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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., Competing Interests: Compliance with ethical standards. Conflict of interest: The authors declare no competing interests. Ethics approval: All data, being in the public domain, were exempt from institutional review board oversight as per applicable national and local regulations., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: Among childhood cancer survivors, the cumulative incidence rate of differentiated thyroid carcinomas (DTCs) is estimated to be 8-11%. Although the association of DTC with prior radiotherapy is well-studied, the association with chemotherapy remains less understood. Most studies focused on young adults, leaving a knowledge gap on subsequent DTC occurring in childhood and adolescence. Methods: In this retrospective cohort study, we analyzed DTCs in children and adolescents under 18 years of age who were registered with the national multicenter Malignant Endocrine Tumor studies in Germany (1997-2023). We compared patients with first primary DTC to those with subsequent DTC that developed after a history of childhood cancer or hematopoietic stem cell transplantation (HSCT). In the subsequent DTC subgroup, we compared DTCs following chemotherapy only to those following chemo- and radiotherapy. Results: Of 505 patients with DTCs, 66 (13.1%) (38 male, 28 female) were subsequent DTCs. The median age at subsequent DTC diagnosis was 12.7 years (range, 5.1-17.9), with a median latency of 7.3 years (range, 2.2-15.6) from the first malignancy or HSCT. The 5-year overall survival (OS) and thyroid-related adverse event-free survival (EFS) estimates from the diagnoses of a subsequent DTC were 100.0% and 82.5%, respectively. Prior treatment included chemotherapy in 64 patients, with 18 receiving chemotherapy alone. In all, 46 subsequent DTC patients had a history of external radiotherapy, including 2 treated with radiotherapy only and 14 with total body irradiation. Two patients received 131 I-metaiodobenzylguanidine treatment. Subsequent DTCs versus first DTCs were smaller in size but more frequently multifocal. Subsequent DTCs following chemotherapy only, compared with chemo- and radiotherapy, developed after a shorter latency (median 6.2 vs. 7.8 years), and were larger (median 1.86 vs. 1.18 cm). Patients with subsequent DTCs following chemotherapy only were younger at diagnosis (median 11.5 vs. 13.7 years). No differences were observed for OS and EFS. Conclusions: Presenting features of subsequent DTCs differ from primary counterparts, although the prognosis is not significantly different. Subsequent DTCs following chemotherapy only versus chemo- and radiotherapy DTCs were larger and diagnosed in younger patients after a shorter latency. More research is needed to identify risk factors and mechanisms potentially contributing to thyroid tumorigenesis post-chemotherapy.

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., (© 2024 Wiley Periodicals LLC.)

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., Competing Interests: Declaration of competing interest The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported., (Copyright © 2024 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

This study describes the external quality assessment (EQA) scheme for molecular testing of RET alterations in non-small cell lung cancer (NSCLC), medullary thyroid carcinomas (MTC), and non-MTC. The lead panel institute and Quality Assurance Initiative in Pathology (Qualitätssicherungs-Initiative Pathologie [QuIP] GmbH) selected formalin-fixed paraffin-embedded (FFPE) tissue from MTC for RET mutation testing by next-generation sequencing (NGS) methods and FFPE tissue from NSCLC and non-MTC for RET gene fusion testing using either in situ hybridisation (ISH) or NGS methods, forming 3 sub-schemes of the EQA scheme. Tissue material underwent an internal validation phase followed by an external testing phase. The internal validation phase served as a cross-validation step conducted by panel institutes. In the external testing phase, the number of participating institutes in the RET point mutation sub-scheme, RET fusion (ISH) sub-scheme, and RET fusion (NGS) sub-scheme was 32, 24, and 38, respectively. The reported success rates for external testing were 96.0%, 89.5%, and 93.5% for the RET point mutation, the ISH RET fusion, and the NGS RET fusion EQA sub-schemes, respectively. These findings confirm the reliability of the NGS method in detecting RET alterations and align with current screening recommendations. Overall, 31 institutes were certified for RET point mutation testing by NGS methods, 22 institutes were certified for RET fusion testing by ISH, and 36 institutes were certified for RET fusion testing by NGS methods. Results can be employed to inform real-world diagnostic decisions in Germany, Austria, and Switzerland., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: 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., Methods: This was a retrospective comparative study of consecutive patients with MTC who had neck surgery at a tertiary center over a 30-year period., Results: Included were 1252 patients with MTC (337 hereditary and 915 sporadic), of whom 107 (8.5%) were operated before the age of 18 yrs. Only 4 (3.7%) of the 107 pediatric patients, aged 14, 16, 17 and 17 years, had sporadic MTC. These 4 patients, 3 of whom had been referred for completion surgery, revealed much larger thyroid tumors (medians of 20 mm vs. 1.5-5 mm) than the 103 pediatric patients with hereditary MTC. As for extrathyroid extension and nodal metastases, the 4 patients with sporadic MTC were more comparable to the 37 carriers of highest-risk mutations, 31 (84%) of whom were index patients with de novo disease, than to the 66 carriers of high-risk, intermediate-risk, or low-risk RET mutations (25-38% vs. 0-8%, and medians of 9-9.5 vs. 0 node metastases after dissection of more (medians of 72-91.5 vs. 4.5-9) nodes)., Conclusion: Sporadic MTC, arising rarely, if ever, below the age of 14 years, is exceptional in infancy and childhood, and infrequent in adolescence. At diagnosis, it is almost as widely metastatic as hereditary MTC of the highest-risk category which almost always, like sporadic MTC, presents as de novo disease., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

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.

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., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Endocrinology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

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.

