Extent of Surgery for Medullary Thyroid Cancer and Prevalence of Occult Contralateral Foci.

Importance: Standard treatment for patients with medullary thyroid cancer (MTC) consists of total thyroidectomy with central neck dissection, but the rationale for bilateral surgery in patients with unilateral disease on ultrasonography remains unclear. Objective: To determine the presence of occult contralateral disease (lesions not seen on preoperative ultrasonography) in patients with MTC as a rationale for total thyroidectomy. Design, Setting, and Participants: This multi-institutional, retrospective cohort study was conducted from September 1998 to April 2022 in academic medical centers and included patients with MTC who underwent thyroidectomy with preoperative imaging. Main Outcomes and Measures: The primary end point was the prevalence of sonographically occult foci of MTC in the contralateral lobe among patients with sporadic MTC. Results: The cohort comprised 176 patients with a median age at diagnosis of 55 years (range, 2-87 years), 69 (57.6%) of whom were female. Genetic testing was performed in 109 patients (61.9%), 48 (27.5%) of whom carried germline RET variants. Initial surgical management consisted of total thyroidectomy (161 [91.0%]), lobectomy followed by completion thyroidectomy (7 [4.0%]), and lobectomy alone (8 [4.5%]). Central and lateral neck dissections were performed as part of initial therapy for 146 patients (83.1%). In the entire cohort of 176 patients, 46 (26.0%) had contralateral foci disease and 9 (5.1%) had occult contralateral foci that were not identified on preoperative ultrasonography. Among 109 patients who underwent genetic testing, 38 (34.9%) had contralateral disease, 8 (7.3%) of whom had occult contralateral disease not seen on preoperative ultrasonography. Patients with sporadic MTC experienced a 95.7% reduction in the odds of having a focus of MTC in the contralateral lobe compared with patients with a germline RET variant (odds ratio, 0.043; 95% CI, 0.013-0.123). When adjusting for age, sex, tumor size, and lymph node involvement, the odds ratio of having contralateral MTC in patients with sporadic disease was 0.034 (95% CI, 0.007-0.116). Among patients who underwent lobectomy alone with postoperative calcitonin levels, 5 of 12 (41.7%) achieved undetectable calcitonin levels (<2.0 pg/mL; to convert to pmol/L, multiply by 0.292). Conclusions and Relevance: The results of this cohort study suggest that a staged approach involving initial thyroid lobectomy could be considered in patients with sporadic MTC and no contralateral ultrasonography findings, with no further surgery if calcitonin levels became undetectable. Further work using prospective randomized clinical trials to evaluate lobectomy as a biochemical cure in patients presenting with unilateral disease is warranted.

Tumor Grade and Molecular Characteristics Associated with Survival in Sporadic Medullary Thyroid Carcinoma.

Background: The International Medullary Thyroid Carcinoma Grading System (IMTCGS) divides medullary thyroid carcinoma (MTC) into two categories, high- and low-grade tumors, which has a profound impact on patient outcomes. The aim of this study was to explore the association between IMTCGS grading, clinical data, and molecular status in sporadic MTC. Methods: A retrospective cohort study was performed on consecutive sporadic MTCs from patients undergoing initial surgery between January 2000 and January 2022 at the Padua Endocrine Surgery Unit. Clinical, pathological, and follow-up data were collected, tumors were graded, and somatic mutations of RET and RAS genes were analyzed. Patient outcomes were based on Ct levels and MTC-related deaths. Survival analyses were carried out employing the Kaplan-Meier method and the log-rank test. A Cox proportional hazard regression model was employed for multivariable survival analysis with the following covariates: somatic RET mutation, MTC stage at diagnosis, sex, age at diagnosis, and IMTCGS grade. Results: We included 141 consecutive sporadic MTCs. The median follow-up was 80.0 months (interquartile ranges: 41.5-122.5 months). Seventeen patients (12.1%) died from disease-related causes. 107/141 (76.9%) were classified as low-grade tumors, 32/141 (23.1%) as high-grade. Patients carrying a RET mutation had more aggressive features and shorter disease-specific survival (DSS) (p = 0.001) and were more frequently classified high-grade than low-grade MTC (p < 0.001). At multivariable survival analysis, only IMTCGS grading was independently associated with DSS (hazard ratio 8.8 [confidence interval: 2.7-28.3], p = 0.005). RET mutations, in particular RET-M918T, were more frequent in high-grade than in low-grade MTC (68.8% vs. 29.4% mutated in RET, 46.9% vs. 12.7% mutated in RET-M918T; p < 0.001). None of the high-grade tumors was mutated in the RAS gene, but the mutation was present in 11.8% of low-grade tumors. Conclusions: IMTCGS grading was associated with DSS independently of other clinical, pathological, and molecular factors. Moreover, MTC grading was associated with RET and RAS patterns, which explains, at least in part, the molecular basis of the aggressive behavior of high-grade MTC.

