Andreas Machens

Clinically inapparent node metastases, requiring neck dissection in addition to thyroidectomy, pose a diagnostic challenge in patients with medullary thyroid cancer (MTC). Although desmoplasia negativity has emerged as a powerful marker of node-negative disease, its clinical utility in hereditary MTC remains ill-defined. This cross-sectional investigation employed multivariable logistic regression on, and stratification of clinical variables by, nodal status of 124 RET carriers with MTC who underwent initial total thyroidectomy with at least central neck dissection between 2000 and 2025 at a tertiary center. Unlike tumor size, grade, laterality, index status, and sex, only desmoplasia (>10% vs ≤5%), basal serum calcitonin (>500 pg/mL >> 101–500 pg/mL vs ≤100 pg/mL), and RET category (highest (p.Met918Thr) vs any other) were independently associated with node metastases. In unilateral MTC, desmoplasia ≤5% was always associated with freedom from node metastases (0 of 15 patients), whereas tumor size ≤5 mm and basal serum calcitonin ≤100 pg/mL were associated with node metastases in 4 (18%) of 22 patients and 4 (15%) of 26 patients, respectively. In bilateral MTC, none of the above thresholds were sufficiently discriminatory, suggesting metastatic cross-contamination by the contralateral MTC. In unilateral MTC with desmoplasia ≤5%, node metastases were always absent, regardless of whether basal calcitonin levels were ≤100 (based on 13 patients) or >100 pg/mL (based on 2 patients). This comprehensive proof-of-concept study demonstrates that RET carriers with desmoplasia-negative unilateral MTC may forgo node dissection at specialist centers, similarly to what has been proposed for patients with desmoplasia-negative sporadic MTC.

Conceptually, pitting hereditary mutations, pervading all cells of the body since conception, against the same sporadic mutations, acquired by tumor cells only later in life, could give valuable insights into tumorigenesis and tumor progression. This research sought to explore RET p.Cys634-driven tumorigenesis and progression which, preceding the time of clinical detection, cannot be measured directly. Comparative study of 14 previously untreated index patients with hereditary medullary thyroid cancer (MTC) and 15 previously untreated patients with sporadic MTC who presented with a diagnosis of MTC, for which they underwent initial neck surgery at a tertiary referral center. After Bonferroni correction for multiple testing, only few variables continued to differ significantly between RET p.Cys634-driven hereditary and sporadic MTC: age at thyroidectomy (medians of 33.5 vs. 54 years; P <0.001), and multifocal growth (79 vs. 7%, and medians of 2 foci vs. 1 focus; both P <0.001). The present investigation suggests that tumor progression in MTC before clinical detection is a function of the time passed since tumor onset, whereas tumor onset is defined by the transformatory strength of the RET mutation. This notion, debunking the myth of immanent tumor 'aggressiveness' or "risk" imparted by RET mutations in favor of the concept of genetically encoded tumor onset, emphasizes the need for early diagnosis and intervention, ideally while tumors are still confined to the thyroid.

Purpose This research, drawing on genealogical information gleaned over 40 years, aimed to clarify to what extent RET germline mutations causing multiple endocrine neoplasia 2A have been inherited. Methods Geospatial inheritance of 30 different RET germline mutations was explored by mapping gene carriers to the postal code area of residence and year of birth of the earliest affected common ancestor. Results The geospatial analyses revealed 13 single-family clusters among 30 different RET mutations, which involved 3 of 8 high-risk mutations and 10 of 16 intermediate-risk mutations but none of the 6 low-risk mutations. Of these 30 RET mutations, at least 15 RET mutations had been transmitted to offspring for more than 100 years. The oldest familial RET mutations dated back to the second half of the 19th century: to at least 1876 (p.Cys611Phe/c.1832G>T), 1880 (p.Cys634Arg/c.1900T>C), 1895 (p.Cys634Phe/c.1901G>T), 1897 (p.Ser891Ala/c.2671T>G), and 1899 (p.Cys618Phe/c.1853G>T). Another set of 10 RET mutations extended to the early 20th century: to at least 1902 (p.Glu768Asp/c.2304G>C), 1903 (p.Cys634Tyr/c.1901G>A), 1904 (p.Leu790Phe/c.2370G>T), 1905 (p.Cys618Ser/c.1852T>A), 1908 (p.Val804Met/c.2410G>A), 1910 (p.Cys611Phe/c.1832_1833delinsTT), 1914 (p.Cys609Gly/c.1825T>G, p.Cys634Gly/c.1900T>G, and p.Leu790Phe/c.2370G>C), and 1919 (p.Cys620Phe/c.1859G>T). The remaining 15 RET mutations could be traced back no farther than to between 1924 (p.Cys611Tyr/c.1853G>A) and 1966 (p.Cys618Arg (c.1852T>C) but exhibited geographical patterns suggestive of, or consistent with, consecutive migration outside of the area of familial origin. Conclusion The longstanding transmission of the MEN2A trait across multiple generations, often over centuries, requires meticulous identification of all RET mutation carriers who stand to gain tremendously from earlier, hence more limited, surgical interventions.

Purpose The tumor microenvironment often induces a scarring process known as tumor fibrosis or desmoplasia, which plays an important role in the initiation, progression, and clinical outcome of many types of cancer. This report aimed to highlight recent progress made in the field of de-escalation surgery for sporadic medullary thyroid cancer (MTC), building a bridge from basic science to current and emerging medical practice. Methods This narrative review entails a holistic description and interpretation of the English-language literature on MTC desmoplasia. Results Absence of primary tumor desmoplasia on intraoperative frozen section and definitive histopathology goes hand in hand with absence of node metastases in up to one-third of patients with sporadic MTC. Patients with desmoplasia-negative MTC require no more than hemithyroidectomy for cure. Conclusion Thyroid desmoplasia is a powerful predictive tissue biomarker for the intraoperative management of patients with sporadic MTC, outpacing conventional tumor classification systems that depend on definitive histopathology.