PURPOSE: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. METHODS: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. RESULTS: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). CONCLUSION: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.

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 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.

Earlier guidelines for multiple endocrine neoplasia type 2 (MEN 2) imply that certain RET germline mutations cause more “aggressive” MEN 2 phenotypes, specifically more “aggressive” medullary thyroid cancer (MTC). This research aimed to evaluate tumor onset versus tumor invasion and metastasis in MEN 2. Tumor onset (tumorigenesis) versus tumor invasion and metastasis (aggressiveness) were explored using Kaplan-Meier analyses and log-rank test stratified by RET category, index status, tumor entity (MTC, pheochromocytoma, primary hyperparathyroidism), and MTC progression (node metastases, extranodal growth, distant metastases). Included were 708 patients (222 index and 486 non-index patients) with germline mutations falling into the highest (55 carriers), high (249 carriers), intermediate (182 carriers) and low (222 carriers) RET category. Onset and penetrance of MTC, pheochromocytoma and primary hyperparathyroidism differed significantly between RET categories, with little difference between index and non-index patients. Only 1 (0.5

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.

This article provides an overview of surgically relevant diagnostic and operative aspects of medullary thyroid carcinoma (MTC) regarding current trends from recent studies and the expected adaptation of national S3 guidelines. The article addresses individual patient treatment options based on recognizable risk factors, the intraoperative resection strategy and standard procedures as well as the characteristics of sporadic and hereditary MTC with the concept of prophylactic thyroidectomy.

Background The frequency and distribution of neck node metastases are ill-defined for the growing subset of patients with hereditary and sporadic medullary thyroid cancer (MTC) who present with preoperative basal calcitonin serum levels ≤100 pg/ml. Methods This study, evaluating 30-year data from a tertiary surgical center, aimed to provide that information. Results Included were 256 previously untreated patients with basal calcitonin levels ≤100 pg/ml: 125 patients with hereditary MTC, 9 (7.2 %) of whom harbored node metastases; and 131 patients with sporadic MTC, 17 (13.0 %) of whom revealed node metastases (P = 0.150).With basal calcitonin levels ≤40 pg/ml, node metastases were less frequent (5 % [5 of 97 patients] for hereditary MTC; 9 % [6 of 69 patients] for sporadic MTC) than above that mark (14 % [4 of 28 patients] for hereditary MTC; and 18 % [11 of 62 patients] for sporadic MTC).Node metastases limited to the ipsilateral lateral neck, sparing the central neck, were found in 2 (22 %) of 9 node-positive patients with hereditary MTC and 5 (29 %) of 17 node-positive patients with sporadic MTC.The lowest basal calcitonin levels associated with nodal disease were 15.7 pg/ml in a 24-year-old male non-index patient with hereditary MTC, and 14.1 pg/ml and 14.3 pg/ml in two 46- and 68-year-old female patients with sporadic MTC. Conclusion Central node dissection at the time of thyroidectomy may be beneficial in experienced hands at increased basal calcitonin levels ≤100 pg/ml. When preoperatively increased calcitonin levels persist after central neck dissection, exploration of the ipsilateral lateral neck may be worthwhile.

BACKGROUND:Conceptually, thyroid tumor desmoplasia may be better suited for excluding node metastases in sporadic MTC than preoperative serum calcitonin levels. METHODS:This analysis included 181 patients with unilateral sporadic MTC graded on the 7-grade desmoplasia scale after thyroidectomy and neck dissection. RESULTS:When thyroid tumor desmoplasia reached 1% and ≥50%, node metastases increased from 0% to 7% (median of 0 metastases) and 83% (median of 7.5 metastases), microscopic lymphatic invasion from 0% to 3% and 35%, extrathyroid extension from 0% to 5% and 22%, and extranodal growth from 0% to 0% and 44%, whereas biochemical cure declined from 100% to 95% and 25%. Thyroid tumor diameters and basal calcitonin overlapped widely among the seven desmoplasia groups, precluding differentiation by thyroid tumor size or serum calcitonin levels. CONCLUSIONS:Thyroid tumor desmoplasia, unlike serum calcitonin levels, discriminates extremely well between node-negative and node-positive sporadic MTC, opening new avenues for precision surgery.