Patterns of Treatment Failure After Selective Rearranged During Transfection (RET) Inhibitors in Patients With Metastatic Medullary Thyroid Carcinoma.

PURPOSE: Medullary thyroid cancer (MTC) harbors frequent mutations in RET oncogene. Selective RET inhibitors (RETi) have emerged as effective treatments. However, resistance almost invariably occurs. METHODS: MTC patients who were initiated on RETi between 2018 and 2022 were included. Baseline characteristics, RET mutational status, RETi response, available tumor tissue and molecular profiles sampled pre- and post-RETi were analyzed. RESULTS: Among 46 MTC patients on RETi during the study period, 26 patients had discontinued at data cut-off because of progression (n = 16), death (n = 4), and toxicity (n = 6). The most frequent RET mutations at baseline were p.M918T (n = 29), and p.C634X (n = 6). Pre- and post-RETi molecular profiles were available in 14 patients. There was no primary resistance on pre-RETi samples. Post-RETi profiles revealed a bypass mechanism of resistance in 75% of the cases including RAS genes mutations (50%), FGFR2 and ALK fusions and and MYC p.P44L. RET solvent from and hinge region mutations was the only resistance mechanisms in 25% of the cases. Tumor samples from initial thyroidectomy, pre- and post-RETi, from six patients, showed an increase of the mean Ki 67-index of 7%, 17% and 40% respectively (P = 0.037) and a more aggressive poorly differentiated histology in three patients. DISCUSSION: Bypass resistance may be the most frequent mechanism of progression under RETi. A more aggressive histology may arise following RETi and warrants further investigation.

Medullary thyroid carcinoma.

INTRODUCTION: Medullary thyroid carcinoma (MTC) constitutes approximately 5-10% of all thyroid cancers. Although the tumor forms in the thyroid, it doesn't originate from thyroid cells, but from the C cells or parafollicular cells which produce and release a hormone called calcitonin (CT). Starting from the second half of the 1900s, MTC was progressively studied and defined. AREAS COVERED: This study aims to analyze the history, clinical presentation and biological behavior of MTC, bio-humoral and instrumental diagnosis, molecular profiling, genetic screening, preoperative staging and instrumental procedures, indispensable in expert and dedicated hands, such as high-resolution ultrasonography, CT-scan, MRI and PET/TC. We examine recommended and controversial surgical indications and procedures, prophylactic early surgery and multiple endocrine neoplasia surgery. Also, we discuss pathological anatomy classification and targeted therapies. The role of serum CT is valued both as undisputed and constant preoperative diagnostic marker, obscuring cytology and as early postoperative marker that predicts disease persistence. EXPERT OPINION: With a complete preoperative study, unnecessary or useless, late and extended interventions can be reduced in favor of tailored surgery that also considers quality of life. Finally, great progress has been made in targeted therapy, with favorable impact on survival.

Chromosomal alterations in sporadic medullary thyroid carcinoma and correlation with outcome.

