[Individualization of treatment in sporadic and hereditary medullary thyroid cancer]. / Therapieindividualisierung beim sporadischen und hereditären medullären Schilddrüsenkarzinom.

BACKGROUND: Routine preoperative assessment of the tumor marker calcitonin for medullary thyroid cancer (MTC) and the generally improved diagnostics with high-resolution ultrasound, elastography and Doppler function as well as functional imaging, enable the earlier detection of organ-limited, non-metastasized MTC. Thereby, a new treatment option arises for surgical de-escalation in sporadic MTC, moving from routine thyroidectomy with bilateral central lymph node dissection towards unilateral thyroidectomy with ipsilateral central lymph node dissection. MATERIAL AND METHODS: A search was carried out in PubMed for surgical approaches and selection of publications with results from limited resection in sporadic MTC. RESULTS: In selected patient cohorts limited resection surgery can achieve adequate oncological results but requires long-term follow-up. DISCUSSION: When sporadic unifocal primary tumors are identified and intraoperative frozen section pathological investigation is consistently employed for assessing the grade of desmoplasia and breach of the tumor capsule, the extent of resection can be intraoperatively adapted. Pivotal prerequisites for this personalized concept include consideration of preoperative clinical criteria and intraoperative surgical assessment in conjunction with the intraoperative frozen section examination in order to achieve an adequate oncological tumor resection and a biochemical cure.

Comparing nodal with primary tumor desmoplasia uncovers metastatic patterns in multiple endocrine neoplasia 2B.

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.

Susceptibility Genes and Chromosomal Regions Associated With Non-Syndromic Familial Non-Medullary Thyroid Carcinoma: Some Pathogenetic and Diagnostic Keys.

Thyroid cancer is the malignant tumor that is increasing most rapidly in the world, mainly at the expense of sporadic papillary thyroid carcinoma. The somatic alterations involved in the pathogenesis of sporadic follicular cell derived tumors are well recognized, while the predisposing alterations implicated in hereditary follicular tumors are less well known. Since the genetic background of syndromic familial non-medullary carcinoma has been well established, here we review the pathogenesis of non-syndromic familial non-medullary carcinoma emphasizing those aspects that may be useful in clinical and pathological diagnosis. Non-syndromic familial non-medullary carcinoma has a complex and heterogeneous genetic basis involving several genes and loci with a monogenic or polygenic inheritance model. Most cases are papillary thyroid carcinoma (classic and follicular variant), usually accompanied by benign thyroid nodules (follicular thyroid adenoma and/or multinodular goiter). The possible diagnostic and prognostic usefulness of the changes in the expression and/or translocation of various proteins secondary to several mutations reported in this setting requires further confirmation. Given that non-syndromic familial non-medullary carcinoma and sporadic non-medullary thyroid carcinoma share the same morphology and somatic mutations, the same targeted therapies could be used at present, if necessary, until more specific targeted treatments become available.

State of the art and future directions in the systemic treatment of medullary thyroid cancer.

PURPOSE OF REVIEW: Systemic treatment is the only therapeutic option for patients with progressive, metastatic medullary thyroid cancer (MTC). Since the discovery of the rearranged during transfection (RET) proto-oncogene (100% hereditary, 60-90% sporadic MTC), research has focused on finding effective systemic therapies to target this mutation. This review surveys recent findings. RECENT FINDINGS: Multikinase inhibitors are systemic agents targeting angiogenesis, inhibiting growth of tumor cells and cells in the tumor environment and healthy endothelium. In the phase III EXAM and ZETA trials, cabozantinib and vandetanib showed progression-free survival benefit, without evidence of prolonged overall survival. Selpercatinib and pralsetinib are kinase inhibitors with high specificity for RET; phase I and II studies showed overall response rates of 73% and 71% in first line, and 69% and 60% in second line treatment, respectively. Although resistance mechanisms to mutation-driven therapy will be a challenge in the future, phase III studies are ongoing and neo-adjuvant therapy with selpercatinib is being studied. SUMMARY: The development of selective RET-inhibitors has expanded the therapeutic arsenal to control tumor growth in progressive MTC, with fewer adverse effects than multikinase inhibitors. Future studies should confirm their effectiveness, study neo-adjuvant strategies, and tackle resistance to these inhibitors, ultimately to improve patient outcomes.

Molecular targets of tyrosine kinase inhibitors in thyroid cancer.

