Hereditary Medullary Thyroid Carcinoma Research Articles

Comprehensive Assessment of Copy Number Alterations Uncovers Recurrent AIFM3 and DLK1 Copy Gain in Medullary Thyroid Carcinoma.

Simple SummaryMedullary thyroid cancer (MTC) is often discovered in its advanced stage. Although a rare disease, advanced MTC cases have poor prognosis and the treatment is often palliative. Several studies have reported the existence of an association between copy number alterations (CNAs) burden and cancer progression. Moreover, the accumulation of broad CNAs, which contribute to intra-tumor heterogeneity, might be required for immune evasion. The identification of the recurrent CNAs associated with tumor phenotype aided in discovering new therapeutics options in several cancer types. To our knowledge, CNA is not well characterized in MTC. We analyzed recurrent focal CNAs on MTC. Our analysis provides a novel insight on MTC biology and may help in uncovering novel potential therapeutic targets.Medullary thyroid carcinoma (MTC) is a malignant tumor originating from thyroid C-cells that can occur either in sporadic (70–80%) or hereditary (20–30%) form. In this study we aimed to identify recurrent copy number alterations (CNA) that might be related to the pathogenesis or progression of MTC. We used Affymetrix SNP array 6.0 on MTC and paired-blood samples to identify CNA using PennCNV and Genotyping Console software. The algorithms identified recurrent copy number gains in chromosomes 15q, 10q, 14q and 22q in MTC, whereas 4q cumulated losses. Coding genes were identified within CNA regions. The quantitative PCR analysis performed in an independent series of MTCs (n = 51) confirmed focal recurrent copy number gains encompassing the DLK1 (14q32.2) and AIFM3 (22q11.21) genes. Immunohistochemistry confirmed AIFM3 and DLK1 expression in MTC cases, while no expression was found in normal thyroid tissues and few MTC samples were found with normal copy numbers. The functional relevance of CNA was also assessed by in silico analysis. CNA status correlated with protein expression (DLK1, p = 0.01), tumor size (DLK1, p = 0.04) and AJCC staging (AIFM3 p = 0.01 and DLK1 p = 0.05). These data provide a novel insight into MTC biology, and suggest a common CNA landscape, regardless of if it is sporadic or hereditary MTC.

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 ≥ 35years). 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.

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.

Management of medullary thyroid carcinoma

: Medullary thyroid carcinoma (MTC) is a rare malignancy arising from parafollicular C-cells and accounts for 3–10% of all thyroid malignancies. MTC occurs mostly as a sporadic disease, but in at least 30% of cases is hereditary, caused by RET germline mutations. In this setting, different germline RET mutations lead to distinct clinical phenotypes of hereditary MTC such as familial MTC and multiple endocrine neoplasia 2A and 2B. RET genetic screening should be performed in all new discovered cases of MTC since about 4–10% of patients with apparently sporadic MTC have RET germline mutations and therefore an inheritable disease. Calcitonin (CT) is the most reliable marker of MTC for both diagnosis and follow-up after thyroidectomy. In sporadic MTC, a routine determination of CT in patients with nodular goiter has been correlated to a lower rate of advanced tumor stages. Surgery is the only curative treatment. Since the relatively high risk of multifocal and bilateral disease and the early spread to cervical lymph nodes, total thyroidectomy and central neck lymph node dissection is the standard initial treatment. Lateral neck lymph node dissection might be considered according to imaging results and CT levels. The potential benefit of neck reiterative surgery for persistent or recurrent MTC should be balanced against the increased surgical morbidity in a scarred operative field. The treatment of locally advanced MTC that is not amenable to surgery or metastatic MTC benefits of tyrosine kinase inhibitors that have shown some effects on disease progression. External radiotherapy and cytotoxic chemotherapy have demonstrated little benefit. Prognosis strictly depends on stage of disease at diagnosis, with lower survival and cure rate for stage IV disease. The purpose of this review is to describe the management and treatment of patients with MTC, focusing on biochemical and imaging diagnostic tools, preoperative work-up, treatment and prophylactic surgery for hereditary variants.