Somatic copy number alterations (SCNA) involving either a whole chromosome or just one of the arms, or even smaller parts, have been described in about 88% of human tumors. This study investigated the SCNA profile in 40 well-characterized sporadic medullary thyroid carcinomas by comparative genomic hybridization array. We found that 26/40 (65%) cases had at least one SCNA. The prevalence of SCNA, and in particular of chromosome 3 and 10, was significantly higher in cases with a RET somatic mutation. Similarly, SCNA of chromosomes 3, 9, 10 and 16 were more frequent in cases with a worse outcome and an advanced disease. By the pathway enrichment analysis, we found a mutually exclusive distribution of biological pathways in metastatic, biochemically persistent and cured patients. In particular, we found gain of regions involved in the intracellular signaling and loss of regions involved in DNA repair and TP53 pathways in the group of metastatic patients. Gain of regions involved in the cell cycle and senescence were observed in patients with biochemical disease. Finally, gain of regions associated with the immune system and loss of regions involved in the apoptosis pathway were observed in cured patients suggesting a role of specific SCNA and corresponding altered pathways in the outcome of sporadic MTC.

Medullary Thyroid Carcinomas Classified According to the International Medullary Carcinoma Grading System and a Surveillance, Epidemiology, and End Results-Based Metastatic Risk Score: A Correlation With Genetic Profile and Angioinvasion.

Due to the lack of a standardized tool for risk-based stratification, the International Medullary Carcinoma Grading System (IMTCGS) has been proposed for medullary thyroid carcinomas (MTCs) based on necrosis, mitosis, and Ki67. Similarly, a risk stratification study using the Surveillance, Epidemiology, and End Results (SEER) database highlighted significant differences in MTCs in terms of clinical-pathological variables. We aimed to validate both the IMTCGS and SEER-based risk table on 66 MTC cases, with special attention to angioinvasion and the genetic profile. We found a significant association between the IMTCGS and survival because patients classified as high-grade had a lower event-free survival probability. Angioinvasion was also found to be significantly correlated with metastasis and death. Applying the SEER-based risk table, patients classified either as intermediate- or high-risk had a lower survival rate than low-risk patients. In addition, high-grade IMTCGS cases had a higher average SEER-based risk score than low-grade cases. Moreover, when we explored angioinvasion in correlation with the SEER-based risk table, patients with angioinvasion had a higher average SEER-based score than patients without angioinvasion. Deep sequencing analysis found that 10 out of 20 genes frequently mutated in MTCs belonged to a specific functional class, namely chromatin organization, and function, which may be responsible for the MTC heterogeneity. In addition, the genetic signature identified 3 main clusters; cases belonging to cluster II displayed a significantly higher number of mutations and higher tumor mutational burden, suggesting increased genetic instability, but cluster I was associated with the highest number of negative events. In conclusion, we confirmed the prognostic performance of the IMTCGS and SEER-based risk score, showing that patients classified as high-grade had a lower event-free survival probability. We also underline that angioinvasion has a significant prognostic role, which has not been incorporated in previous risk scores.

A Contemporary Review of the Treatment of Medullary Thyroid Carcinoma in the Era of New Drug Therapies.

Medullary thyroid cancer (MTC) is a rare neuroendocrine tumor that can be sporadic or inherited and is often associated with mutations in the RET (Rearranged during Transfection) oncogene. The primary treatment for MTC is surgical resection of all suspected disease, but recent advances in targeted therapies for MTC, including the selective RET inhibitors selpercatinib and pralsetinib, have led to changes in the management of patients with locally advanced, metastatic, or recurrent MTC. In this article, we review updates on the evaluation and management of patients with MTC, focusing on new and emerging therapies that are likely to improve patient outcomes.

Biomarker testing in patients diagnosed with advanced/metastatic medullary thyroid cancer in the USA.

Aim: To describe real-world testing patterns for RET in US patients with advanced/metastatic medullary thyroid cancer and determine consistency of real-world testing practices with national guidelines. Materials & methods: The authors performed a retrospective medical record analysis of patients with advanced/metastatic medullary thyroid cancer who initiated systemic therapy between 2013 and 2018. Seventy-five US-based oncologists collected the data using a customized electronic data collection form. Results: A total of 59.6% (121 of 203) of patients underwent testing for RET, and 37.2% (45 of 121) had a RET mutation, of which 55.6% were identified as RET mutation-positive before initial diagnosis. Overall, 90 (44.3%) patients were tested for biomarkers on or after initial diagnosis, with RET being the most tested (95.6%) biomarker. Conclusion: The authors' findings suggest an opportunity to improve testing rates in accordance with treatment guidelines.