Thyroid cancer (TC) is the eighth most frequently diagnosed cancer worldwide with a rising incidence in the past 20 years. Surgery is the primary strategy of therapy for patients with medullary TC (MTC) and differentiated TC (DTC). In DTC patients, radioactive iodine (RAI) is administered after thyroidectomy. Neck ultrasound, basal and thyroid-stimulating hormone-stimulated thyroglobulin are generally performed every three to six months for the first year, with subsequent intervals depending on initial risk assessment, for the detection of possible persistent/recurrent disease during the follow up. Distant metastases are present at the diagnosis in ∼5 % of DTC patients; up to 15 % of patients have recurrences during the follow up, with a survival reduction (70 %-50 %) at 10-year. During tumor progression, the iodide uptake capability of DTC cancer cells can be lost, making them refractory to RAI, with a negative impact on the prognosis. Significant advances have been done recently in our understanding of the molecular pathways implicated in the progression of TCs. Several drugs have been developed, which inhibit signaling kinases or oncogenic kinases (BRAFV600E, RET/PTC), such as those associated with Platelet-Derived Growth Factor Receptor and Vascular Endothelial Growth Factor Receptor. Tyrosine kinase receptors are involved in cancer cell proliferation, angiogenesis, and lymphangiogenesis. Several tyrosine kinase inhibitors (TKIs) are emerging as new treatments for DTC, MTC and anaplastic TC (ATC), and can induce a clinical response and stabilize the disease. Lenvatinib and sorafenib reached the approval for RAI-refractory DTC, whereas cabozantinib and vandetanib for MTC. These TKIs extend median progression-free survival, but do not increase the overall survival. Severe side effects and drug resistance can develop in TC patients treated with TKIs. Additional studies are needed to identify a potential effective targeted therapy for aggressive TCs, according to their molecular characterization.

Controversy on the management of patients carrying RET p.V804M mutation.

CONTEXT: RET p.V804M is classified as a moderate risk mutation for familial medullary thyroid cancer (FMTC). There is a significant controversy on the management of patients carrying this mutation. We describe a family incidentally discovered to have this mutation and review the literature on RET p.V804M mutation. RESULTS: The proband was born to first-degree relative parents. He was noticed to have hypertrophy of some parts of the body and vascular skin changes. Whole-exome sequencing of DNA extracted from a skin biopsy showed a mutation in the PIK3CA (c.3132T>G, p.ASN1044LYS). This variant was not found in DNA extracted from blood. This confirmed the diagnosis of CLOVES syndrome (Congenital Lipomatous Overgrowth, Vascular malformations, Epidermal nevi and Scoliosis, skeletal or spinal anomalies). Another incidentally found mutation in the skin biopsy and blood sample was RET p.V804M. Although there was no family history of MTC or MEN 2 syndromes, family screening revealed RET p.V804M mutation and FMTC in the proband's father, paternal grandmother, one sister, and one aunt. There was significant interfamilial heterogeneity in the age of presentation and pathology. A review of literature showed that RET p.V804M mutation is a moderate risk mutation associated with late-onset FMTC, usually at middle to old age. CONCLUSION: Despite the controversy and the heterogeneous presentation of patients with RET p.V804M mutation, our study and review of the literature suggest that this seemingly "low" risk mutation is associated with late-onset but potentially aggressive MTC. This indicates the need for follow-up and timely intervention based on calcitonin level elevation.

How does nintedanib overcome cancer drug-resistant mutation of RET protein-tyrosine kinase: insights from molecular dynamics simulations.

Targeted drug therapies represent a therapeutic breakthrough in the treatment of human cancer. However, the emergence of acquired resistance inevitably compromises therapeutic drugs. Rearranged during transfection (RET) proto-oncogene, which encodes a receptor tyrosine kinase, is a target for several kinds of human cancer such as thyroid, breast, and colorectal carcinoma. A single mutation L881V at the RET kinase domain was found in familial medullary thyroid carcinoma. Nintedanib can effectively inhibit the RET L881V mutant, whereas its analog compound 1 is unable to combat this mutant. However, the underlying mechanism was still unexplored. Here, molecular dynamics (MD) simulations, binding free energy calculations, and structural analysis were performed to uncover the mechanism of overcoming the resistance of RET L881V mutant to nintedanib. Energetic analysis revealed that the L881V mutant remained sensitive to the treatment of nintedanib, whereas it was insensitive to the compound 1. Structural analysis further showed that the distribution of K758, D892, and N879 network had a detrimental effect on the binding of compound 1 to the L881V mutant. The obtained results may provide insight into the mechanism of overcoming resistance in the RET kinase.