HEREDITARY ENDOCRINE TUMOURS: CURRENT STATE-OF-THE-ART AND RESEARCH OPPORTUNITIES: Early thyroidectomy in multiple endocrine neoplasia: a four decade experience.

Forty years ago, physicians caring for the J-kindred, a 100+ member family with multiple endocrine neoplasia type 2A (MEN2A), hypothesized that early thyroidectomy based on measurement of the biomarker calcitonin could cure patients at risk for development of medullary thyroid carcinoma (MTC). We re-evaluated 22 family members with proven RET proto-oncogene mutations (C634G) who underwent thyroidectomy and central lymphadenectomy between 1972 and 1994 based on stimulated calcitonin abnormalities. Current disease status was evaluated by serum calcitonin measurement and neck ultrasound in 18 of the 22 prospectively screened patients. The median age of the cohort at thyroidectomy was 16.5 years (range 9-24). The median duration of follow-up at the time of examination was 40 years (range 21-43) with a median current age of 52 years (range 34-65). Fifteen of the 18 patients had no detectable serum calcitonin (<2 pg/mL). Three had detectable serum calcitonin measurements, inappropriately elevated following total thyroidectomy. None of the 16 patients imaged had an abnormal ultrasound. Survival analysis shows no MTC-related deaths in the prospectively screened patients, whereas there were many in prior generations. Early thyroidectomy based on biomarker testing has rendered 15 of 18 MEN2A patients (83%) calcitonin-free with a median follow-up period of 40 years. There have been no deaths in the prospectively screened and thyroidectomized group. We conclude that early thyroidectomy and central lymph node dissection is an effective prophylactic treatment for hereditary MTC.

Kinetic analysis of the growth rate of sporadic and hereditary medullary thyroid carcinoma: comparing the postoperative calcitonin-doubling rate with the hypothetical preoperative tumor volume-doubling rate

BackgroundOur previous kinetic analyses of changes in the tumor volume (TV) of papillary thyroid microcarcinomas during active surveillance revealed that the tumors’ growth varied over time from rather rapid growth to shrinkage and that the hypothetical TV-doubling rates (DRs) before the patients’ presentation were much larger than their observed TV-DRs, indicating that rapid growth phases preceded their presentation. Whether this phenomenon also occurs in medullary thyroid carcinoma (MTC) was unknown.MethodsWe retrospectively analyzed the cases of 46 MTC patients (18 hereditary, 28 sporadic; 9–80 years old at surgery, median 53.5 years; 19 males and 27 females) with elevated postoperative calcitonin (Ct) measured with the electrochemiluminescence immunoassay suggesting persistent disease. We calculated each patient’s Ct-DR and his/her hypothetical TV-DR, using the tumor size and age at surgery.ResultsCt-DRs (/year) after surgery were > 0.5, 0.1–0.5, − 0.1–0.1, and < − 0.1 in 9, 21, 12, and 4 patients, respectively (median 0.17). The hypothetical TV-DRs (/year) before surgery were > 1, 0.5–1.0, 0.1–0.5 and < 0.1 in 11, 21, 14, and 0 patients, respectively (median 0.60). The hypothetical TV-DR was higher than the observed Ct-DR in 41 of the 46 MTC patients and all 18 patients with hereditary MTC, suggesting that a rapid growth phase preceded surgery in these patients.ConclusionsIn this series of MTC patients, the pre-surgery calculated hypothetical TV-DRs were significantly higher than the Ct-DRs observed post-surgery, suggesting that there were rapid growth periods before surgery in the vast majority of these MTC patients.

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

BackgroundHereditary 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 presentationThe 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.ConclusionsThis 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.