Background: Skip metastases, node metastases in the lateral neck sparing the ipsilateral central neck, challenge the current concept of central-to-lateral lymphatic spread. This study sought to delineate patterns of central and lateral neck involvement in unilateral papillary thyroid cancer (PTC) and medullary thyroid cancer (MTC). Methods: This was a retrospective correlative analysis of nodal patterns in surgical specimens from patients with unilateral PTC or MTC who had undergone thyroidectomy with at least ipsilateral central neck dissection between November 1994 and January 2024 at a tertiary referral center. Results: Included were 833 patients with unilateral PTC and 640 patients with unilateral MTC. Simultaneous presence or absence of node metastases was noted in ipsilateral central and lateral neck compartments in 76.6-78.1% of patients with PTC (both node positive in 27.0-54.7% and both node negative in 23.4-49.6%) and 77.3-80.0% of patients with MTC (both node positive in 26.6-33.2% and both node negative in 44.1-53.4%). Only one ipsilateral neck compartment was node positive in 21.9-23.4% of patients with PTC and 20.0-22.7% of patients with MTC. The ipsilateral central, but not the ipsilateral lateral compartment, was node positive in 8.8-16.9% with PTC and 8.6-8.8% of patients with MTC, whereas the ipsilateral lateral, but not the ipsilateral central compartment, was node positive in 6.5-13.1% with PTC and 11.3-14.1% with MTC. Ipsilateral lateral neck involvement sparing the ipsilateral central neck was 1.5-2 times more frequent in patients with node positive MTC than patients with node positive PTC (24.2-25.2% vs. 12.9-17.1%). Greater numbers of node metastases in the ipsilateral central neck compartment were associated with more frequent involvement of the ipsilateral lateral, contralateral central, and contralateral lateral neck compartments. Thyroid tumor diameter intensified nodal spread without changing nodal spread patterns. Conclusions: These histopathological findings, which need to be interpreted in light of the respective tumor biology, offer an unprecedented glimpse at the metastatic patterns of unilateral PTC and MTC. Customizing neck dissection to the patterns of nodal spread, considering operative status (initial vs. reoperative surgery) and experience with neck dissection, may require more frequent concomitant dissections of ipsilateral central and ipsilateral lateral neck compartments.

Medullary thyroid cancer (MTC) is the most frequent manifestation of multiple endocrine neoplasia type 2 (MEN2) that determines the oncological outcome. Germline mutations in the rearranged during transfection (RET) protooncogene, a tumor suppressor gene on chromosome 10q11.2, were identified 30 years ago as the genetic basis of MEN2 and published in 1993 and 1994. These seminal findings gave rise to the concept of prophylactic thyroidectomy for asymptomatic gene mutation carriers based on a positive RET gene test, which has become the standard of care ever since. Clinical genetic investigations showed genotype-phenotype correlations with respect to the individual gene mutation regarding the penetrance and onset of MTC and to a lesser extent also with respect to the other components of MEN2, pheochromocytoma and primary hyperparathyroidism. From this a clinically relevant risk stratification could be derived. Initially, the optimal timing of prophylactic thyroidectomy was primarily based on the RET genotype alone, which was not sufficient for a precise age recommendation and subsequently required additional consideration of calcitonin serum levels for fine tuning. Calcitonin levels first show the risk of lymph node metastasis when they exceed the upper normal limit of the assay independent of carrier age and RET mutation. Routine calcitonin screening of patients with nodular thyroid disease, screening of families on identification of MEN2 index patients, and pre-emptive thyroidectomy in carriers of gene mutations with normal calcitonin levels have led to the fact that nowadays, 30 years after the first description of the gene mutations causing the disease, the life-threatening hereditary MTC has become curable: a shining example for the success of translational transnational medical research for the benefit of patients.

The age-specific development of the three constituent components of multiple endocrine neoplasia type 2 (MEN 2) is incompletely characterized for many of the >30 causative rearranged during transfection (RET) mutations, which this genetic association study aimed to specify. Included in the study were 683 carriers of heterogeneous RET germline mutations: 53 carriers with 1 highest-risk mutation (codon 918); 240 carriers with 8 different high-risk mutations (codon 634); 176 carriers with 16 different intermediate-risk mutations (codon 609, 611, 618, 620, or 630); and 214 carriers with 6 different low-risk mutations (codon 768, 790, 804, or 891).There was a strong genotype-specific development of MEN 2 constituent components, with distinct age gradients from C cell disease to node negative medullary thyroid cancer (MTC), from node negative to node positive MTC, from node positive MTC to pheochromocytoma, and from pheochromocytoma to primary hyperparathyroidism. Primary hyperparathyroidism was not observed among the 53 MEN 2B patients who carried highest-risk mutations (age range: 0.5-50 years), of whom no more than 12 (23%) and 3 (6%) carriers were older than age 30 years and 35 years, respectively. The age-specific development of MTC differed significantly between the four RET risk categories, whereas the age-specific development of pheochromocytoma differed significantly only between the two strongest RET risk categories. No significant differences were noted in the development of primary hyperparathyroidism. These findings delineate age-specific disease manifestation corridors for the three constituent components of MEN 2 by RET genotype. These corridors are useful for initial risk assessment and organ-specific surveillance of newly identified RET carriers going forward.