Background: While primary tumor desmoplasia is a powerful biomarker of node metastases in sporadic medullary thyroid cancer (MTC), information for hereditary MTC is sparse., Methods: This proof-of-concept study, comprising 3 consecutive children with multiple endocrine neoplasia 2B, evaluated simultaneously the metastatic behavior of multiple primary thyroid tumors of disparate size and extent of desmoplasia within patients., Results: Altogether, MTC typically involved the ipsilateral central neck before spreading to the ipsilateral lateral and the contralateral neck. Medullary thyroid cancer in the upper thyroid lobe leaped the ipsilateral central neck to invade the ipsilateral lateral neck. Unlike the desmoplasia-positive 6-mm high-grade and 7-mm low-grade primary thyroid tumors, the desmoplasia-negative 8-, 11-, and 16-mm low-grade primary thyroid tumors did not spread to ipsilateral neck nodes. With extranodal growth, the extent of nodal desmoplasia was greater than with intranodal growth., Conclusion: This proof-of-concept study suggests that primary tumor desmoplasia is an equally powerful biomarker of node metastasis in hereditary MTC., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Society of Endocrinology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose of Review: Significant advances have transformed our understanding of the molecular biology and natural history of multiple endocrine neoplasia type 2 (MEN2). This progress enacted a paradigm shift with regard to routine neck dissection for medullary thyroid cancer and total adrenalectomy for pheochromoytoma. The purpose of this review is to summarize key molecular and clinical data underpinning the current risk-based approach to MEN2 that integrates molecular and biomarker results., Recent Findings: Early identification and biochemical monitoring of rearranged during transfection ( RET ) carriers yield important lead time. Within these ' windows of opportunity ', total thyroidectomy alone, avoiding incremental morbidity from node dissection; ' tissue-sparing ' subtotal adrenalectomy, balancing risks of steroid dependency with pheochromocytoma recurrence in adrenal remnants; and parathyroidectomy of enlarged glands only, weighing risks of postoperative hypoparathyroidism against hyperactive parathyroid glands left behind, are adequate therapies., Summary: All that is needed to determine a RET carriers' risk of medullary thyroid cancer, pheochromocytoma and/or primary hyperparathyroidism in the molecular era is patient age, underlying RET mutation, and biomarker levels. As broader testing begins to penetrate healthcare, the needle on population genomic screening and education needs to be moved forward to complete the transition from symptom-based to preventive healthcare., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The absence of primary tumor desmoplasia, a marker of node metastases, on frozen section may help reduce the extent of surgery without compromising the biochemical cure. We aimed to clarify whether hemithyroidectomy with diagnostic ipsilateral central neck dissection can replace total thyroidectomy with routine central neck dissection in patients with sporadic medullary thyroid cancer., Methods: We retrospectively evaluated data collected from patients who had undergone primary neck surgery for hypercalcitoninemic sporadic medullary thyroid cancer between January 2017 and December 2022 at one institution., Results: Of the 25 patients we examined, 19 had desmoplasia-negative and 6 desmoplasia-positive primary thyroid tumors on frozen section. The desmoplasia-negative patients had undergone less surgery with fewer nodes removed than the desmoplasia-positive patients (medians of 6 vs 31 nodes, P < .001). The desmoplasia-negative patients had predominantly undergone hemithyroidectomy with ipsilateral central neck dissection. None of the desmoplasia-negative tumors was multifocal (0 of 19 desmoplasia-negative vs 2 of 6 desmoplasia-positive or 0% vs 33%, P = .050) or node-positive (0 of 19 vs 6 of 6 patients or 0% vs 100%; medians of 0 vs 3.5 node metastases; both P < .001). Despite limited surgery, all desmoplasia-negative patients attained and maintained biochemical cure., Conclusion: Hemithyroidectomy combined with diagnostic ipsilateral central neck dissection is a viable risk-reducing and curative strategy for desmoplasia-negative and node-negative, nonmetastatic unifocal tumors, for which we propose the term sporadic noninvasive medullary thyroid neoplasm (SNMTP)., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Purpose: Differences in syndromic manifestations of multiple endocrine neoplasia 2 A (MEN2A) between index and non-index patients are ill-defined., Methods: Cross-sectional analysis of 602 REarranged during Transfection (RET) carriers (156 index and 446 non-index patients) who underwent thyroidectomy, adrenalectomy, and/or parathyroidectomy between 1985 and 2022, stratified by mutational risk., Results: Index patients were 5.8-13.9 years older at thyroidectomy than non-index patients, at which point they had developed 10.6-14.4 mm larger medullary thyroid cancers. Correlations between index status and primary tumor size (ρ = 0.489-0.544) were stronger than correlations between index status and age at thyroidectomy (ρ = 0.359-0.438). For pheochromocytoma and primary hyperparathyroidism, no significant differences were noted. When stratified by time of surgery before vs. in the new millennium, age at thyroidectomy fell significantly only for non-index patients in the new millennium: from 28.6 to 21.2 years (moderate-high risk mutations; P = 0.049) and from 23.1 to 12.3 years (high-risk mutations; P < 0.001). All other inter-millennium comparisons did not reach statistical significance., Conclusion: These findings imply that differences between index and non-index patients impact the first syndromic manifestation without extending to subsequent syndromic manifestations. Because they exhibited similar age and tumor characteristics for the secondary and tertiary manifestations of MEN2A, screening for these syndromic components remains an integral element of MEN2A management in index and non-index patients alike. Wider use of population genomic screening may work to diminish the observed disparities between index and non-index patients going forward., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Context: Early genetic association studies yielded too high risk estimates for multiple endocrine neoplasia (MEN2A), suggesting a need for extended surgery., Objective: The objective was to delineate temporal changes in MEN2A presentation by birth cohort analyses., Methods: Birth cohort analyses (10-year increments; ≤1950 to 2011-2020) of carriers of rearranged during transfection (RET) mutations who underwent surgery for MEN2A., Results: Included in this study were 604 carriers (155 index, 445 nonindex, 4 additional patients), with 237 carriers harboring high-risk mutations, 165 carriers moderate-high risk mutations, and 202 carriers low-moderate risk mutations. With increasing recency of birth cohorts, there was a continual decline in index patients from 41-74% to 0% (P < .001) and of medullary thyroid cancer (MTC) from 96-100% to 0-33% (P < .001). Node metastases diminished from 62-70% to 0% (P ≤ .001; high and low-moderate risk mutations), whereas biochemical cure after thyroidectomy surged from 17-33% to 100% (P ≤ .019; high and low-moderate mutations). Surgical interventions for MEN2A-related tumors were performed increasingly earlier, causing median carrier age to fall: from 51-63 to 3-5 years at thyroidectomy (P < .001); from 46-51 to 24-25 years at first adrenalectomy (P ≤ .013; high and moderate-high risk mutations); and from 43.5-66 to 16.5-32 years at parathyroidectomy. MTC diameters were more effectively decreased from 14-32 to 1-4 mm (P ≤ 002) than pheochromocytoma diameters (nonsignificant)., Conclusion: These insights into MEN2A presentation, adjusted by birth year, illustrate the shift from reactive to preventative medicine, enabling less extensive risk-reducing surgery., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Anaplastic thyroid carcinoma has a very poor prognosis. We analyzed the effect of surgery, radiotherapy and chemotherapy on survival time and side effects in patients with ATC., Methods: We retrospectively analyzed all patients (n = 63) with histologically confirmed ATC who presented at our clinic between 1989 and 2020. We analyzed the survival with Kaplan-Meier curves and cox proportional hazard models and acute toxicities with logistic regression models., Results: Out of 63 patients, 62 received radiotherapy, 74% underwent surgery and 24% received combined chemotherapy. A median radiation dose of 49 Gy (range 4-66 Gy) was applied. In 32% of the cases opposing-field technique was used, in 18% 3D-conformal, in 27% a combination of opposing field and 3D-conformal technique and 21% obtained IMRT (intensity modulated radiotherapy) or VMAT (volumetric modulated arc radiotherapy). Median overall survival (OS) was 6 months. We identified five predictive factors relevant for survival: absence of distant metastases at the time of diagnosis (OS 8 months), surgery (OS 9.8 months), resection status R0 (OS 14 months), radiation dose of 50 Gy or higher (OS 13 months) and multimodal therapy (surgery, radiotherapy and chemotherapy) with a median OS of 9.7 months., Conclusion: In spite of the dismal outcome, longer survival can be achieved in some patients with ATC using surgery and radiotherapy with a high radiation dose. Compared to our previous study, there are no significant advantages in overall survival. Trial registration Retrospectively registered., (© 2023. The Author(s).)