Modulatory Role of Single Nucleotide Polymorphisms of Distinct Genetic Pathways on Clinical Behavior of Medullary Thyroid Carcinoma.

Role of RET proto-oncogene as predisposing gene for Medullary Thyroid Carcinoma is well established which provides the basis for clinical management of patients. However clinical behavior of MTC varies considerably among patients. Several studies have investigated whether SNPs in low penetrance genes could modulate the clinical behavior of MTC but with conflicting or inconclusive results. The present study aimed to investigate the modifier effect of 13 SNPs of three distinct genetic pathways -Detoxification, Cell cycle regulation and RET on the clinico-pathological features of hereditary and sporadic MTC. SNPs were genotyped using RFLP or TaqMan method. The genotypes were correlated with various clinico-pathological parameters (age and calcitonin levels at MTC diagnosis, tumor volume, nodal and distant metastasis). Nodal metastasis was the only clinico-pathological parameter showing significant association with any SNP. In the hereditary MTC group (n=77), incidence of nodal metastases was significantly higher in wild type allele for Cyp1A1m1, CDKN2A and CDKN2C (p=0.01 for all three). In sporadic MTC group (n=361) CDKN2C wild type allele had higher nodal metastasis (p=0.03). In this largest MTC cohort with comprehensive analysis of modulatory role of 13 most frequently studied SNPs with MTC clinical outcome, we observed a statistically significant association of few SNPs with nodal metastasis. However as these SNPs did not show association with any other clinico-pathological parameters like tumor volume or Calcitonin, they may not be true modifier of MTC. Additional large cohort studies with clinico-pathological details and long-term follow-up are needed to identify genetic modifiers of MTC behavior.

Update on the Treatment of Medullary Thyroid Carcinoma in Patients with Multiple Endocrine Neoplasia Type 2.

Medullary Thyroid Carcinoma (MTC) is a rare neuroendocrine cancer that accounts for 1-2% of thyroid cancers in the United States (U.S.). While most cases are sporadic, 25% of MTC cases are hereditary. These hereditary cases occur in the setting of Multiple Endocrine Neoplasia Type 2A (MEN2A) or 2B (MEN2B) driven by mutations in the Rearranged during Transfection RET proto-oncogene. This article discusses hereditary MTC in the setting of MEN2 and the treatment options available for it. The first line treatment for this disease is typically a total thyroidectomy and tyrosine kinase inhibitors. Two tyrosine kinase inhibitors, vandetanib and cabozantinib, have been approved for treatment of advanced MTC, but options beyond those are limited. However, several promising treatments are being studied, which are discussed in this review.

Medullary Thyroid Cancer - Feature Review and Update on Systemic Treatment.

SUMMARYMedullary thyroid carcinoma (MTC) is a rare malignancy that originates from parafollicular (C cells) of the thyroid and accounts for 2-4% of all thyroid malignancies. MTC may be sporadic or inherited, the latter as part of the MEN 2 syndromes. Germline mutations in the RET proto-oncogene (REarranged during Transfection) are driver mutations in hereditary MTC, whereas somatic RET mutations and, less frequently, RAS mutations, have been described in tumor tissues of sporadic MTC. Genetic screening for germline mutations in RET proto-oncogene identifies gene carriers of germline mutations. That enables primary prevention (the avoidance of disease onset by total prophylactic thyroidectomy), or at least secondary prevention (early detection) of the disease. Radical surgery with complete tumor resection is still pivotal in attaining cure for MTC. Despite recent advances, the treatment of advanced, metastatic, and progressive MTC remains challenging. Metastatic MTC can have an indolent clinical course; therefore, it is necessary to assess which patient to cure and when to initiate the treatment. Multidisciplinary boards of various specialists involved in the diagnostics and therapy of the patients with MTC in highly specialized centers with a high volume of patients provide optimal patient management. Multikinase inhibitors (MKI) vandetanib and cabozantinib were approved for the treatment of progressive or symptomatic metastatic/unresectable MTC. Although these treatments have been shown to improve progression-free survival (PFS) with higher overall response rates (ORR) compared with placebo, no MKI has been shown to increase the overall survival (OS) yet, except in the subgroup of patients with RETM918T-mutations on cabozantinib therapy. As these drugs are nonselective, significant off-target toxicities may occur. Recently, next-generation small-molecule tyrosine kinase inhibitors (TKIs) have been developed. These highly selective RET-inhibitors are specifically designed for highly potent and selective targeting of oncogenic RET alterations, making them promising drugs for the treatment of advanced MTC. The selective RET-inhibitor selpercatinib has been very recently registered for the treatment of RET-mutated thyroid cancer.