Calcitonin and complementary biomarkers in the diagnosis of hereditary medullary thyroid carcinoma in children and adolescents.

OBJECTIVES: Medullary thyroid carcinoma (MTC) is a rare malignancy that is effectively curable by surgery. Unlike in adults, hereditary MTC has a predominant role in children. A fast and safe diagnosis is important to assure the good prognosis for the patients. A major cornerstone is the assessment of biomarkers, but the interpretation must respect their pre-, post- and analytical features. Especially calcitonin (Ctn) is a challenging biomarker in daily laboratory diagnostics. However, Ctn is of particular relevance for the diagnostic in MTC. The American Thyroid Association recommends thyroidectomy if the upper reference range of Ctn is exceeded. Interestingly, age-dependent reference ranges for children and adolescents have become available only recently for Ctn assays. With this review, we aim to highlight the importance of a timely diagnosis of MTC in children and adolescents. CONTENT: Recent developments in pediatric biochemical diagnostics of MTC were summarized. This includes guidance on interpretation of RET, Ctn, procalcitonin, carcinoembryonic antigen, carbohydrate antigen 19-9, and chromogranin A. SUMMARY: Currently, Ctn is the most investigated biomarker in the diagnosis of MTC in children and adolescents. Other biomarkers as PCT suggest complementary evidence about pediatric MTC but their interpretation based largely on adult's data. A successful treatment of MTC requires, besides results of biomarkers, information about medical history, RET gene analysis and recent guideline knowledge. OUTLOOK: More research is required to validate complementary biomarkers of Ctn in children. Additionally, the effect of different confounder on pediatric Ctn levels has to be further clarified.

Similar Stage-dependent Survival and Outcome in Sporadic and Hereditary Medullary Thyroid Carcinoma.

CONTEXT: Long-term data are scarce on large cohorts with sporadic (sMTC) and hereditary medullary thyroid carcinoma (hMTC). OBJECTIVES: To compare long-term disease-specific survival (DSS) and outcomes between sMTC and hMTC groups. DESIGN: Retrospective analysis. SETTING: German tertiary referral center. PATIENTS: A total of 673 patients with MTC that underwent surgery from January 1974 to July 2019. INTERVENTION: None (observational study). MAIN OUTCOME MEASURE: Differences between sMTC and hMTC in long-term, stage-dependent survival and outcomes. RESULTS: Surgery was performed at median ages of 49 years for sMTC (n = 477, 44% male) and 29 years for hMTC (n = 196, 43% male; P < 0.0001). The mean follow-up times were 9.2 ± 8.0 (sMTC) and 14.6 ± 10.3 years (hMTC). Age and tumor stage at diagnosis were significantly different between the 2 groups (P < 0.0001). The sMTC and hMTC groups had different overall DSS (log rank, P = 0.0183), but similar stage-dependent DSS (log rank, P = 0.1242-0.8981). In a multivariate analysis, sMTC and hMTC did not differ in DSS (hazard ratio [HR] = 1.56; 95% CI, 0.94-2.57), but in both groups, a worse DSS was significantly associated with age at diagnosis (HR = 1.04; 95% CI, 1.02-1.05), male sex (HR = 0.49; 95% CI, 0.32-0.76), and stages III and IV at diagnosis (HR = 20.00; 95% CI, 2.74-145.91 and HR = 97.47; 95% CI, 13.07-726.67, respectively). The groups had significantly different (P < 0.0001) outcomes (i.e., cured, minimal residual disease, structural detectable disease, and death), but similar stage-dependent outcomes (P = 0.9449-0.0511), except for stage III (P = 0.0489). CONCLUSION: Patients with sMTC and hMTC had different ages of onset, but similar stage-dependent DSS and outcomes after the MTC diagnosis. This finding suggested that tumor behavior was similar in sMTC and hMTC.

Genomics and Epigenomics of Medullary Thyroid Carcinoma: From Sporadic Disease to Familial Manifestations.