Purpose: Thirty years into the genomic era, this study sought to explore events that helped transform the clinical landscape of hereditary medullary thyroid cancer (MTC)., Method: This retrospective analysis of prospectively collected data included all RET carriers referred to a tertiary center for neck surgery that was performed between 1986 and 2021, using descriptive statistics and Poisson regression analysis., Results: Altogether, 496 RET carriers were referred for thyroidectomy (388 carriers) or neck reoperation (108 carriers). Of these, 44 carriers had highest risk mutations (p.Met918Thr), 164 carriers high risk mutations (p.Cys634Arg/Gly/Phe/Ser/Trp/Tyr/insHisGluLeuCys), 116 carriers moderate-high risk mutations (p.Cys609/611/618/620/630Arg/Gly/Phe/Ser/Tyr) and 172 carriers low-moderate risk mutations (p.Glu768Asp, p.Leu790Phe, p.Val804Leu/Met, or p.Ser891Ala). Three event clusters drove referral numbers upward: a string of first reports of causative RET mutations between 1993 and 1998; the international consensus guidelines for diagnosis and therapy of MEN type 1 and type 2 in 2001; and the revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma in 2015. Referrals for neck reoperation declined sluggishly over 30 years, ending in 2018. Index patients continued to be referred into 2021. Referrals for thyroidectomy, grouped in 5-year increments, peaked in 1996-2000 for carriers of highest and high risk mutations, and in 2006-2010 for carriers of moderate-high and low-moderate risk mutations, some 10 years later., Conclusion: International management guidelines are critical in building and increasing the pressure towards screening of sporadic-appearing disease and offspring of known gene families by encompassing the complete disease spectrum early on., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: In medullary thyroid cancer (MTC), it is unclear which nodal classification system, metastatic lymph node ratio (MLNR), number of node metastases, or TNM/AJCC N classification, predicts cancer-specific survival best., Methods: Kaplan-Maier analysis of cancer-specific survival after operation at a tertiary center., Results: Included were 505 MTC patients. The spread of the survival curves was greatest after stratification by MLNR (in 0.20 increments), followed by number of node metastases (in 10-node and 20-node increments) and TNM/AJCC classification (N0, N1a, N1b). After collapsing overlapping survival curves, all adjacent curves (MLNRs ≤0.20 vs. 0.21-0.60 vs. >0.60; 0 vs. 1-20 vs. >20 node metastases; and TNM/AJCC N classification N0/N1a vs. N1b) significantly differed between each other., Conclusions: In MTC, MLNR, reflecting intensity of lymphatic spread, predicts cancer-specific survival better than number of node metastases or TNM/AJCC N classification. The applicability of these findings to patients with limited neck dissection requires more research., (© 2022 Wiley Periodicals LLC.)

There are no data on the impact of parent-of-origin effects on the expression of multiple endocrine neoplasia type 2A (MEN2A). The present study aimed to explore effects of parent-of-origin and offspring gender in MEN2A. In total, 224 carriers harbored heterozygous RET (REarranged during Transfection) p.Cys634 missense variants, for 169 of whom information on parent-of-origin gender was available. Altogether, offspring from affected fathers harbored more often node metastases from medullary thyroid cancer (45 vs. 19%; P = 0.006) and bilateral pheochromocytoma (24 vs. 10%; P = 0.021) than offspring from affected mothers. The former also also tended to be older at most recent follow-up (medians of 21 vs. 14 years; P = 0.056) and tended to have more often pheochromocytoma (33 vs. 19 yrs.; P = 0.051) and primary hyperparathyroidism (13 vs. 4%; P = 0.090) than the latter. Daughters from affected fathers harbored more often node metastases (39 vs. 15%; P = 0.043) than daughters from affected mothers. This difference decreased in male offspring when sons from affected fathers were compared with sons from affected mothers (52 vs. 40%; P = 0.111). There was also a slight deficit of male offspring: 1.1 sons each per affected mother and father vs. 1.2 daughters per affected mother and 1.4 daughters per affected father. These data suggest a parent-of-origin effect in MEN2A, warranting international collaborative research., (© 2021. The Author(s), under exclusive licence to Springer Nature B.V.)

The association of Hashimoto thyroiditis and Graves' disease with papillary, follicular, and medullary thyroid cancer has not been comprehensively investigated until now. This comparative clinicopathological study of consecutive patients thyroidectomized at a surgical referral center aimed to explore interdependencies between chronic autoimmune thyroiditis and thyroid cancer. Altogether, there were 852 (58.4%) patients with papillary thyroid cancer, 181 (12.4%) patients with follicular thyroid cancer, and 426 (29.2%) patients with sporadic medullary thyroid cancer, of whom 75 (5.1%) patients also had Hashimoto thyroiditis and 40 (2.7%) patients also had Graves' disease. Patients with papillary (medians of 42 vs. 48 years; P  =0.008) and follicular (medians of 33 vs. 63 years; P =0.022) thyroid cancer, unlike patients with medullary thyroid cancer (medians of 57.5 vs. 57 years; P =0.989), were younger at thyroidectomy when they had Hashimoto thyroiditis concomitantly. No such associations were seen with Graves' disease. Primary thyroid cancers tended to be more localized in conjunction with Hashimoto thyroiditis, and less so with Graves' disease, although patterns were not consistent across tumor types. In conclusion, Hashimoto thyroiditis, but not Graves' disease, may be associated with differentiated (papillary and follicular) thyroid cancer but not with medullary thyroid cancer., Competing Interests: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this research., (Thieme. All rights reserved.)

Objectives: The aim of this study was to define the suitability of microscopic lymphatic and venous invasion for prediction of lymph node and distant metastases in papillary thyroid cancer., Design: Stratification by microscopic lymphatic and venous invasion, and multivariable analyses on lymph node and distant metastases including microscopic lymphatic and venous invasion as independent variables., Setting: Tertiary referral centre., Participants: 422 patients who had ≥5 lymph nodes removed at initial thyroidectomy., Main Outcome Measures: Lymph node and distant metastases., Results: Patients with microscopic lymphatic invasion had larger primary tumours than patients without and more often revealed microscopic venous invasion, multifocal tumour growth and lymph node metastases. Patients with microscopic venous invasion exhibited larger primary tumours than patients without and more commonly had microscopic lymphatic invasion, poor tumour differentiation, lymph node metastases and distant metastases. Prediction of lymph node metastases by microscopic lymphatic invasion was better than prediction of distant metastases by microscopic venous invasion regarding sensitivity (61.0 vs. 33.3%) and positive predictive value (92.6 vs. 20.9%), comparable regarding specificity (89.6 and 93.4%), and worse regarding negative predictive value (51.9 vs. 95.3%) and accuracy (70.1 vs. 87.7%). On multivariable logistic regression analysis, microscopic lymphatic invasion was associated with lymph node metastasis (odds ratio [OR] 11.1) and multifocal tumour growth (OR 2.4), whereas primary tumour size (OR 5.8 for tumours >40 mm relative to tumours ≤20 mm) and multifocal tumour growth (OR 3.1) were associated with distant metastasis., Conclusion: Stricter histopathological criteria are warranted to enhance the utility of microscopic vascular invasion for prediction of distant metastases in papillary thyroid cancer., (© 2022 John Wiley & Sons Ltd.)