The role of postoperative adjuvant radiotherapy in the local control in medullary thyroid carcinoma.

The value of postoperative radiotherapy in the treatment of medullary thyroid carcinoma (MTC) has not been unequivocally demonstrated. Therefore our study aimed to answer the question of whether adjuvant radiotherapy showed any impact on the risk of local recurrence and whether there were any differences in response to radiotherapy between hereditary and sporadic MTC.MethodsA retrospective analysis involved 254 MTC patients, among them 73 patients with a hereditary disease. Two hundred and twenty-four patients, including 43 persons at a high risk of local relapse, underwent only initial surgery; 18 other patients were operated due to MTC recurrences, whereas the remaining 12 patients had cytoreductive procedure or were not amenable for surgery. Radiotherapy was carried out in 132 patients. One hundred and twenty patients underwent adjuvant radiotherapy, among them 102 patients after initial surgery. The median follow-up was 10 years (range 0.5–29 years).ResultsLocal recurrence occurred in 107/254 patients, among them in 63 subjects after prior radiotherapy. The frequency of relapse showed significantly increasing trend toward higher MTC stages (P <0.001). More relapses occurred in patients with lymph node metastases present at MTC onset. Adjuvant radiotherapy was associated with a lower risk of nodal recurrence only in high-risk patients, particularly if lymph node metastases were present at MTC diagnosis. The differences between hereditary and sporadic subgroups were not significant.ConclusionsAdjuvant radiotherapy has a limited importance in MTC treatment. It should be considered in high-risk MTC patients. The presence of RET mutation does not influence the response to radiation.

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.

Current surgical management in RET mutation carriers [Aktualne postępowanie 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.

Genetic risk association of CDKN1A and RET gene SNPs with medullary thyroid carcinoma: Results from the largest MTC cohort and meta-analysis.

BackgroundMedullary thyroid carcinoma (MTC) is a rare subtype of thyroid cancer. Other than gain‐of‐function RET mutations, no other genetic, lifestyle or environmental risk associations have been established for MTC. Several case‐control studies and meta‐analysis have examined the risk association of different SNPs with MTC in different populations but with contradictory or inconclusive results.MethodsIn a large cohort of 438 Indian MTC cases and 489 gender and ethnicity matched healthy controls from 1000 genome project, a comprehensive risk association of 13 SNPs of three pathways—detoxification, cell cycle regulation and RET was performed along with meta‐analysis of RET SNPs.ResultsMultivariate logistic regression analysis identified a protective risk association of CDKN1ASer31Arg SNP with both hereditary (OR 0.26; 95% confidence interval [CI] 0.13‐0.55; P < .001) and sporadic MTC (OR 0.53; 95% CI 0.36‐0.78; P = .001). An increased risk association was identified for NAT2Y94Y SNP (OR 1.62, 95% CI 1.17‐2.25, P = .004) and CDKN2A3′UTR SNP (OR 1.89, 95% CI 1.19‐2.98, P = .006) with sporadic MTC and RET S904S with hereditary MTC (OR 2.82, 95% CI 1.64‐4.86, P < .001). Meta‐analysis of RET SNPs including our cohort identified increased risk association of all four RET SNPs with MTC.ConclusionIn this largest SNP risk association study for MTC and the only risk association study of the 13 most commonly studied MTC associated SNPs in a single cohort of this rare cancer, a significant protective risk association of CDKN1ASer31Arg SNP with MTC was shown for the first time. Meta‐analysis identified significant risk association of all four RET SNPs, not observed in previous meta‐analysis.