Our understanding of the genomics and epigenomics of medullary thyroid carcinoma (MTC) has advanced since the initial recognition of RET as a driver of MTC tumorigenesis in familial MTC. We now have insight into the frequency and prognostic significance of specific RET mutations in sporadic MTC. For example, the most common RET mutation in sporadic MTC is the RET Met918Thr mutation, the same mutation that underlies MEN2B and a poor prognosticator. This mutation is relatively infrequent in medullary thyroid microcarcinomas but is over-represented in advanced-stage disease. RAS mutations are detected in 70% of sporadic, RET wild-type MTC. Although next-generation and whole-exome sequencing studies have shown that tumors that are wild-type for RET and RAS mutations essentially lack other recurrent mutations, additional pathways and epigenetic alterations have been implicated in MTC tumorigenesis. Increased insight into the clinical course of patients with familial MTC with specific RET mutations has guided treatment recommendations for these patients. Finally, an understanding of the genomics has informed treatment for patients with advanced MTC. In this review, we will examine the genomics and epigenomics of sporadic and familial MTC, along with the prognostic significance of molecular alterations, management of patients with germline RET mutations, and treatment strategies for MTC patients.

Inherited Follicular Epithelial-Derived Thyroid Carcinomas: From Molecular Biology to Histological Correlates.

Cancer derived from thyroid follicular epithelial cells is common; it represents the most common endocrine malignancy. The molecular features of sporadic tumors have been clarified in the past decade. However the incidence of familial disease has not been emphasized and is often overlooked in routine practice. A careful clinical documentation of family history or familial syndromes that can be associated with thyroid disease can help identify germline susceptibility-driven thyroid neoplasia. In this review, we summarize a large body of information about both syndromic and non-syndromic familial thyroid carcinomas. A significant number of patients with inherited non-medullary thyroid carcinomas manifest disease that appears to be sporadic disease even in some syndromic cases. The cytomorphology of the tumor(s), molecular immunohistochemistry, the findings in the non-tumorous thyroid parenchyma and other associated lesions may provide insight into the underlying syndromic disorder. However, the increasing evidence of familial predisposition to non-syndromic thyroid cancers is raising questions about the importance of genetics and epigenetics. What appears to be "sporadic" is becoming less often truly so and more often an opportunity to identify and understand novel genetic variants that underlie tumorigenesis. Pathologists must be aware of the unusual morphologic features that should prompt germline screening. Therefore, recognition of harbingers of specific germline susceptibility syndromes can assist in providing information to facilitate early detection to prevent aggressive disease.

A rare RET mutation in an Indian pedigree with familial medullary thyroid carcinoma.

Familial medullary thyroid carcinoma (FMTC) is a variant of multiple endocrine neoplasia type 2 (MEN2) associated with the RET gene mutation. We report a rare RET mutation of c.2671T>G; p.Ser891Ala in Exon 15 of the RET gene in an Indian pedigree where seven family members out of 14 screened were found to be positive for the same. RET genetic analysis should be considered as an early approach in the diagnosis of medullary thyroid carcinoma (MTC) since it improves the prognosis and permits surveillance of other family members.

Hereditary medullary thyroid carcinoma syndromes: experience from western India.

The data from the Indian subcontinent on Medullary thyroid carcinoma (MTC) and associated endocrinopathies in hereditary MTC (HMTC) syndromes are limited. Hence, we analyzed clinical and biochemical characteristics, management, and outcomes of HMTC and other associated endocrinopathies [Pheochromocytoma (PCC) and Primary hyperparathyroidism (PHPT)] and compared with apparently sporadic MTC. The records of 97 (51 sporadic and 46 hereditary) consecutive MTC patients were retrospectively analyzed. RET mutation was available in 38 HMTC patients. HMTC group was subclassified into Multiple endocrine neoplasia (MEN) 2A index (n = 25), MEN2B index (n = 8), and MEN2A detected by familial screening (n = 12). Patients with HMTC and MEN2B index were younger at presentation than sporadic MTC. MEN2A patients detected by familial screening, but not MEN2A index and MEN2B index patients, had significantly lower serum calcitonin, smaller thyroid nodule size, more frequent early stage presentation (AJCC Stage ≤ II), and higher cure rate than sporadic MTC, which emphasizes the need for early diagnosis. RET (REarranged during Transfection) 634 mutations were the most common cause of HMTC and more frequently associated with PCC (overall 54% and 100% in those aged ≥ 35 years). Patients in ATA-Highest (HST) group had a universal presentation in stage IV with no cure. In contrast, the cure rate and postoperative disease progression (calcitonin doubling time) were similar between ATA-High (H) and ATA- Moderate (MOD) groups, suggesting the need for similar follow-up strategies for the latter two groups. Increased awareness of endocrine (PCC/PHPT) and non endocrine components may facilitate early diagnosis and management.