Background: Predictive criteria to determine the absence of node metastases from thyroid specimens are scarce for sporadic medullary thyroid cancer., Methods: Histopathologic stratification of patients with unifocal sporadic medullary thyroid cancer ≤25 mm with ≥10 neck nodes at thyroidectomy to evaluate the suitability of desmoplasia (7 increments) and tumor capsule integrity (5 decrements) for intraoperative prediction of node metastasis in unifocal sporadic medullary thyroid cancer., Results: Paraffin-embedded thyroid specimens were available for 139 eligible patients. Significant (P < .001) associations were found between increasing desmoplasia and decreasing tumor capsule integrity and nodal disease (from 0 to 79% and 0 to 62%); the number of node metastases (medians, from 0 to 3 and 0 to 2 nodes); and biochemical cure (from 100 to 36% and 100 to 58%). Desmoplasia (low-moderate to high, with fibrosis >10%) and breach of the tumor capsule (>3 extensions; 1 extension >3 mm in width; or diffuse growth without tumor capsule) yielded excellent sensitivity and negative predictive value (100%), with moderate specificity (57 and 48%) and positive predictive value (50 and 46%). In retrospect, node dissection proved unnecessary in 55 (57%) and 47 (48%) patients who harbored desmoplasia-negative and encapsulated tumors. When available frozen sections were histopathologically compared with matching paraffin-embedded thyroid tumor specimens, concordance was 98% (53 of 54 pairs): 1 of 7 upgrades changed the diagnosis to desmoplasia, whereas 1 of 3 downgrades shifted the diagnosis of tumor capsule breach from "present" to "absent.", Conclusions: Patients with desmoplasia-negative encapsulated sporadic medullary thyroid cancer may forgo node dissection at specialist centers., (Copyright © 2021 Elsevier Inc. All rights reserved.)

This study of 542 patients with follicular thyroid cancer, 366 patients with the follicular variant and 1452 patients with the classical variant of papillary thyroid cancer, and 819 patients with sporadic medullary thyroid cancer operated at a tertiary referral center aimed to determine risk patterns of distant metastasis for each tumor entity, which are ill-defined. On multivariable logistic regression analyses, lymph node metastasis consistently emerged as an independent risk factor of distant metastasis, yielding odds ratios (ORs) of 2.4 and 2.8 for follicular thyroid cancer and the follicular variant of papillary thyroid cancer, and ORs of 5.9 and 6.4 for the classical variant of papillary thyroid cancer and sporadic medullary thyroid cancer. Another independent risk factor consistently associated with distant metastasis, most strongly in follicular thyroid cancer and the follicular variant of papillary thyroid cancer (OR 3.5 and 4.0), was patient age >60 years. Altogether, 2 distinct risk patterns of distant metastasis were identified, which were modulated by other cancer type-dependent risk factors: one with lymph node metastasis as leading component (classical variant of papillary thyroid cancer and sporadic medullary thyroid cancer), and another one with age as leading component (follicular thyroid cancer and the follicular variant of papillary thyroid cancer). Distant metastasis was exceptional in node-negative patients with sporadic medullary thyroid cancer (1.7%) and the classical variant of papillary thyroid cancer (1.4%), and infrequent in node-negative patients with the follicular variant of papillary thyroid cancer (4.4%). These findings delineate windows of opportunity for early surgical intervention before distant metastasis has occurred., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Context: Against the background of increasing incidence, pediatric differentiated thyroid carcinoma (DTC) frequently presents with advanced disease and high recurrence rates while prognosis remains excellent., Background: We investigated the use of a pediatric classification and an adult response to therapy risk stratification for pediatric DTC patients and their implications for adaptation of treatment and follow-up., Methods: Data from patients aged <18 years with a diagnosis of primary DTC, registered with the German Pediatric Oncology Hematology-Malignant Endocrine Tumor registry since 1995, were analyzed. For risk prediction, patients were retrospectively assigned to the American Thyroid Association (ATA) risk groups and evaluated for response to therapy., Results: By October 2019, 354 patients with DTC had been reported (median age at diagnosis 13.7 years, range 3.6-17.9) with lymph node and distant metastases in 74.3% and 24.5%. Mean follow-up was 4.1 years (range 0-20.6). Ten-year overall and event-free survival (EFS) rates were 98.9% and 78.1%. EFS was impaired for patients with lymph node and distant metastases (P < .001), positive postoperative thyroglobulin (P = .006), incomplete resection (P = .002), sequential surgeries to achieve total thyroidectomy (P = .042), invasion of capsule (P < .001) and lymph vessels (P = .005), infiltration of surrounding soft tissues (P < .001), tumor multifocality (P < .001), ATA intermediate- and high-risk group (P < .001), and age <10 years (P < .001). Multivariate analysis revealed age <10 years at diagnosis, ATA high-risk level, and poor response to therapy as significant negative prognostic factors for EFS., Conclusion: Age, ATA risk group, and response to therapy emerged as significant prognostic factors for EFS in pediatric patients with DTC, requiring risk-adapted individualized therapy and follow-up., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: Magnetic resonance imaging is used to stage thyroid tumors. Diffusion weighted imaging (DWI) and apparent diffusion coefficient (ADC) can be used to reflect tumor microstructure. Our aim was to compare ADC values of malignant and benign thyroid lesions based on a large sample., Methods: MEDLINE library, EMBASE and SCOPUS databases were screened for the associations between ADC values and thyroid lesions up to August 2021. The primary endpoint of the systematic review were ADC values of benign and malignant thyroid lesions. In total, 29 studies were suitable for the analysis and were included into the present study., Results: The included studies comprised a total of 2137 lesions, 1118 (52.3%) benign and 1019 (47.7%) malignant lesions. The pooled mean ADC value of the benign thyroid lesions was 1.88 × 10 -3  mm 2 /s [95% CI 1.77-2.0] and the pooled mean ADC value of malignant thyroid lesions was 1.15 × 10 -3  mm 2 /s [95% CI 1.04-1.25]., Conclusions: ADC can well discriminate benign and malignant thyroid tumors. Therefore, DWI should be implemented into the presurgical diagnostic work-up in clinical routine., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The metastatic risk profile of microscopic lymphatic and venous invasion in medullary thyroid cancer is ill-defined. This evidence gap calls for evaluation of the suitability of microscopic lymphatic and venous invasion at thyroidectomy for prediction of lymph node and distant metastases in medullary thyroid cancer. In this study of 484 patients with medullary thyroid cancer who had≥5 lymph nodes removed at initial thyroidectomy, microscopic lymphatic and venous invasion were significantly associated with greater primary tumor size (27.6 vs. 14.5 mm, and 30.8 vs. 16.2 mm) and more frequent lymph node metastasis (97.0 vs. 25.9%, and 85.2 vs. 39.5%) and distant metastasis (25.0 vs. 5.1%, and 32.8 vs. 7.3%). Prediction of lymph node metastases by microscopic lymphatic invasion was better than prediction of distant metastases by microscopic venous invasion regarding sensitivity (97.0 vs. 32.8%) and positive predictive value (58.4 vs. 39.2%); comparable regarding negative predictive value (98.5 vs. 90.5%) and accuracy (80.4 vs. 85.1%); and worse regarding specificity (74.1 vs. 92.7%). On multivariable logistic regression, microscopic lymphatic invasion predicted lymph node metastasis better (odds ratio [OR] 65.6) than primary tumor size (OR 4.6 for tumors>40 mm and OR 2.7 for tumors 21-40 mm, relative to tumors≤20 mm), whereas primary tumor size was better in predicting distant metastasis (OR 8.3 for tumors>40 mm and OR 3.9 for tumors 21-40 mm, relative to tumors≤20 mm) than microscopic venous invasion (OR 3.2). These data show that lymphatic invasion predicts lymph node metastases better in medullary thyroid cancer than venous invasion heralds distant metastases., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Context: Risk factors of lymph node and distant metastases have rarely been analyzed in hereditary and sporadic medullary thyroid cancer (MTC) using large genetic-clinical data sets., Objective: This comprehensive investigation aimed to explore risk factors of lymph node and distant metastases and interdependencies between age at thyroidectomy, primary tumor size, lymph node metastasis, and distant metastasis in patients with hereditary and sporadic MTC., Methods: We performed comparative analyses of risk factors of metastasis, stratified by hereditary MTC (4 mutational risk categories) and sporadic MTC., Results: There were 1115 patients with hereditary MTC (307 patients) or sporadic MTC (808 patients). Age at thyroidectomy increased proportionately from 12.2, 22.7, 34.3, and 49.8 years for patients with decreasing mutational risk, compared with 52.1 years for patients with sporadic MTC. Metastatic primary tumors overall were 10.7 to 19.4 mm larger in node-positive patients and 15.9 to 19.3 mm larger in distant metastatic patients at thyroidectomy than nonmetastatic tumors. Distant metastases were noted in 13% to 50% of node-positive vs 0% of node-negative hereditary MTC, and in 23.5% of node-positive vs 1.7% of node-negative sporadic MTC. In multivariable logistic regression analysis for sporadic MTC, lymph node metastasis contributed to distant metastasis (odds ratio 12.4) more than primary tumor size (odds ratios of 7.8, 5.5, and 2.4 for tumors measuring >60, 41-60, and 21-40 mm, respectively)., Conclusion: When thyroidectomy is performed before lymph node metastases have developed, distant metastases are exceptional, both in patients with hereditary MTC (irrespective of mutational risk level) and patients with sporadic MTC., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Intraoperative neural monitoring (IONM) is now an integral aspect of thyroid surgery in many centers. Interest in IONM and the number of institutions that perform monitored thyroidectomies have increased throughout the world in recent years. For surgeons considering the introduction of IONM in their practice, specific training in IONM devices and procedures can substantially shorten the learning curve. The International Neural Monitoring Study Group (INMSG) has been at the forefront of IONM technology and procedural adoption since the introduction of neural monitoring in thyroid and parathyroid surgery. The purpose of this document is to define the INMSG consensus on essential elements of IONM training courses. Specifically, this document describes the minimum training required for teaching practical application of IONM and consensus views on key issues that must be addressed for the safe and reliable introduction of IONM in surgical practice. The intent of this publication is to provide societies, course directors, teaching institutions, and national organizations with a practical reference for developing IONM training programs. With these guidelines, IONM will be implemented optimally, to the ultimate benefit of the thyroid and parathyroid surgical patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor declared a past co-authorship with one of the authors GR., (Copyright © 2021 Wu, Randolph, Barczyński, Schneider, Chiang, Huang, Karcioglu, Konturek, Frattini, Weber, Liu, Dralle and Dionigi.)