Medullary thyroid carcinoma beyond surgery: advances, challenges, and perspectives.

Medullary thyroid carcinoma (MTC) is a rare type of tumor that originates from thyroid C cells and accounts for 2-4% of all malignant thyroid neoplasms. MTC may occur sporadically or be inherited, as part of the MEN 2 syndrome. Germline mutations of the RET (REarranged during Transfection) proto-oncogene cause hereditary cancer, whereas somatic RET mutations and, less frequently, RAS mutations have been described in sporadic MTC samples. Since early surgery with complete resection of tumor mostly determines the likelihood of attaining cure for MTC, the broader use of RET genetic screening has dramatically changed the prognostic of gene carriers in hereditary MTC. Nevertheless, despite recent advances, the management of advanced, progressive MTC remains challenging. The multikinase inhibitors (MKI), vandetanib and cabozantinib, were approved for the treatment of progressive or symptomatic MTC, and several other compounds have exhibited variable efficacy. Although these drugs have been shown to improve progression-free survival, no MKI has been shown to increase the overall survival. As these drugs are nonselective, significant off-target toxicities may occur, limiting achievement of the required TK-specific inhibition. Recently, next-generation small-molecule TKI has been developed. These TKI are specifically designed for highly potent and selective targeting of oncogenic RET alterations, making them promising drugs for the treatment of advanced MTC. Here, we summarize the current understanding of the intracellular signaling pathways involved in MTC pathogenesis as well as the therapeutic approaches and challenges for the management of advanced MTC, focusing on targeted molecular therapies.

MON-561 Medullary Thyroid Cancer in a Single Institution: Factors Associated With Biochemical Failure

Background: Medullary thyroid carcinoma (MTC) is a rare thyroid cancer with a disproportionate high mortality and can be sporadic or familial. Surgery is the only potentially curative treatment. Our aim was to access demographic, clinical and pathological characteristics of MTC patients associated with biochemical failure after surgery. Methods: Retrospective observational study of patients with MTC diagnosed between 1984 and 2018 and followed-up in our institution. Results: We evaluated 76 individuals with MTC, 27.6% with hereditary MTC, 69.7% female, median of age 49 years-old (IQR 33.50-60.00). The median of preoperative calcitonin levels was 1121 pg/mL (IQR 445-4383), being ≥500 pg/mL in 72.3%. Preoperative calcitonin levels, when performed, had a sensitivity of 97.9%. According to TNM staging (AJCC 8th ed.), 35.9% were in stage I, 15.6% in stage II, 1.6% in stage III and 46.9% in stage IV. One patient had poor functional status, contraindicating surgery. A total of 75 patients were submitted to thyroidectomy (or completion thyroidectomy when indicated) with lymph node dissection at our institution (n=50) or an outside one (n=25). Biochemical cure (BC) was achieved in 48 (64%) patients after surgery; of these, 7 (14.58%) relapsed. BC was 95.7% in stage II, 100% in stages II/III and 24.1% in stage IV (p<0.001). Biochemical failure occurred in 36% of patients, all of them with preoperative calcitonin levels ≥500 pg/mL (p<0.001). There were no significant differences in sex, age, presence of germline RET mutation and results of fine-needle aspiration cytology between groups. Regarding histological features, patients with biochemical failure had higher tumor size (2.5 cm vs. 1.9 cm, p=0.025), multifocality (66.7% vs. 37.5%, p=0.024), vascular invasion (76.5% vs. 43.8%, p=0.028), perineural invasion (23.4 % vs. 0%, p=0.024), capsular invasion (82.4% vs. 12.1%, p<0.001), extrathyroidal extension (57.9% vs. 7.9%, p<0.001), surgical margin positivity (57.9% vs. 7.9%, p<0.001) and lymph node positivity (100% vs. 33.3%, p<0.001). Preoperative calcitonin levels (OR per increments of 500 pg/mL=1.183; p=0.012), tumor size in cm (OR=2.093; p=0.003), multifocality (OR=2.769; p=0.049), vascular invasion (OR=4.250; p=0.024), capsular invasion (OR=27.000; p<0.001), extrathyroidal extension (OR=85.000; p<0.001), surgical margins positivity (OR=17.455; p=0.001) and lymph nodes positivity (OR=62.500; p<0.001) were predictors of biochemical failure. The 5-year survival rate was higher in the BC group (91.7% vs. 74.1%; p=0.049). Conclusions: Several tumor histological characteristics were the best predictors for biochemical failure and preoperative calcitonin level was the only significant predictor performed before surgery. Demographic data, RET mutation and cytology were not associated with BC. These findings highlight that early detection is important to achieve BC in MTC.