A novel germline variant in RET gene resulting in an additional cysteine in a family with familial medullary thyroid carcinoma.

Multiple endocrine neoplasia type 2 (MEN 2) is an autosomal dominant inherited disease, characterized by germ-line variants in RET proto-oncogene. Variants are frequently located in the RET extracellular cysteine-rich region domain, mainly affecting cysteines which are replaced by an alternative amino acid, resulting in a mispaired cysteine and the generation of RET dimers. We describe a novel c.1765A > T variant of RET proto-oncogene in a family with medullary thyroid carcinoma (MTC) that predicts the creation of an additional cysteine p.(Ser589Cys) in the cysteine-rich domain. In this site only three other punctual variants have been described, giving rise to extra cysteines. We have characterized the clinical phenotype of this family. The index case was a 79-year-old woman with MTC in both thyroid lobes. This variant co-segregates in this family in four affected members. One member was operated on at 31 years of age and already presented MTC, indicating that prophylactic thyroidectomy was appropriated. Variants predicting additional cysteines are not frequent in RET, and when present, they allow us to understand their implication in the disease. According to clinical data obtained in this family, this variant could be categorized as a moderate-risk of the disease.

Predicting Outcomes in Sporadic and Hereditary Medullary Thyroid Carcinoma over Two Decades.

Background: Medullary thyroid cancer (MTC) can be associated with significant morbidity and mortality in advanced cases. Hence, we aimed to identify factors at the time of MTC surgery that predict overall survival (OS), disease-specific survival (DSS), locoregional recurrence/persistence (LR), and distant metastases (DM). Methods: We performed a retrospective study of clinicopathologic, radiological, and laboratory data in MTC patients who underwent thyroidectomy at Mayo Clinic from January 1995 to December 2015. Results: We identified 163 patients (mean age 48.4 years, 48% males), 102 with sporadic MTC and 61 with hereditary disease (n = 46 multiple endocrine neoplasia [MEN] 2A, n = 3 MEN 2B, n = 12 familial MTC) with a median follow-up time of 5.5 years. On univariate analysis, age >55 years, male sex, DM at the time of surgery (M1), lateral neck lymph node (LN) involvement (N1b), gross extrathyroidal extension (ETE), American Joint Committee on Cancer (AJCC) stage 3/4, tumor size (T) 3/4, tumor size, and postoperative calcitonin (Ctn) and carcinoembryonic antigen (CEA) were significant predictors of worse OS and DSS. On multivariable analysis, both gross ETE (hazard ratio [HR] 4.62, 6.58) and M1 (HR 5.11, 10.45) remained significant predictors of worse OS as well as DSS, while age >55 years (HR 3.21), male sex (HR 2.42), and postoperative Ctn (HR 1.002 for every 100 pg/mL increase) were significant only for worse OS. On univariate analysis, male sex, M1, N1b, gross ETE, stage 3/4, T 3/4, tumor size, number of LNs involved, and postoperative Ctn were significant predictors of LR and DM; age >55 years was additionally significant for DM. On multivariable analysis, gross ETE (HR 3.16, 5.93) and N1b (HR 4.31, 4.64) remained significant predictors of LR and DM; ratio of resected/involved LN (HR 10.91) was additionally predictive for LR and postoperative Ctn (HR 1.003 for every 100 pg/mL increase) for DM. Conclusions: Disease burden at initial surgery, especially gross ETE, lateral neck LN involvement, and DM, as well as the biochemical response to surgery appear to be more important than demographic factors in terms of MTC prognosis. These findings highlight the importance of rigorous perioperative assessment to better predict MTC outcomes.

Lymph node metastasis in hereditary medullary thyroid cancer is independent of the underlying RET germline mutation.

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.

Chinese siblings with hereditary medullary thyroid carcinoma caused by RET mutation: implications for RET oncogene detection.