Although the onset of hereditary medullary thyroid cancer (MTC) depends on mutational risk, the impact of that risk on lymph node metastasis is unclear. Included in this investigation were 387 carriers of RET germline mutations with node-negative MTC (201 carriers) or node-positive MTC (186 carriers). Age at thyroidectomy increased significantly from highest (p.Met918Thr; 45 carriers), high (p.Cys634Arg/Gly/Phe/Ser/Trp/Tyr; 138 carriers) and moderate-high risk (p.Cys609/611/618/620Arg/Gly/Phe/Ser/Trp/Tyr; 93 carriers) to low-moderate risk (p.Glu768Asp, p. Leu790Phe, p. Val804Leu/Met, p. Ser891Ala; 111 carriers). In contrast, tumor progression to lymph node metastasis was similar, taking 8.6-9.1 years with moderate risk mutations and 13.6-14.5 years with high and highest risk mutations. Primary tumor size across the mutational risk spectrum changed little, measuring 18.1-22.1 mm with and 2.7-7.3 mm without lymph node metastasis. Because the biological behavior of hereditary MTC is similar after disease onset, equal treatment of comparable tumors is warranted regardless of the underlying RET mutation., Competing Interests: Declaration of competing interest The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported., (Copyright © 2020 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

There is no evidence-based guidance on the extent of prophylactic neck surgery for second-generation multiple endocrine neoplasia type 2B (MEN 2B), a newly emerging entity in the molecular era. In this investigation of MEN 2B children who inherited the M918T RET germline mutation from a phenotypically affected MEN 2B parent, 6 MEN 2B children (4 girls and 2 boys) from 5 MEN 2B parents (4 mothers and 1 father) were identified. None of the 6 second-generation MEN 2B children who had preoperative calcitonin serum levels between 2 and 105 pg/mL and underwent prophylactic total thyroidectomy before the age of 4 years after receiving a positive RET gene test harbored node metastases. There was no recurrent laryngeal nerve palsy or postoperative hypoparathyroidism. Within the limitations of this study, total thyroidectomy alone is adequate therapy for second-generation MEN 2B children aged 1-4 years old with preoperative calcitonin serum levels ≤100 pg/mL., (Copyright © 2020 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Background: The impact of intraoperative frozen section (iFS) analysis on the frequency of completion thyroidectomy for the management of thyroid carcinoma is controversial. Although specialized endocrine centres have published their respective results, there are insufficient data from primary and secondary healthcare levels. The aim of this study was to analyse the utility of iFS analysis., Methods: In the Prospective Evaluation Study Thyroid Surgery (PETS) 2 study, 22 011 operations for benign and malignant thyroid disease were registered prospectively in 68 European hospitals from 1 July 2010 to 31 December 2012. Group 1 consisted of 569 patients from University Medical Centre (UMC) Mainz, and group 2 comprised 21 442 patients from other PETS 2 participating hospitals. UMC Mainz exercised targeted but liberal use of iFS analysis for suspected malignant nodules. iFS analysis was compared with standard histological examination regarding the correct distinction between benign and malignant disease. The percentage of completion thyroidectomies was assessed for the participating hospitals., Results: iFS analysis was performed in 35.70 per cent of patients in group 1 versus 21.80 per cent of those in group 2 (risk ratio (RR) 1.6, 95 per cent c.i. 1.5 to 1.8; P < 0.001). Sensitivity of iFS analysis was 75.0 per cent in group 1 versus 63.50 per cent in group 2 (RR 1.2, 1.2 to 1.3; P = 0.040). Completion surgery was necessary in 8.10 per cent of patients in group 1 versus 20.8 per cent of those in group 2 (RR 0.4, 0.2 to 0.7; P = 0.001)., Conclusion: iFS analysis is a useful tool in determining the appropriate surgical management of thyroid disease. Targeted use of iFS was associated with a significantly higher sensitivity for the detection of malignancy, and with a significantly reduced necessity for completion surgery., (© The Author(s) 2021. Published by Oxford University Press on behalf of BJS Society Ltd.)