Mutations in the RET gene are common in patients with medullary thyroid cancer (MTC). As RET mutations are involved in the development of MTC, several treatment guidelines recommend counseling patients and testing for mutations in the RET gene in all patients with MTC. However, limited data are available on RET testing patterns in the USA in this patient population. In this study, the authors determined testing patterns for RET in patients with advanced or metastatic MTC in the USA using real-world data and found that only 60% of patients were tested for RET (i.e., testing for presence of RET mutations was observed in less than two-thirds of all patients included in the study). These results demonstrate the need for improved testing for RET mutations in patients with MTC in alignment with the treatment guidelines in routine clinical practice in the USA.

[Hereditary medullary thyroid cancer]. / Hereditäres medulläres Schilddrüsenkarzinom.

Parafollicular C cells progress via C cell hyperplasia to medullary thyroid cancer (MTC), which can be present even in the first years of life in multiple endocrine neoplasia (MEN) type 2A and 2B patients. Basal calcitonin and carcinoembryonic antigen (CEA) are useful tumor markers for the diagnosis and monitoring. The prognosis depends on the stage when the disease is diagnosed and there is a good genotype-phenotype correlation with the RET proto-oncogene, which can be used for estimation of the risk. The risk-stratified prophylactic thyroidectomy plays a decisive role in the prognosis of known gene mutation carriers.

Clinical Evolution of Sporadic Medullary Thyroid Carcinoma With Biochemical Incomplete Response After Initial Treatment.

CONTEXT: The clinical response after surgery is a determinant in the management of patients with medullary thyroid carcinoma (MTC). In case of excellent or structural incomplete response, the follow-up strategies are well designed. Conversely, in case of biochemical incomplete response (BiR) the management is not clearly defined. OBJECTIVE: This work aimed to evaluate the overall and per-site prevalence of structural disease detection in sporadic MTC patients with BiR and to assess the predictive value of various clinical, biochemical, and genetic features. METHODS: We evaluated data of 599 consecutive patients surgically treated for sporadic MTC (2000-2018) and followed-up at the endocrine unit of the University Hospital of Pisa. RESULTS: After a median of 5 months from surgery, 145 of 599 (24.2%) patients were classified as BiR. Structural disease was detected in 64 of 145 (44.1%), after a median time of 3.3 years. In 73.6%, structural disease was detected at a single site, prevalently cervical lymph nodes. Among several others, at the time of first evaluation after surgery, only basal calcitonin (bCTN) and stage IVa/b were independent predictive factors. Also, structural disease was more frequent in patients with shorter CTN doubling time and somatic RET mutation. CONCLUSION: In sporadic MTC patients with BiR, the risk of detection of structural disease was about 50% at 10 years. Higher bCTN levels and staging predicted the risk of detecting structural disease. According to these findings, stricter follow-up should be reserved for MTC with BiR and elevated values of bCTN and to those with an advanced stage. Long follow-up should be considered for all BiR patients since 50% of them develop structural disease within 10 years.

Thyroidectomy Outcomes in Patients Identified With RET Pathogenic Variants Through a Population Genomic Screening Program.

Importance: Population-based genomic screening can facilitate early detection of medullary thyroid carcinoma (MTC) in patients with pathogenic/likely pathogenic (P/LP) RET variants. Objective: To evaluate the clinical treatment and patient outcomes after identification of P/LP RET proto-oncogene variants associated with the risk of MTC via a population genomic screening program. Design, Setting, Participants: This retrospective cross-sectional study was completed between June 1, 2016, and May 31, 2022, for a mean follow-up period of 22.4 months (range, 2-76 months). The study included patients who were identified as having P/LP RET variants through a population genomic screening program at a rural tertiary care center and who underwent thyroidectomy after results disclosure. Main Outcomes and Measures: The outcomes of interest were preoperative evaluation and treatment-related outcomes. Measures included imaging and laboratory findings, extent of surgery, pathologic diagnosis, and staging. Results: Seventy-five patients were identified as having P/LP RET variants exclusively through genomic screening. Twenty of these patients (27%; 11 women [55%] and 9 men [45%]; median age, 48 years [range, 22-73 years]) underwent total thyroidectomy; 13 of these patients (65%) also had a central neck dissection. No patients had clinically apparent disease at the time of surgery. Pathologic findings indicated MTC for 12 patients and papillary thyroid carcinoma in 2. Of patients with MTC, 10 had stage I disease, 1 had stage II disease, 1 had stage III disease, and none had stage IV disease. Based on postoperative surveillance imaging and laboratory results, no patient had evidence of recalcitrant disease. Conclusions and Relevance: In this cross-sectional study, all malignant neoplasms identified on surgical pathology were clinically occult, with surgical intervention based solely on the identification of the P/LP RET variant via population genomic screening. This finding suggests that genomic screening may provide opportunities for early detection and treatment of MTC, with the potential for improved patient outcomes.

