.5 years; 19 males and 27 females) with elevated postoperative calcitonin (Ct) suggesting persistent disease. We calculated each patient's Ct-DR and his/her hypothetical TV-DR, using the tumor size and age at surgery. Results Ct-DRs (/year) after surgery were >0.5, 0.1–0.5, −0.1–0.1, and <������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������

Kinetic analysis of the growth rate of sporadic and hereditary medullary thyroid carcinoma: Comparing the postoperative calcitonin-doubling rate with hypothetical the preoperative tumor volume-doubling rate

Background Our previous kinetic analyses of changes in the tumor volume (TV) of papillary thyroid microcarcinomas during active surveillance revealed that the tumors' growth varied over time from rather rapid growth to shrinkage and that the hypothetical TV-doubling rates (DRs) before the patients' presentation were much larger than their observed TV-DRs, indicating that rapid growth phases preceded their presentation. Whether this phenomenon also occurs in medullary thyroid carcinoma (MTC) was unknown. Methods We retrospectively analyzed the cases of 46 MTC patients (18 hereditary, 28 sporadic; 9–80 years old at surgery, median 53.5 years; 19 males and 27 females) with elevated postoperative calcitonin (Ct) suggesting persistent disease. We calculated each patient's Ct-DR and his/her hypothetical TV-DR, using the tumor size and age at surgery. Results Ct-DRs (/year) after surgery were >0.5, 0.1–0.5, −0.1–0.1, and ≤0.1 in 9, 21, 12, and 4 patients, respectively (median 0.17). The hypothetical TV-DRs (/year) before surgery were >1, 0.5–1.0, 0.1–0.5 and <0.1 in 11, 21, 14, and 0 patients, respectively (median 0.60). The hypothetical TV-DR was higher than the observed Ct-DR in 41 of the 46 MTC patients and all 18 patients with hereditary MTC, suggesting that a rapid growth phase preceded surgery in these patients. Conclusions In this series of MTC patients, the pre-surgery calculated hypothetical TV-DRs were significantly higher than the Ct-DRs observed post-surgery, suggesting that there were rapid growth periods before surgery in the vast majority of these MTC patients, especially those with hereditary MTC.

Twenty-Five Years Experience on RET Genetic Screening on Hereditary MTC: An Update on The Prevalence of Germline RET Mutations

Background: Pathogenic germline mutations affecting the RET proto-oncogene underlie the development of hereditary medullary thyroid carcinoma (MTC). The aims of this study were to evaluate the prevalence of germline RET mutations in a large series of MTC, collected over the last 25 years, and to reappraise their clinical significance. Methods: We performed RET genetic screening in 2031 Italian subjects: patients who presented with sporadic (n = 1264) or hereditary (n = 117) MTC, plus 650 relatives. Results: A RET germline mutation was found in 115/117 (98.3%) hereditary and in 78/1264 (6.2%) apparently sporadic cases: in total, 42 distinct germline variants were found. The V804M mutation was the most prevalent in our cohort, especially in cases that presented as sporadic, while mutations affecting cysteine residues were the most frequent in the group of clinically hereditary cases. All M918T mutations were “de novo” and exclusively associated with MEN2B. Several variants of unknown significance (VUS) were also found. Conclusions: a) RET genetic screening is informative in both hereditary and sporadic MTC; b) the prevalence of different mutations varies with V804M being the most frequent; c) the association genotype–phenotype is confirmed; d) by RET screening, some VUS can be found but their pathogenic role must be demonstrated before screening the family.