Clinical utility of genetic diagnosis for sporadic and hereditary medullary thyroid carcinoma

Medullary thyroid cancer (MTC) is a rare thyroid tumor whose prevalence is 3–5% among all thyroid tumors. The pathogenesis of MTC is mainly related to germline or somatic RET activating point mutations that are causative of hereditary and sporadic cases, respectively. Hereditary MTC can occur as multiple endocrine neoplasia type 2A (MEN 2A), type 2B (MEN 2B) and familial MTC (FMTC) that differ for the association with other endocrine neoplasia. Germline RET point mutations are prevalently localized in exons 5, 8, 10–11, 13–16 and a significant genotype-phenotype correlation has been observed. RET genetic screening is mandatory in all patients with a diagnosis of MTC regardless from their apparent sporadic origin. The identification of RET germline mutation in an apparently sporadic case is of great clinical utility because it allows the identification of those subjects who will develop the tumor. RET positive relatives must undergo clinical and biochemical tests to verify if the MTC is already present and, according to the type of RET mutation, they have to be screened for the presence of pheochromocytoma and/or hyperparathyroidism. If a MTC is already present patients must be surgically treated. If MTC is not yet present subjects will be followed up with basal and stimulated calcitonin serum measurement, which is the serum marker of MTC. Indeed, RET negative subjects can be reassured that they do not run any risk to develop the disease as well as their children. In conclusions RET genetic screening allows the identification of the hereditary/sporadic nature of MTC and of a relevant percentage of hidden familial MTC. Furthermore, it favors the early diagnosis of MTC in RET positive subjects. RET positive patients and no clinical evidence of MTC can be followed and surgical treatment can be delayed. Finally RET negative relatives do not need to be further monitored.

Survival and Long-Term Biochemical Cure in Medullary Thyroid Carcinoma in Denmark 1997-2014: A Nationwide Study.

Background: Survival of medullary thyroid carcinoma (MTC) subgroups in relation to the general population is poorly described. Data on the factors predicting long-term biochemical cure in MTC patients are nonexistent at a population level. A nationwide retrospective cohort study of MTC in Denmark from 1997 to 2014 was conducted, aiming to detect subgroups with survival similar to that of the general population and to identify prognostic factors for disease-specific survival and long-term biochemical cure.Methods: The study included 220 patients identified from the nationwide Danish MTC cohort between 1997 and 2014. As a representative sample of the general population, a reference population matched 50:1 to the MTC cohort was used.Results: Patients diagnosed with hereditary MTC by screening (hazard ratio [HR] = 1.5 [confidence interval (CI) 0.5–4.3]), patients without regional metastases (HR = 1.4 [CI 0.9–2.3]), and patients with stage I (HR = 1.3 [CI 0.6–3.1]), stage II (HR = 1.1 [CI 0.6–2.3]), and III (HR = 1.3 [CI 0.4–4.2]) disease had an overall survival similar to the reference population. On multivariate analysis, the presence of distant metastases (HR = 12.3 [CI 6.0–25.0]) predicted worse disease-specific survival, while the absence of regional lymph node metastases (odds ratio = 40.1 [CI 12.0–133.7]) was the only independent prognostic factor for long-term biochemical cure.Conclusions: Patients with hereditary MTC diagnosed by screening, patients without regional metastases, and patients with stages I, II, and III disease may have similar survival as the general population. The presence of distant metastases predicted worse disease-specific survival, while the absence of regional metastases predicted long-term biochemical cure.