Temporal trends in referrals of RET gene carriers for neck surgery to a tertiary surgical center in the era of international management guidelines.

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.

Medullary carcinoma of the ampulla has distinct clinicopathologic characteristics including common association with microsatellite instability and PD-L1 expression.

Medullary carcinomas have not yet been fully characterized in the ampulla. Here, 359 ampullary carcinomas (ACs) were reviewed and 11 medullary-type carcinomas (3%) were found and analyzed. In addition to the diagnostic medullary pattern, 6 showed focal mucinous and 8 had focal abortive gland-like formations. They occurred in younger patients (57 versus 65 y; P = .02), had larger invasion size (mean, 3.2 versus 1.9 cm; P = .01), formed nodular polypoid or plaque-like tumors, and often lacked preinvasive component. In addition to the lymphoplasmacytic infiltrates, they also had prominent eosinophils in 5 of 11 cases. Eight were papilla Vateri-NOS (not otherwise specified) tumors, 2 were ampullary-duodenal origin, 1 had a minor intra-ampullary papillary tubular neoplasm component, and none were ampullary-ductal. Although they had pushing-border infiltration, perineural and vascular invasion was common. They were strongly associated with DNA mismatch repair (MMR) protein deficient (7/11, 64%). The 5-yr survival rate (53%) appeared to be comparable with, and perhaps even better than that of nonmedullary ACs (47%), although this did not reach statistical significance (P = .47). Programmed cell death ligand-1 (PD-L1) expression levels were assessed in 8, and all 4 that were MMR deficient were positive both by combined positive score (CPS) ≥1 and tumor proportion score (TPS) ≥1, and of the 4 MMR proficient cases, 3 were positive by CPS; 2 by TPS. Overall, only 1 of the 8 available for analysis failed to show PD-L1 positivity by CPS. In contrast, nonmedullary MMR-deficient carcinomas expressed PD-L1 in only 33% of tumors by CPS, and none by TPS. One medullary carcinoma was also EBV associated. Unlike 'medullary carcinomas' of the kidney, INI1 was retained in all 8 cases tested. In conclusion, medullary carcinomas are 3% of ACs, have a strong association with MMR-D, and may be less aggressive despite their larger size. PD-L1 expression appears to be closely associated with medullary ACs regardless of MMR status, and thus targeted therapies can be considered for all medullary carcinomas of this site.

Medullary thyroid cancer with RET V804M mutation: more indolent than expected?

BACKGROUND: Significant genotype-phenotype variability among multiple endocrine neoplasia type 2A patients with a RET V804M mutation has been reported. METHODS: Patients with a RET V804M mutation treated at a single center were identified (January 1996-December 2020). The baseline characteristics, operative details, pathology, biochemical, and long-term data were analyzed. RESULTS: There were 79 patients; none developed pheochromocytoma or hyperparathyroidism or died in the study period. The mean age was 41.5 years (range = 1.0-81.0 years); 46.8% were men. Of 68 surgical patients, 53 (77.9%) underwent total thyroidectomy and 15 (22.1%) underwent total thyroidectomy with central neck dissection with or without lateral neck dissection. Twenty-four patients had elevated preoperative calcitonin, of whom 12 underwent total thyroidectomy (median = 7.5; range = 5.0-237.0 pg/mL), 10 underwent total thyroidectomy + central neck dissection (median = 27.6; range = 5.1-147.0 pg/mL), and 2 underwent total thyroidectomy + central neck dissection + lateral neck dissection (median = 3182.0; range = 361.0-6003.0 pg/mL). Pathology was benign (27.9%), papillary thyroid cancer alone (1.5%), C-cell hyperplasia (23.5%), and medullary thyroid cancer (47.1%; median tumor size = 3.0 mm). Three patients had elevated calcitonin postoperatively (median follow-up time = 60.0 months). In adjusted modeling, a preoperative calcitonin >5 pg/mL was associated with having medullary thyroid cancer on final pathology (odds ratio = 13.3; 95% confidence interval, 3.2-56.3; P < .001). CONCLUSION: In this large United States cohort of surgical patients with a RET V804M mutation, most had indolent disease and were without classic multiple endocrine neoplasia type 2A features. Calcitonin >5 pg/mL may serve as a meaningful value to guide surveillance and timing of surgery.