Little is known about axillary node metastasis of medullary thyroid cancer (MTC). To address this, a comparative study of patients with and without axillary node metastases of MTC was conducted. Among 1215 consecutive patients with MTC, 482 patients had node-negative MTC and 733 patients node-positive MTC. Among the 733 patients with node-positive MTC, 4 patients (0.5%) had axillary node metastases, all of which were ipsilateral. Patients with axillary node metastases had 5.7-6.9-fold more node metastases removed, both at the authors' institution (medians of 34.5 vs. 5 metastases; p=0.011) and in total (medians of 57 vs. 10 metastases; p=0.013), developed more frequently distant metastases (3 of 4 vs. 178 of 729 patients, or 75 vs. 24%; p=0.049), specifically to bone (2 of 4 vs. 67 of 729 patients, or 50 vs. 9%; p=0.046) and brain (1 of 4 vs. 4 of 729 patients, or 25 vs. 0.5%; p=0.027), and more often succumbed to cancer-specific death (3 of 4 vs. 52 of 729 patients, or 75 vs. 14%; p=0.005). Altogether, patients with axillary node metastases revealed 4-8-fold more node metastases in the ipsilateral lateral neck (medians of 11 vs. 3 metastases; p=0.021) and in the ipsilateral central neck (medians of 8 vs. 1 metastases; p=0.079) patients without axillary node metastases. Cancer-specific survival of patients with vs. patients without axillary node metastases of MTC was significantly shorter (means of 41 vs. 224 months; plog-rank<0.001). These findings show that patients with axillary node metastases of MTC have massive metastatic dissemination with poor survival.

BACKGROUND:Whether inherited in the context of multiple endocrine neoplasia 2B at germline level or acquired in a lifetime, all RET p.M918T (RET c.2753T>C) mutations should activate the RET tyrosine kinase receptor alike, with similar degrees of medullary thyroid cancer (MTC) progression when disparities in disease onset and multifocal growth are accounted for. METHODS:This cross-sectional analysis of RET p.M918T-driven progression of hereditary MTC (33 patients) vs. sporadic MTC (36 patients) sought to explore this hypothesis. RESULTS:Patients with hereditary disease were significantly younger at thyroidectomy (medians of 10 vs. 57 yrs.) and featured significantly more often multifocal growth (69 vs. 14 %) with more thyroid tumor foci (medians of 2 foci vs. 1 focus) than patients with sporadic disease. Although the former had 3.6-fold smaller primary thyroid tumor diameters (medians of 5 vs. 18 mm) and twice as many neck nodes dissected (medians of 66.5 vs. 32 nodes) than the latter, extrathyroid tumor extension (42 vs. 36 %), node metastasis (64 vs. 77 %), distant metastasis (33 vs. 17 %), and biochemical cure rates (45 vs. 35 %) were fairly comparable, as was the number of dissected node metastases (medians of 7 vs. 8 involved nodes). Sensitivity analyses, with breakdown of patients by tumor multifocality and nodal status, corroborated these findings. CONCLUSION:RET p.M918T-driven progression of MTC is similar in hereditary and sporadic disease, barring earlier development and more frequent multifocal growth of hereditary MTC. This makes a compelling case for referral of patients with RET p.M918T-driven MTCs to specialist surgical centers.