BACKGROUND: Hereditary medullary thyroid carcinoma (MTC) is mainly caused by germline mutations in the RET proto-oncogene, which accounts for 20-30% of all MTC according to foreign studies. However, no English literatures have reported Chinese hereditary MTC. Here, we reported two Chinese brothers with MTC that caused by germline RET mutation. CASE PRESENTATION: The younger brother was diagnosed with MTC at 29 years ago and suffered recurrence more than 10 years. For elder brother, the diagnosis of MTC was made by postoperative pathological examination at age 61. Both patients received total thyroidectomy and lymph node dissection. Since they had a significant family history for MTC, genetic detection was performed and identified a germline mutation in RET exon 10 (p.C620Y). This mutation was also detected in their offspring, indicating a moderate risk of MTC. CONCLUSIONS: This is the first report presenting a Chinese family with hereditary MTC caused by the RET p.C620Y variant. This case series emphasize the importance of genetic detection of RET proto-oncogene for MTC patients, and bring out managements for individuals after detection of RET mutations.

Current surgical management in RET mutation carriers [Aktualne postepowanie chirurgiczne u nosicieli mutacji proto-onkogenu RET].

Medullary thyroid carcinoma (MTC) still remains a rare endocrine tumor. 20-25% of MTC cases are genetically determined. The detection of the RET proto-oncogene mutation in 1993 allowed to understand the unique genotype-phenotype relationships in hereditary medullary thyroid carcinoma (HMTC) and formed the basis for therapeutic decisions based on the molecular results. Currently, prophylactic thyroidectomy is a commonly adopted and accepted therapeutic method. The decision on the time and extent of surgery should be made based on the results of molecular examination, the assessment of calcitonin (Ct) concentration and family history. Treatment of patients with HMTC requires the cooperation of a multidisciplinary team of experts and should be done in specialized centers only. The study is a review of the current guidelines for surgical management in the MEN2 syndrome.

Long-Term Oncologic Outcomes After Curative Resection of Familial Medullary Thyroid Carcinoma.

INTRODUCTION: Long-term outcomes after curative resection in patients with germline RET mutations and medullary thyroid cancer (MTC) are highly variable and mutation-specific oncologic outcomes are not well-described. METHODS: Sixty-six patients identified from 1986 to 2017 from a single-institution cancer database were assessed for recurrence and survival using Kaplan-Meier estimates, and correlated with clinicopathologic features using log-rank or Cox proportional hazards. RESULTS: Median follow-up was 9.3 years (range 0.3-31.5), median tumor diameter was 1.5 cm (range 0.1-7.5), and preoperative calcitonin was known in 41 patients [median 636 (range 0-9600)]. Overall survival (OS) of the cohort was 94% at 10 years, the cumulative incidence of locoregional recurrence was 38% at 10 years, and 19/24 (79%) patients underwent repeat neck operation. The cumulative incidence of distant recurrence was 27% at 10 years. Predictors of distant recurrence were tumor size, positive lymph nodes, and pre- and postoperative carcinoembryonic antigen, but not calcitonin. M918T mutation-bearing patients had 10-year distant recurrence-free survival of 0%, compared with 83% in all other patients (p < 0.001), and equivalent 10-year OS (100% vs. 92%; p = 0.49). CONCLUSIONS: Structural and metastatic recurrence is common in patients with germline RET mutations, and MTC and can occur 20 years after initial treatment, however survival remains high. Management should focus on optimal surveillance strategies and long-term control of structural disease.

Twenty-Five Years Experience on RET Genetic Screening on Hereditary MTC: An Update on The Prevalence of Germline RET Mutations.

BACKGROUND: Pathogenic germline mutations affecting the RET proto-oncogene underlie the development of hereditary medullary thyroid carcinoma (MTC). The aims of this study were to evaluate the prevalence of germline RET mutations in a large series of MTC, collected over the last 25 years, and to reappraise their clinical significance. METHODS: We performed RET genetic screening in 2031 Italian subjects: patients who presented with sporadic (n = 1264) or hereditary (n = 117) MTC, plus 650 relatives. RESULTS: A RET germline mutation was found in 115/117 (98.3%) hereditary and in 78/1264 (6.2%) apparently sporadic cases: in total, 42 distinct germline variants were found. The V804M mutation was the most prevalent in our cohort, especially in cases that presented as sporadic, while mutations affecting cysteine residues were the most frequent in the group of clinically hereditary cases. All M918T mutations were "de novo" and exclusively associated with MEN2B. Several variants of unknown significance (VUS) were also found. CONCLUSIONS: a) RET genetic screening is informative in both hereditary and sporadic MTC; b) the prevalence of different mutations varies with V804M being the most frequent; c) the association genotype-phenotype is confirmed; d) by RET screening, some VUS can be found but their pathogenic role must be demonstrated before screening the family.