[A Case Report of Multiple Endocrine Neoplasia Type 2A(MEN2A)Diagnosed with Medullary Thyroid Carcinoma].

We experienced a case of multiple endocrine neoplasia type 2A(MEN2A)diagnosed with medullary thyroid carcinoma. The patient was a 50s woman who was referred for a thyroid nodule detected in the right lobe during a carotid ultrasound examination. After undergoing a hemithyroidectomy, it was determined that the tumor was medullary carcinoma. RET gene test was performed, confirming a mutation at codon768, leading to the diagnosis of MEN2A. A completion thyroidectomy was performed to remove the remaining thyroid tissue. Postoperatively, the patient is undergoing systemic surveillance.

Medullary carcinoma of the colon: A comprehensive analysis of the National Cancer Database.

PURPOSE: Medullary carcinomas (MC) of the colon are uncommon tumors. In this study, we analyzed demographic and disease characteristics as well as survival outcomes of MC versus undifferentiated (UDA) and poorly differentiated (PDA) adenocarcinomas (AC) of the colon. MATERIALS AND METHODS: The National Cancer Database (2004-2018) was utilized to identify patients with colon cancer. Patient demographics (including age, gender, race), disease characteristics (including grade, TNM stage, carcinoembryonic levels, perineural and lymphovascular invasion, lymph node status, microsatellite stability, KRAS mutation, and primary tumor site), and facility type and location were evaluated. Chi-square tests were used to compare descriptive data. Cox Regression and Kaplan Meier analyses were used to analyze survival characteristics. RESULTS: 1,041,753 patients with colon cancer were identified of whom 2709 patients had MC and 897,902 had AC (136,597 PDA and 18,042 UDA). MC was seen in older patients (mean age 74 ± 13 years) and women (72.5% vs. 27.5% males). Most MCs were poorly differentiated (63.3%), and 82.4% of patients with MC had microsatellite instability. Fewer patients with MC had perineural invasion (15.6% vs. 22.0% in PDA and 22.4% in UDA, p < 0.001) and positive lymph nodes (38.4% versus 59.9% with PDA and 59.7% with UDA, p < 0.0001). MC diagnosis increased by year (Cochran-Armitage trend test, p < 0.0001). Kaplan Meir analysis revealed a better prognosis for patients with MC when compared to PDA or UDA (p < 0.001). CONCLUSION: Given the rarity, pathologists should maintain a high suspicion for MC when encountering poorly differentiated or undifferentiated right-sided colon cancer with associated MSI-H.

Multiple endocrine neoplasia type 2 (MEN2) and RET specific modifications of the ACMG/AMP variant classification guidelines and impact on the MEN2 RET database.