Thyroid cancer is the only nonreproductive cancer with striking female predominance, although men with thyroid cancer develop more aggressive disease. This study aimed to quantify sex-specific differences in medullary thyroid cancer (MTC) spread after controlling for primary thyroid tumor size. Included in this retrospective analysis were all patients with unilateral solitary MTC who underwent initial neck surgery at a tertiary referral center. A total of 565 patients, 255 men and 310 women, were identified, of whom 467 had sporadic and 98 hereditary MTC. When stratified by sex, and after correction for multiple testing, men had higher preoperative basal calcitonin levels (medians of 655 vs 181 pg/mL; P < 0.001), more frequent extrathyroid extension (25 vs 9%; P < 0.001) and node metastasis (53 vs 27%; P < 0.001) with more involved nodes (medians of 2 vs 0 nodes; P < 0.001) than women but achieved less often biochemical cure (53 vs 74%; P < 0.001). Although absent in patients with very small (≤5 mm) thyroid tumors, sex disparities were immediately apparent in patients with 5.1–40 mm (node metastasis and biochemical cure) and 10.1–40 mm (extrathyroid extension) large thyroid tumors but were lost in patients with thyroid tumors >40 mm as women caught up. Sex disparities were strongest for node metastasis with a 27–41% (overall 24.0%) point difference, followed by biochemical cure with a −15–35% (overall −20.3%) point difference and extrathyroid extension with a 17–24% (14.2% overall) point difference. These findings indicate that the male predominance in MTC aggressiveness is largely biologically driven, warranting further research.

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. This narrative review entails a holistic description and interpretation of the English-language literature on MTC desmoplasia. 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. 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.

(1) Background: The wider adoption of a preoperative ultrasound and calcitonin screening complemented by an intraoperative frozen section has increased the number of patients with occult sporadic medullary thyroid cancer (MTC). These advances offer new opportunities to reduce the extent of the initial operations, minimizing operative morbidity and the risk of postoperative thyroxin supplementation without compromising the cure. (2) Methods: This systematic review of the international literature published in the English language provides a comprehensive update on the latest progress made in the risk-adapted surgery for sporadic and hereditary MTC guided by an intraoperative frozen section. (3) Results: The current evidence confirms the viability of a hemithyroidectomy for desmoplasia-negative sporadic MTC. To add an extra safety margin, the hemithyroidectomy may be complemented by a diagnostic ipsilateral central node dissection. Despite the limited extent of the surgery, all the patients with desmoplasia-negative sporadic tumors achieved a biochemical cure with excellent clinical outcomes. A hemithyroidectomy decreases the need for postoperative thyroxine substitution, but a total thyroidectomy may be required for bilateral nodular thyroid disease. Hereditary MTC is a different issue. Because each residual thyroid C cell carries its own risk of malignant progression, a total thyroidectomy remains mandatory for hereditary MTC. (4) Conclusion: In experienced hands, a hemithyroidectomy, which minimizes morbidity without compromising the cure, is an adequate therapy for desmoplasia-negative sporadic MTC.

Das medulläre Schilddrüsenkarzinom (MTC) ist die häufigste das onkologische Outcome bestimmende Manifestation der multiplen endokrinen Neoplasie (MEN) Typ 2. Vor 30 Jahren konnten die Keimbahnmutationen im RET(REarranged-during-Transfection)-Protoonkogen, einem Tumorsuppressorgen auf Chromosom 10q11.2, als Ursache der MEN2 identifiziert und 1993 und 1994 erstveröffentlicht werden. Hieraus entwickelte sich das Konzept der prophylaktischen Thyreoidektomie für asymptomatische Genmutationsträger, das seither Therapiestandard ist. Klinisch-genetische Untersuchungen zeigten hinsichtlich der individuellen Genmutation eine Genotyp-Phänotyp-Korrelation sowohl hinsichtlich der Penetranz und des Entstehungszeitraums des MTC und in geringerem Ausmaß auch hinsichtlich der anderen MEN2-Komponenten Phäochromozytom und primärer Hyperparathyreoidismus. Daraus konnte eine klinisch relevante Risikostratifizierung abgeleitet werden. Die allein genotypbasierte, aber nicht hinreichend genaue Altersempfehlung für den besten Zeitpunkt der prophylaktischen Thyreoidektomie wurde in der Folgezeit durch Kombination des RET-Genotyps mit dem Kalzitoninwert präzisiert, der mutations- und altersunabhängig erst bei Überschreiten des oberen Kalzitoninnormwertes das Risiko einer Lymphknotenmetastasierung anzeigt. Die routinemäßige Kalzitoninbestimmung bei Knotenstrumen, das Familienscreening bei MEN2-Indexpatienten und die karzinompräventive prophylaktische Thyreoidektomie bei normokalzitoninämischen Genmutationsträgern haben dazu geführt, dass heute, 30 Jahre nach der Erstbeschreibung der krankheitsverursachenden Genmutationen, das lebensbedrohende hereditäre MTC heilbar geworden ist: ein leuchtendes Beispiel für den Erfolg translational transnationaler medizinischer Forschung zum Wohl der Betroffenen.