Revisiting the Significance of Prominent C Cells in the Thyroid.

C cell hyperplasia is considered a precursor lesion for hereditary forms of medullary thyroid carcinoma. It has therefore been suggested as a morphological marker to distinguish hereditary from sporadic medullary thyroid carcinoma and to triage genetic testing in resource poor settings. However, numerous definitions for C cell hyperplasia have been suggested, and there is surprisingly little data regarding the number of C cells present in thyroid glands removed for conditions other than medullary carcinoma. We therefore sought to investigate the specificity of different criteria for C cell hyperplasia. We examined the number of C cells and solid cell nests (ultimobranchial body remnants) present in 118 completion thyroidectomy specimens from patients without medullary carcinoma and with no risk factors for MEN2. Morphological review was performed on all H&E-stained slides, and immunohistochemistry for calcitonin was performed on one block from each case. Solid cell nests were found in 4 (3.3%) of thyroids. Increased numbers of C cells sufficient to fulfil criteria for C cell hyperplasia were found in 5 (4.2%) to 36 (30.5%) cases depending on the criteria used. We conclude that large numbers of C cells are commonly found in thyroids not associated with medullary carcinoma. Therefore, regardless of which criteria are used, the presence of C cell hyperplasia is not a specific marker for hereditary medullary thyroid carcinoma.

Completeness of RET testing in patients with medullary thyroid carcinoma in Denmark 1997-2013: a nationwide study.

BackgroundThe completeness of REarranged during Transfection (RET) testing in patients with medullary thyroid carcinoma (MTC) was recently reported as 60%. However, the completeness on a population level is unknown. Similarly, it is unknown if the first Danish guidelines from 2002, recommending RET testing in all MTC patients, improved completeness in Denmark. We conducted a nationwide retrospective cohort study aiming to evaluate the completeness of RET testing in the Danish MTC cohort. Additionally, we aimed to assess the completeness before and after publication of the first Danish guidelines and characterize MTC patients who had not been tested.MethodsThe study included 200 patients identified from the nationwide Danish MTC cohort 1997–2013. To identify RET tested MTC patients before December 31, 2014, the MTC cohort was cross-checked with the nationwide Danish RET cohort 1994–2014. To characterize MTC patients who had not been RET tested, we reviewed their medical records and compared them with MTC patients who had been tested.ResultsCompleteness of RET testing in the overall MTC cohort was 87% (95% CI: 0.81–0.91; 173/200). In the adjusted MTC cohort, after excluding patients diagnosed with hereditary MTC by screening, completeness was 83% (95% CI: 0.76–0.88; 131/158). Completeness was 88% (95% CI: 0.75–0.95; 42/48) and 81% (95% CI: 0.72–0.88) (89/110) before and after publication of the first Danish guidelines, respectively. Patients not RET tested had a higher median age at diagnosis compared to those RET tested. Median time to death was shorter in those not tested relative to those tested.ConclusionThe completeness of RET testing in MTC patients in Denmark seems to be higher than reported in other cohorts. No improvement in completeness was detected after publication of the first Danish guidelines. In addition, data indicate that advanced age and low life expectancy at MTC diagnosis may serve as prognostic indicators to identify patients having a higher likelihood of missing the compulsory RET test.