Hereditary Medullary Thyroid Carcinoma Research Articles

Clinical characteristics of hereditary and sporadic medullary thyroid carcinoma.

To study the clinical characteristics and outcomes of the hereditary medullary thyroid carcinoma (HMTC) and the sporadic medullary thyroid carcinoma (SMTC). The clinical data of 78 patients with medullary thyroid carcinoma who underwent surgery in our hospital between July 1980 and May 2011 were retrospectively analyzed. Of these 78 patients, there were 23 HMTC cases and 55 SMTC cases. The HMTC group was significantly younger age of onset [(36.4±13.5) years vs. (46.6±11.2) years, P<0.01] and a lower pre/post-operative serum calcitonin levels [(850.4±110.20) ng/L vs. (1450.4±118.3) ng/L, P<0.01 and (410.8±133.2) ng/L vs. (1585.4±129.5) ng/L, P<0.01] than the SMTC group. In addition, the mean tumor diameter was also significantly smaller in the HMTC group (14.3 mm vs. 21.0 mm in SMTC group, P<0.05). Tumor multifocality was seen in a significantly higher proportion of HMTC cases compared with the SMTC cases (56.6% vs. 29.1%, P<0.05). The overall 10-year survival was 100% in HMTC group and 80.2% in SMTC group (P<0.05). HMTC has a better prognosis than SMTC.

MicroRNA Profiles in Familial and Sporadic Medullary Thyroid Carcinoma: Preliminary Relationships with RET Status and Outcome

MicroRNAs (miRNAs) are involved in the pathogenesis of human cancers, including medullary thyroid carcinoma (MTC). The aim of this study was to test the hypothesis that different miRNA profiles are related to RET status and prognosis in patients with hereditary MTC (hMTC) and sporadic MTC (sMTC). We analyzed the expression of nine miRNAs (miR-21, miR-127, miR-154, miR-224, miR-323, miR-370, miR-9*, miR-183, and miR-375) by quantitative real-time-polymerase chain reaction in 34 cases of sMTC, 6 cases of hMTC, and 2 cases of C-cell hyperplasia (CCH). We also analyzed the immunohistochemical expression of PDCD4, an miR-21 gene target. sMTC (n=34) was genotyped for somatic RET and RAS mutations. Disease status was defined on the basis of the concentration of serum calcitonin at the latest follow-up and other parameters as indicated in the results. MTC and CCH were both characterized by a significant overexpression of the whole set of miRNAs (the increase being 4.2-fold for miR-21, 6.7-fold for miR-127, 8.8-fold for miR-154, 6.6-fold for miR-224, 5.8-fold for miR-323, 6.1-fold for miR-370, 13-fold for miR-9*, 6.7-fold for miR-183, and 10.1 for miR-375, p<0.0001). PDCD4 expression was significantly downregulated in MTC samples, consistent with miR-21 upregulation. Significantly lower miR-127 levels were observed in sMTC carrying somatic RET mutations in comparison to sMTC carrying a wild-type RET. In sMTC and familial MTC, the miR-224 upregulation correlated with the absence of node metastases, lower stages at diagnosis, and with biochemical cure during follow-up. miRNAs are significantly dysregulated in MTC, and this dysregulation is probably an early event in C-cell carcinogenesis. miR-224 upregulation could represent a prognostic biomarker associated with a better outcome in MTC patients.

Recent advances in the molecular pathogenesis and targeted therapies of medullary thyroid carcinoma

This review will focus on the recent advances in molecular pathogenesis and targeted therapies for medullary thyroid carcinoma (MTC). Unlike hereditary MTC in which rearranged during transfection (RET) mutations are the most important precipitating events, in sporadic MTC the genetic or molecular biomarkers are yet to be established. Targeted molecular therapies that inhibit RET and other tyrosine kinase receptors involved in angiogenesis have shown great promise in the treatment of metastatic or locally advanced MTC and are under investigation. In addition, the recent findings of H-RAS mutations in 56% of RET-negative sporadic MTC and the activation of the mammalian target of rapamycin (mTOR) intracellular signaling pathway in hereditary MTC suggests that additional or alternative genetic events are important for MTC pathogenesis. Recently, vandetanib (ZD6474), an inhibitor of vascular endothelial growth factor receptor (VEGFR) 2 and VEGFR 3, RET, and epidermal growth factor receptor (EGFR), was approved for the treatment of adults with symptomatic or progressive MTC. Significant advantages for vandetanib over placebo were seen in terms of response rate, disease control rate, and biochemical response in a phase III study. Furthermore, cabozantinib (XL184), an inhibitor of VEGFR 1 and VEGFR 2, hepatocyte growth factor receptor (MET), and RET, was associated with partial response and stable disease in 29 and 41%, respectively.