The Multiple Endocrine Neoplasia type 2 (MEN2) RET proto-oncogene database, originally published in 2008, is a comprehensive repository of all publicly available RET gene variations associated with MEN2 syndromes. The variant-specific genotype/phenotype information, age of earliest reported medullary thyroid carcinoma (MTC) onset, and relevant references with a brief summary of findings are cataloged. The ACMG/AMP 2015 consensus statement on variant classification was modified specifically for MEN2 syndromes and RET variants using ClinGen sequence variant interpretation working group recommendations and ClinGen expert panel manuscripts, as well as manuscripts from the American Thyroid Association Guidelines Task Force on Medullary Thyroid Carcinoma and other MEN2 RET literature. The classifications for the 166 single unique variants in the MEN2 RET database were reanalyzed using the MEN2 RET specifically modified ACMG/AMP classification guidelines (version 1). Applying these guidelines added two new variant classifications to the database (likely benign and likely pathogenic) and resulted in clinically significant classification changes (e.g., from pathogenic to uncertain) in 15.7% (26/166) of the original variants. Of those clinically significant changes, the highest percentage of changes, 46.2% (12/26), were changes from uncertain to benign or likely benign. The modified ACMG/AMP criteria with MEN2 RET specifications will optimize and standardize RET variant classifications.

Unilateral Surgery for Medullary Thyroid Carcinoma: Seeking for Clinical Practice Guidelines.

Optimized preoperative diagnostic tools with calcitonin tests, ultrasound features, functional imaging modalities, and genetic testing to detect hereditary forms have led to an increased rate of earlier diagnosis and surgery for medullary thyroid cancer (MTC). This helps to adapt the primary surgery to the tumor stage and avoid surgical overtreatment for localized tumor growth, i.e., deviating from the regularly recommended thyroidectomy with bilateral central lymph node dissection in favor of a limited unilateral approach. To limit primary surgical therapy, it is crucial that the MTC is clinically unifocal, sporadic, and confined to the thyroid, and that calcitonin levels indicate biochemical recovery after surgery. The main requirement for such a limited approach is the availability of frozen section studies that reliably indicate (i) R0 resection of the MTC, (ii) absence of infiltration of the organ capsule, (iii) lack of desmoplasia (i.e., evidence of the metastatic potential of the MTC), (iiii) absence of contralateral disease or precancerous lesions. Informed consent is mandatory from the patient, who has been fully informed of the advantages, disadvantages, and potential risks of not undergoing the "classic" surgical procedure. The aim of this article is to review the guidelines for the management of early-stage MTC.

RET gene mutational diagnosis and precision medicine in Mexico.

Precision medicine is a reality in some diseases; it supports the development of accurate and specific diagnostic methods, new drugs and molecules. Our research team in Mexico, made up of clinical and biomedical researchers, has been performing free RET gene mutational diagnosis for medullary thyroid cancer and multiple endocrine neoplasia (MEN) 2 and 3 for 20 years. RET pathogenic variants in the Mexican population are consistent with reported data: most common mutations are 634/NEM2 and 918/NEM3. Currently, new nanobiotechnology methods are being developed for this type of determination in order to obtain faster, simpler, more sensitive and specific results applicable in all types of laboratories.

La medicina de precisión en algunas enfermedades es una realidad; respalda el desarrollo de métodos diagnósticos certeros y específicos, de nuevas drogas y moléculas. Nuestro equipo de investigación en México, conformado por investigadores clínicos y biomédicos, desde hace 20 años realiza de forma gratuita el diagnóstico mutacional del gen RET y su relación con el cáncer medular de tiroides y la neoplasia endocrina múltiple (NEM) 2 y 3. Las variantes patogénicas de RET en la población mexicana coinciden con los datos reportados: la mayoría con 634/NEM2 y 918/NEM3. Actualmente se están desarrollando nuevos métodos de nanobiotecnología para este tipo de determinaciones, de tal forma que puedan obtenerse resultados más rápidos, simples, sensibles y específicos aplicables en todo tipo de laboratorio.

Recent Advances in Renal Medullary Carcinoma.

Renal medullary carcinoma (RMC) is a rare renal malignancy that has been associated with sickle hemoglobinopathies. RMC is aggressive, difficult to treat, and occurs primarily in adolescents and young adults of African ancestry. This cancer is driven by the loss of SMARCB1, a tumor suppressor seen in a number of primarily rare childhood cancers (e.g., rhabdoid tumor of the kidney and atypical teratoid rhabdoid tumor). Treatment options remain limited due in part to the limited knowledge of RMC biology. However, significant advances have been made in unraveling the biology of RMC, from genomics to therapeutic targets, over the past 5 years. In this review, we will present these advances and discuss what new questions exist in the field.