Anaplastic thyroid carcinomas (ATC) are rare, but represent the most lethal malignancy of the thyroid. Selective molecular markers and drivers distinguishing ATC from other thyroid carcinomas of follicular origin remain largely unknown, limiting advances in diagnosis and treatment. In a retrospective study, we analyzed gene expression in 36 ATC, 18 poorly differentiated, 132 papillary, and 55 follicular thyroid carcinoma, as well as 124 paired and unpaired normal thyroid tissues in three independent cohorts by RNA-sequencing and immunohistochemistry. RNA-sequencing data in the test cohort suggested selective ATC protein biomarkers. Evaluation of these revealed that ATCs are characterized by the de novo expression of various testis antigens, including melanoma-associated antigen A3 (MAGEA3), but most importantly the oncofetal IGF2 mRNA binding protein 1 (IGF2BP1). Shallow whole genome sequencing essentially excluded that IGF2BP1 upregulation results from gene copy number alterations. Immunohistochemical analyses in all three tumor cohorts confirmed the selective de novo expression of IGF2BP1 protein in ATC. In sum, 75% (27/36) of all tested ATC and 0.5% (1/204) of poorly and well-differentiated thyroid carcinoma tissue samples were positive for IGF2BP1 protein. This indicates that IGF2BP1 protein expression identifies ATC with a diagnostic odds ratio of 612 (95% CI: 74.6-5021). In addition, we found that MAGEA3 is exclusively, although less consistently upregulated in ATC, presenting with an odds ratio of 411 (95% CI: 23.8-7098.7). Importantly, we provide confirmatory evidence that IGF2BP1 and MAGEA3 expression distinguishes ATC from poorly differentiated thyroid carcinoma. IGF2BP1 furthermore identified ATC foci within low-grade follicular thyroid carcinoma. In conclusion, IGF2BP1 represents the most promising single-gene marker available for ATC, followed by MAGEA3, improving on current techniques. Robust markers are essential to help distinguish this high-grade malignancy from other thyroid carcinomas, to guide surgical decision making, therapy and post-resection/therapy monitoring strategies.

Altered expression and/or localization of cysteine cathepsins is believed to involve in thyroid diseases including cancer. Here, we examined the localization of cathepsins B and V in human thyroid tissue sections of different pathological conditions by immunolabeling and morphometry. Cathepsin B was mostly found within endo-lysosomes as expected. In contrast, cathepsin V was detected within nuclei, predominantly in cells of cold nodules, follicular and papillary thyroid carcinoma tissue, while it was less often detected in this unusual localization in hot nodules and goiter tissue. To understand the significance of nuclear cathepsin V in thyroid cells, this study aimed to establish a cellular model of stable nuclear cathepsin V expression. As representative of a specific form lacking the signal peptide and part of the propeptide, N-terminally truncated cathepsin V fused to eGFP recapitulated the nuclear localization of endogenous cathepsin V throughout the cell cycle in Nthy-ori 3-1 cells. Interestingly, the N-terminally truncated cathepsin V-eGFP was more abundant in the nuclei during S phase. These findings suggested a possible contribution of nuclear cathepsin V forms to cell cycle progression. Indeed, we found that N-terminally truncated cathepsin V-eGFP expressing cells were more proliferative than those expressing full-length cathepsin V-eGFP or wild type controls. We conclude that a specific molecular form of cathepsin V localizes to the nucleus of thyroid epithelial and carcinoma cells, where it might involve in deregulated pathways leading to hyperproliferation. These findings highlight the necessity to better understand cathepsin trafficking in health and disease. In particular, cell type specificity of mislocalization of cysteine cathepsins, which otherwise act in a functionally redundant manner, seems to be important to understand their non-canonical roles in cell cycle progression., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Purpose: To determine whether published disease penetrance estimates of 50% for pheochromocytoma and 20-30% for primary hyperparathyroidism in multiple endocrine neoplasia (MEN 2A), conceivably reflecting overrepresentation of index patients with completely developed MEN 2A, may be too high., Methods: Cross-sectional study of carriers at high risk of MEN 2A from a tertiary referral center., Results: There were 213 carriers of RET mutations in codon 634, born between 1922 and 2014. Median age of thyroidectomy was 17 years, with MTC being present in 76.5%; pheochromocytoma in 31.0% at a median of 34 years in the first, and in 18.8% at a median of 35 years in the second adrenal; and primary hyperparathyroidism in 10.8% at a median of 39 years. MTC, pheochromocytoma and primary hyperparathyroidism, stratified by year of birth, were diagnosed earlier over time: for MTC from 51 to 4 years; for pheochromocytoma from 51 to 22.5 years in the first, and from 51 to 29.5 years in the second adrenal, and for primary hyperparathyroidism from 46 to 12 years (P ≤ 0.008). This decline in age was paralleled by diminishing tumor diameters, more strongly in the thyroid (from 20 to 1.8 mm; P < 0.001) than in the adrenals (from 43 to 30 mm in the first, and from 20-57.5 to 30.5 mm in the second adrenal; statistically nonsignificant)., Conclusions: The lower disease penetrance estimates and sluggish decline of adrenal tumor diameters call for more widespread adoption of adrenal-sparing and parathyroid preservation surgery based on early and regular biochemical screening.

Background: The impact of number of node metastases versus metastatic lymph node ratio versus AJCC node category on biochemical cure in medullary thyroid cancer (MTC) is not well defined., Methods: Multivariable logistic regression analysis was used to determine clinical and histopathological variables that contribute to biochemical cure in node-positive MTC., Results: Some 584 of 1026 patients with MTC underwent systematic lymph node dissections for node-positive disease; 27·4 per cent (54 of 197) were biochemically cured after the initial operation and 13·5 per cent (42 of 310 patients) after repeat surgery. Cured patients had significantly less extrathyroid extension (11-14 versus 33·2-55·6 per cent), fewer lymph node metastases (median 2-4 versus 12-16), a lower metastatic lymph node ratio (median 0·05-0·08 versus 0·23-0·28), and were less likely to have AJCC pN1b disease (56-76 versus 89·9-91·6 per cent) and distant metastases (0 versus 28·4-37·1 per cent) than patients who were not cured. Biochemical cure curves advanced steadily up to 7-12 node metastases and a metastatic lymph node ratio of 0·33, eventually levelling off after 16-17 node metastases and metastatic lymph node ratios of 0·45-0·65. In logistic regression analysis, number of lymph node metastases (odds ratio (OR) 17·24 for more than 20 metastases, OR 5·28 for 11-20 metastases, OR 2·22 for 6-10 metastases), preoperative basal serum calcitonin (OR 6·24 for over 1000 pg/ml), reoperation (OR 5·34) and extrathyroid extension (OR 2·42) independently predicted failure to reach biochemical cure., Conclusion: Number of lymph node metastases, unlike metastatic lymph node ratio or AJCC node category, determines likelihood of biochemical cure after initial and repeat surgery for node-positive MTC., (© 2020 BJS Society Ltd Published by John Wiley & Sons Ltd.)

Angiotensin-converting enzymes, ACE and ACE2, play not only a pivotal role in the regulation of blood pressure, but are involved in the processes of pathophysiology, including thyroid dysfunction or progression of several neoplasia such as cancers of skin, lungs, pancreas and leukemia. However, their role in the thyroid carcinogenesis remains unknown. We examined in this study the expression of ACE and ACE2 in thyroid tissues and their possible employment as biomarkers for thyroid cancer progression. Thyroid tissues, including 14 goiters (G), 12 follicular adenomas (FA), 10 follicular thyroid carcinomas (FTC), 14 papillary thyroid carcinomas (PTC) and 11 undifferentiated thyroid carcinomas (UTC), were subjected to RT-PCR and protein analyses with primers or antibodies specific for ACE and ACE2, respectively. FA revealed significantly increased ACE compared to other groups and FTC was significantly higher than UTC. ACE2 was significantly increased in PTC in comparison to G, FA and UTC, and in FTC as compared to G. The ratio ACE/ACE2 decreased, while ACE2/ACE increased with the differentiation grade of thyroid carcinoma. ACE was significantly diminished in individuals older than 50. Both ACEs were significantly diminished in M1 patients, ACE2 additionally in higher tumor masses. ACE and ACE2 are regulated within thyroid benign and malignant tissues. As the transcript ratio between both enzymes correlate proportional with the differentiation status of thyroid cancer, ACE and ACE2 may serve as new markers for thyroid carcinoma.

