Revisiting the genotype‐phenotype correlation in children with medullary thyroid carcinoma: A report from the GPOH‐MET registry

Abstract

Background Medullary thyroid carcinomas (MTC) account for 3% to 5% of all thyroid cancers. In most cases, MTC is hereditary and occurs as part of the multiple endocrine neoplasia (MEN) type 2A and 2B syndromes. There is a strong genotype‐phenotype correlation associated with the respective RET mutations, making risk‐adapted management possible. Procedure We report the prospectively collected data on children and adolescents of the multicenter nonrandomized German GPOH‐MET registry. Children and adolescents with MTC and C‐cell hyperplasia (CCH) were included. Results From 1997 to June 2019, a total of 57 patients with MTC and 17 with CCH were reported. In patients with MTC, median follow‐up was five years (range, 0‐19) and median age at diagnosis 10 years (range, 0‐17). Overall survival and event‐free survival (EFS) were 87% and 52%, respectively. In total 96.4% of patients were affected by MEN2 syndromes, which was in 37/42 MEN2A and 3/28 MEN2B (M918T mutation) inherited. EFS in MEN2A was 78%, and in MEN2B 38% (P < 0.001). In multivariate analyses, lymph node (LN) status and postoperatively elevated calcitonin were significant prognostic factors for EFS. Notably, modest‐risk mutation carriers presented with MTC at a rather young age, without raised calcitonin, and LN metastases. Conclusions Identification of children carrying de novo RET M918T mutations by means of the characteristic phenotype is crucial to detect MTC at an early stage, which will be associated with improved survival. As calcitonin levels may be false‐negative and modest‐risk mutation carriers present with a variable phenotype, particular attention should be paid to these children.

Pseudohypoxic pheochromocytomas and paragangliomas dominate in children

“…We included children and adolescents aged 0–18 years with histologically confirmed PPGLs who had been reported to the GPOH‐MET study center between 1997 and December 2019. Details on the GPOH‐MET 97 study protocol and the GPOH‐MET registry and data collection are provided elsewhere 16 . The GPOH‐MET 97 protocol and the recommendations of the GPOH‐MET registry document were conducted according to the Declaration of Helsinki and approved by the ethical committees of the University of Luebeck (97‐125) and Otto von Guericke University Magdeburg (174/12), Germany.…”

Clinic Heterogeneity and Management of Pediatric Patients With Germline RET Proto-oncogene Mutation: Single-center Experience

“…In MEN2A, it can occur from adolescence to early adulthood and even middle age, whereas in MEN2B, it occurs early in life. 5 In pediatric ages, germline RET mutations are usually detected during the screening of MEN families, such as in most of our cases. Only 2 patients were symptomatic.…”

“…However, the age of onset of MTC varies with genotype. In MEN2A, it can occur from adolescence to early adulthood and even middle age, whereas in MEN2B, it occurs early in life 5 …”

Active Surveillance in RET Gene Carriers Belonging to Families with Multiple Endocrine Neoplasia

“…However, in any case before 5 years and in cases at moderate risk (other mutations), basal and stimulated CT (bCT and sCT) should guide thyroid surgery timing [ 8 ]. This latter suggestion is not always followed in the real clinical world and several centers still follow the indication to operate immediately after the RET screening, warning against the use of serum CT in this clinical scenario [ 9 ].…”