Die präoperative Routinebestimmung des Tumormarkers Kalzitonin für das medulläre Schilddrüsenkarzinom (MTC) und die allgemein verbesserte Diagnostik mit hochauflösendem Ultraschall, Elastographie und Dopplerfunktion sowie funktioneller Bildgebung ermöglicht es, MTC in früherem, also im organbegrenzten und nichtmetastasierten Stadium zu diagnostizieren. Damit eröffnet sich beim sporadischen MTC die Möglichkeit zur Deeskalation des primären Operationsausmaßes weg von der Thyreoidektomie mit bilateraler zentraler Lymphknotendissektion hin zur limitierten Resektion als Hemithyreoidektomie mit ipsilateraler zentraler Lymphknotendissektion. PubMed-Recherche zum operativen Vorgehen und Auswahl von Publikationen mit Ergebnissen limitierter Operationsverfahren beim sporadischen MTC. Im selektionierten Patientengut können limitierte Resektionen adäquate onkologische Ergebnisse erzielen, die aber eine Langzeittumornachsorge erfordern. Bei Identifikation sporadischer unifokaler Primärtumoren und konsequenter intraoperativer gefrierschnitthistologischer Erfassung des Desmoplasiegrades und des Kapseldurchbruchs kann das Resektionsausmaß intraoperativ der patientenindividuellen Situation angepasst werden. Entscheidende Voraussetzungen hierfür sind die Berücksichtigung der klinischen präoperativen und intraoperativen chirurgischen sowie der gefrierschnitthistologischen Kriterien, die das onkologische adäquate Ergebnis mit R0-Resektion und biochemischer Heilung erreichen.

Background Homozygous mutations, 2 identical gene versions (alleles), 1 from each biological parent, are exceptional. Clinical descriptions of affected families, comprising few carriers only, are scattered throughout the literature, hindering evidence generation.Methods Included in this literature analysis were 5 RET families with >= 1 homozygous carrier and >= 3 heterozygous carriers per family.Results In consanguineous families with first-degree cousins, homozygotes presented with node-positive medullary thyroid cancer and pheochromocytoma in their mid-teens, whereas heterozygotes presented in their end-30s and early 40s. Homozygotes developed node-positive medullary thyroid cancer 27.4 years and pheochromocytoma 23 years earlier than heterozygotes. These age differences were smaller in the 15 families carrying founder mutation p.Leu666delinsAsnSer, whereas homozygotes developed node-positive medullary thyroid cancer in their mid-40s, 6 years earlier than heterozygotes in their early 50s.Conclusion These results, limited in scope and size and modulated by extent of consanguinity, are consistent with moderate dose-response effects accelerating MEN2A development.

No genomic data have been put forth that prove beyond a shadow of doubt that sporadic medullary thyroid cancer (MTC) occurs in infancy, childhood, and/or adolescence. This was a retrospective comparative study of consecutive patients with MTC who had neck surgery at a tertiary center over a 30-year period. Included were 1252 patients with MTC (337 hereditary and 915 sporadic), of whom 107 (8.5

Multifocal growth is characteristic of hereditary medullary thyroid cancer (MTC), whereas origin and impact of multifocal growth is enigmatic for sporadic MTC.To address this, 460 RET-negative patients with sporadic MTC, stratified by 1 (93.3 %), 2 (5.7 %) and 3 (1.1 %) thyroid tumor foci, were compared with 219 RET-positive patients with hereditary MTC, stratified by 1 (38.4 %), 2 (45.7 %), 3 (6.4 %), 4 (6.8 %) and ≥5 (2.7 %) thyroid tumor foci.For sporadic MTC, significant associations were identified with bilateral thyroid lobe involvement, microscopic lymphatic invasion, extrathyroid extension, node and distant metastases, number of node metastases, preoperative basal calcitonin level, and decreasing biochemical cure.For hereditary MTC, significant associations were limited to bilateral thyroid lobe involvement, largest thyroid tumor diameter, and preoperative basal calcitonin level.In sporadic MTC, multifocal growth is due to lymphatic invasion with frequent node metastases, whereas in hereditary MTC, it reflects malignant progression from C-cell hyperplasia to cancer.