Advances in sequencing technology, providing unprecedented insights into cancer progression, have shifted the treatment paradigm towards precision medicine for hereditary medullary thyroid cancer (MTC), away from the 'one-size-fits-all' approach predicated on genetic risk alone. The DNA-based/biochemical concept, factoring serum calcitonin into the benefit-risk equation, optimizes biochemical cure while minimizing extent of prophylactic surgery and operative morbidity in children at risk. The transformative effect that has taking effect on medical practice has been impressive: Increasingly earlier molecular diagnosis and more limited prophylactic neck operations yielded excellent clinical outcomes at expert facilities 7-16 years postoperatively: biochemical cure rates approximating 100%; absence of residual structural disease or recurrence; and rarely any permanent operative morbidity. These excellent results, contingent on proper health care funding and pediatric surgical specialization, make a case for early prophylactic thyroidectomy in experienced hands once calcitonin serum levels exceed the upper normal limit of the assay in young gene carriers., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Multiple endocrine neoplasia type 2B is a rare syndrome caused mainly by Met918Thr germline RET mutation, and characterised by medullary thyroid carcinoma, phaeochromocytoma, and extra-endocrine features. Data are scarce on the natural history of multiple endocrine neoplasia type 2B. We aimed to advance understanding of the phenotype and natural history of multiple endocrine neoplasia type 2B, to increase awareness and improve detection., Methods: This study was a retrospective, multicentre, international study in patients carrying the Met918Thr RET variant with no age restrictions. The study was done with registry data from 48 centres globally. Data from patients followed-up from 1970 to 2016 were retrieved from May 1, 2016, to May 31, 2018. Our primary objectives were to determine overall survival, and medullary thyroid carcinoma-specific survival based on whether the patient had undergone early thyroidectomy before the age of 1 year. We also assessed remission of medullary thyroid carcinoma, incidence and treatment of phaeochromocytoma, and the penetrance of extra-endocrine features., Findings: 345 patients were included, of whom 338 (98%) had a thyroidectomy. 71 patients (21%) of the total cohort died at a median age of 25 years (range <1-59). Thyroidectomy was done before the age of 1 year in 20 patients, which led to long-term remission (ie, undetectable calcitonin level) in 15 (83%) of 18 individuals (2 patients died of causes unrelated to medullary thyroid carcinoma). Medullary thyroid carcinoma-specific survival curves did not show any significant difference between patients who had thyroidectomy before or after 1 year (comparison of survival curves by log-rank test: p=0·2; hazard ratio 0·35; 95% CI 0.07-1.74). However, there was a significant difference in remission status between patients who underwent thyroidectomy before and after the age of 1 year (p<0·0001). There was a significant difference in remission status between patients who underwent thyroidectomy before and after the age of 1 year (p<0·0001). In the other 318 patients who underwent thyroidectomy after 1 year of age, biochemical and structural remission was obtained in 47 (15%) of 318 individuals. Bilateral phaeochromocytoma was diagnosed in 156 (50%) of 313 patients by 28 years of age. Adrenal-sparing surgery was done in 31 patients: three (10%) of 31 patients had long-term recurrence, while normal adrenal function was obtained in 16 (62%) patients. All patients with available data (n=287) had at least one extra-endocrine feature, including 106 (56%) of 190 patients showing marfanoid body habitus, mucosal neuromas, and gastrointestinal signs., Interpretation: Thyroidectomy done at no later than 1 year of age is associated with a high probability of cure. The reality is that the majority of children with the syndrome will be diagnosed after this recommended age. Adrenal-sparing surgery is feasible in multiple endocrine neoplasia type 2B and affords a good chance for normal adrenal function. To improve the prognosis of such patients, it is imperative that every health-care provider be aware of the extra-endocrine signs and the natural history of this rare syndrome. The implications of this research include increasing awareness of the extra-endocrine symptoms and also recommendations for thyroidectomy before the age of 1 year., Funding: None., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: It remains unclear when postoperative serum calcitonin levels should be measured in patients with medullary thyroid cancer (MTC) and, specifically, whether this decision should be based on the preoperative calcitonin level or nodal status., Methods: A cohort of patients with previously untreated MTC was studied. Kaplan-Meier analyses, stratified by preoperative calcitonin level, nodal status and number of nodal metastases, were performed to determine time to calcitonin normalization after initial surgery, with statistical analysis by means of the log rank test., Results: Some 213 patients with node-negative and 182 with node-positive MTC were included in the study. Postoperative calcitonin levels normalized in a mean of 3·5 versus 3·7 days respectively among patients with preoperative calcitonin levels of 10-100 pg/ml (P = 0·815); 4·8 versus 5·3 days in those with preoperative calcitonin levels of 100·1-500 pg/ml (P = 0·026); 5·3 versus 9·9 days in patients with preoperative calcitonin levels of 500·1-1000 pg/ml (P = 0·004); and 6·6 versus 57·7 days among those with preoperative calcitonin levels exceeding 1000 pg/ml (P < 0·001). Calcitonin levels normalized in a mean of 4·7 days when nodal metastasis was not present, 5·2 days in those with one to five nodal metastases, 7·0 days in patients with six to ten nodal metastases, and 57·1 days among patients with more than ten nodal metastases. Postoperative calcitonin normalization curves paralleled each other in patients with node-negative MTC, but diverged in those with node-positive disease and with more nodal metastases., Conclusion: Calcitonin levels typically normalize within 1 week; and within a fortnight in those with node-positive MTC and preoperative calcitonin levels of 500·1-1000 pg/ml. With node-positive MTC and preoperative calcitonin levels exceeding 1000 pg/ml, and with more than ten nodal metastases, calcitonin normalization takes longer., (© 2019 BJS Society Ltd. Published by John Wiley & Sons Ltd.)

Background: In pediatric Graves' disease, operative morbidity after total thyroidectomy remains ill defined. The present study aimed to clarify whether total thyroidectomy entails greater operative morbidity in children with Graves' disease, in particular when they are very young, as compared with an age-matched reference group of children with hereditary C-cell disease who underwent total thyroidectomy at the same time., Methods: Operative morbidity after total thyroidectomy for Graves' disease was determined in relation to the child's age and in comparison with a reference group of age-matched children with hereditary C-cell disease., Results: Included in the study were 58 children with Graves' disease (51 girls and 7 boys) and 108 children with hereditary C-cell disease (59 girls and 49 boys). When children with Graves' disease and children with hereditary C-cell disease were compared across and within the 4 age increments (≤ 3, 4-6, 7-12, and 13-18 years), operative mortality did not differ significantly among and within age increments. Children with Graves' disease had a 1.7-fold greater overall risk of transient hypoparathyroidism (29% versus 17%; P = .073) than children with hereditary C-cell disease. Permanent hypoparathyroidism was nil in either group. Transient recurrent laryngeal nerve palsy, wound hemorrhage, and wound infections were infrequent (≤ 3% each), resolving spontaneously and after reoperation, respectively., Conclusion: Disease impacts more than age on operative morbidity in children with Graves' disease after total thyroidectomy but is fairly low overall and rarely permanent in experienced hands., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The purpose of this publication was to inform surgeons as to the modern state-of-the-art evidence-based guidelines for management of the recurrent laryngeal nerve invaded by malignancy through blending the domains of 1) surgical intraoperative information, 2) preoperative glottic function, and 3) intraoperative real-time electrophysiologic information. These guidelines generated by the International Neural Monitoring Study Group (INMSG) are envisioned to assist the clinical decision-making process involved in recurrent laryngeal nerve management during thyroid surgery by incorporating the important information domains of not only gross surgical findings but also intraoperative recurrent laryngeal nerve functional status and preoperative laryngoscopy findings. These guidelines are presented mainly through algorithmic workflow diagrams for convenience and the ease of application. These guidelines are published in conjunction with the INMSG Guidelines Part I: Staging Bilateral Thyroid Surgery With Monitoring Loss of Signal. Level of Evidence: 5 Laryngoscope, 128:S18-S27, 2018., (© 2018 The American Laryngological, Rhinological and Otological Society, Inc.)

Purpose: To delineate risk factors for, and examine temporal patterns of, histology-proven recurrent medullary thyroid cancer (MTC) after compartment-oriented surgery., Methods: Multivariate Cox regression on overall, node, and soft tissue infiltrate recurrence per previously dissected neck compartment., Results: Mean follow-up for the 203 (and 158) patients with central (and ipsilateral lateral) neck dissection was 56.1 months. On multivariate Cox regression, tumor size > 20 mm predicted overall and node recurrence in the central neck, whereas extranodal growth predicted overall and node recurrence in the ipsilateral lateral neck. Extrathyroidal extension alone predicted soft tissue infiltrate recurrence in the central neck, and extranodal growth alone soft tissue infiltrate recurrence in the ipsilateral lateral neck. When analyses were restricted to patients not biochemically cured after initial surgery, only extranodal growth predicted overall and node recurrence in the dissected neck compartments., Conclusions: Patients not biochemically cured, specifically those with extranodal growth at the initial operation, carry greater risks of node recurrence.

Although already 25 years into the genomic era, age-related progression of hereditary medullary thyroid cancer (MTC), the prevalence of which is estimated at one in 80,000 inhabitants, remains to be delineated for most unique RET (REarranged during Transfection) mutations. Included in this study were 567 RET carriers. The age-related progression of MTC across histopathological groups (normal thyroid/C-cell hyperplasia; node-negative MTC; node-positive MTC) was statistically significant for 13 unique RET mutations (p.Cys611Phe/c.1832G > T; p.Cys611Tyr; p.Cys618Ser/c.1852T > A; p.Cys620Arg; p.Cys634Arg; p.Cys634Phe; p.Cys634Ser; p.Cys634Tyr; p.Glu768Asp; p.Leu790Phe/c.2370G > T; p.Val804Met; p.Ser891Ala; p.Met918Thr), whereas two unique RET mutations (p.Cys618Phe; p.Cys634Gly) trended toward statistical significance. When grouped by mutational risk (highest; high; moderate-high; low-moderate; polymorphism), the age-related progression of MTC was significant for all four categories of RET mutations, which differed significantly across and within the three histopathological groups. For high, for moderate-high, and for low-moderate risk RET mutations, the age-related progression of MTC by mutated codon was broadly comparable across and within the three histopathological groups, and essentially unaffected by the amino acid substitutions examined. These data argue in favor of splitting the American Thyroid Association's moderate-risk category into moderate-high and low-moderate risk categories, while emphasizing the need to contradistinguish the latter from rare nonpathogenic polymorphisms., (© 2018 Wiley Periodicals, Inc.)

"I have noticed in operations of this kind, which I have seen performed by others upon the living, and in a number of excisions, which I have myself performed on the dead body, that most of the difficulty in the separation of the tumor has occurred in the region of these ligaments…. This difficulty, I believe, to be a very frequent source of that accident, which so commonly occurs in removal of goiter, I mean division of the recurrent laryngeal nerve." Sir James Berry (1887)., (© 2018 Wiley Periodicals, Inc.)

Background: A comprehensive assessment has not been undertaken of long-term outcomes in children carrying germline RET mutations and undergoing prophylactic thyroidectomy with the aim of preventing medullary thyroid cancer (MTC)., Methods: A retrospective outcome study (1994-2017) of prophylactic thyroidectomy in children, with and without central node dissection, was performed at a tertiary surgical centre., Results: Some 167 children underwent prophylactic thyroidectomy, 109 without and 58 with concomitant central node dissection. In the highest-risk mutational category, MTC was found in five of six children (83 per cent) aged 3 years or less. In the high-risk category, MTC was present in six of 20 children (30 per cent) aged 3 years or less, 16 of 36 (44 per cent) aged 4-6 years, and 11 of 16 (69 per cent) aged 7-12 years (P = 0·081). In the moderate-risk category, MTC was seen in one of nine children (11 per cent) aged 3 years or less, one of 26 (4 per cent) aged 4-6 years, three of 26 (12 per cent) aged 7-12 years, and seven of 16 (44 per cent) aged 13-18 years (P = 0·006). Postoperative hypoparathyroidism was more frequent in older children (32 per cent in the oldest age group versus 3 per cent in the youngest; P = 0·002), whether or not central node dissection was carried out. Three children developed recurrent laryngeal nerve palsy; all had undergone central node dissection (P = 0·040). All complications resolved within 6 months. Postoperative normalization of calcitonin serum levels was achieved in 114 (99·1 per cent) of 115 children with raised preoperative values. No residual structural disease or recurrence was observed., Conclusion: Early prophylactic thyroidectomy is a viable surgical concept in experienced hands, sparing older children the postoperative morbidity associated with delayed neck surgery., (© 2018 BJS Society Ltd Published by John Wiley & Sons Ltd.)

Context: Recent long-term outcomes and survival data are lacking for patients with multiple endocrine neoplasia type 2B (MEN2B)., Objectives: To analyze long-term MEN2B outcomes and define prognostic factors., Design, Setting, and Participants: Retrospective comparative study of 75 patients with MEN2B from two German tertiary referral centers. Patients diagnosed and treated before and after 2000 were compared for demographic, biochemical, surgical, and outcome parameters., Intervention: Surgery., Main Outcome Measure: Long-term survival., Results: We identified seven familial and 68 de novo cases of MEN2B; 61 exhibited the RET M918T genotype (2 others exhibited A883F and E768D/L790T mutations). Surgery was performed at a mean age of 16.4 ± 11.2 years. The tumor stages at diagnosis for 71 patients were stage I, 15%; stage II, 6%; stage III, 35%; and stage IV, 44%. The mean follow-up was 9.6 ± 9.0 years. The outcomes were 15 (20%) cured, 9 (12%) with minimal residual disease, 19 (25%) with metastatic disease, and 10 (13%) unknown. Medullary thyroid cancer (MTC) caused 22 deaths (29%) 7.3 ± 6.2 years after diagnosis (mean age, 22.9 ± 10.7 years). The overall survival rates at 5, 10, and 20 years were 85%, 74%, and 58%, respectively. After 2000 (vs before 2000), significantly more patients had stage I and II (32% vs 11%) and more were cured (43% vs 20%), with a higher survival trend (P = 0.058). The only prognostic factor was tumor stage at diagnosis., Conclusions: Patients with MEN2B developed MTC at an early age with wide ranging aggressiveness, but the outcome was generally better after 2000 than before 2000., (Copyright © 2017 Endocrine Society)