The Treatment Outcomes of Medullary Thyroid Carcinoma

Received December 23, 2011 Revised February 16, 2012 Accepted February 21, 2012 Address for correspondence Kang Dae Lee, MD Department of OtolaryngologyHead and Neck Surgery, Kosin University College of Medicine, 262 Gamcheon-ro, Seo-gu, Busan 602-702, Korea Tel +82-51-990-6248 Fax +82-51-245-8539 E-mail kosinent@yahoo.co.kr Background and ObjectivesZZThe aim of this study was to evaluate the treatment outcomes of medullary thyroid carcinoma (MTC) by retrospective data analysis. Subjects and MethodZZWe conducted a retrospective chart review of 17 cases of pathologically proven MTC patients who were treated from 1998 to 2010 at the department of Otolaryngology-Head and Neck Surgery, Kosin University College of Medicine. ResultsZZThe mean tumor size was 2.32 cm (0.5-3.4 cm). Seventy-one percent of patients were diagnosed with advanced stage (III or IV) of MTC. We performed RET genetic screening in 8 of 17 patients. Hereditary MTC was found in 3 of 17 patients (18%) and sporadic MTC was found in 14 of 17 (82%). The preoperative assessment of basal serum calcitonin (CT) level was performed in 15 of 17 patents. Eleven patients had elevated basal calcitonin levels (>13 pg/ mL). After the operation for MTC, the serum CT levels were elevated in 7 patients. Overall 5-year survival rate was 94%. Normalization of serum calcitonin level was accomplished more frequently in the absence of extra thyroidal invasion (p=0.034), multifocal tumor (p=0.02). ConclusionZZThe initial treatment of MTC is total thyroidectomy with central compartment neck dissection with or without lateral neck dissection. To detect recurrence or metastasis, regular checking of serum calcitonin is necessary. A better knowledge of prognostic factors could improve the management of MTC patients. Korean J Otorhinolaryngol-Head Neck Surg 2012;55:166-72

Multiple Endocrine Neoplasia and Familial Medullary Thyroid Carcinoma

Multiple endocrine neoplasia (MEN) is defined as a disorder with neoplasms in two or more different hormonal tissues in several members of a family. MEN1, or Wermer's syndrome, is inherited as an autosomal dominant trait. This syndrome is characterized by neoplasia of the parathyroid glands, enteropancreatic tumors, anterior pituitary adenomas, and other neuroendocrine tumors with variable penetrance. Inherited medullary thyroid carcinoma (MTC) consists of MEN2A, MEN2B, and familial medullary thyroid cancer (FMTC). The identification of hereditary MTC has been facilitated in recent years by direct analysis of germline RET proto-oncogene mutation.

Molecular basis of medullary thyroid carcinoma: the role of RET polymorphisms.

Medullary thyroid carcinoma is a rare malignant tumor originating in parafollicular C cells. It accounts for 5 to 8% of all thyroid cancers. MTC develops in either sporadic (75%) or hereditary form (25%). Genetic and molecular studies have demonstrated the involvement of the RET proto-oncogene in hereditary MTC and, less often, in its sporadic form. Although a strong genotype-phenotype correlation has been described, wide clinical heterogeneity is observed among families with the same RET mutation or even in carriers of the same kindred. In recent years, several single nucleotide polymorphisms of the RET gene have been described in the general population as well as in patients with MTC. Some studies have reported associations between the presence of polymorphisms and development or progression of MTC. Nonetheless, other studies failed to demonstrate any effect of the RET variants. Differences in the genetic background of distinct populations or methodological approaches have been suggested as potential reasons for the conflicting results. Here, we review current knowledge concerning the molecular pathogenesis of sporadic and hereditary MTC. In particular, we analyze the role of RET polymorphisms in the clinical presentation and prognosis of MTC based on the current literature.

Hereditary medullary thyroid carcinoma: the management dilemma

Hereditary medullary thyroid carcinoma (hereditary MTC) is a rare malignancy, accounting for 25-30% of all MTC. It occurs as part of multiple endocrine neoplasia type 2 (MEN 2). Autosomal dominant gain-of-function mutations in the RET proto-oncogene is the cause of the disease, in which the common mutations are codons 609, 611, 618, 620, 630, 634 and 918. In recent years, the spectrum of RET gene mutations has changed. The classical mutations reduced, whereas the less aggressive mutations increased. Hereditary MTC is a time-dependent disease. Stages of the disorder at diagnosis can significantly influence survival rates. Based on the genotype-phenotype, RET mutations have been classified into four risk levels by American Thyroid Association (ATA) at 2009. The classification system guides the hereditary MTC management, including risk assessment, biochemical screenings and surgical intervention. Though the application of genetic testing and codon-specific phenotypes in hereditary MTC diagnosis is effective with high accuracy, there are some difficulties in implementing RET gene testing as a routine for MTC diagnosis. And most of carriers with RET mutations did not undergo thyroidectomy at the age recommended by the ATA guidelines. The aim of the study is to review the hereditary MTC and discuss the management dilemma.

Sporadic medullary thyroid carcinoma with a pedunculated intraluminal internal jugular vein recurrence: A case report and literature review

Medullary thyroid carcinoma (MTC) is an uncommon usually slowly progressing neuroendocrine tumour that arises from calcitonin (CT) producing parafollicular C cells of the thyroid gland. It accounts for approximately 5% of all thyroid cancers. The majority of MTCs are sporadic (75%) whilst 25% are part of the MEN 2 hereditary syndrome (MEN 2A and MEN 2B and familial MTC). Mutations of the proto-oncogene, RET (Rearranged during Transfection), found on chromosome 10q11, are present in more than 95% of hereditary MTCs and about 25% of sporadic MTCs. MTC metastasizes primarily via lymphatic spread, to central, and lateral nodal neck compartments and the anterior and superior mediastinum. Distant haematogenous spread targets the lungs, liver, bone and brain, and is presumed to be secondary to a lymphatic pathway. There are no previously documented reports of a focal pedunculated metastases located within the jugular vein. We present the first reported case of a metastatic MTC lesion found in the right internal jugular vein in a man with recurrent MTC.

Vandetanib in Patients With Locally Advanced or Metastatic Medullary Thyroid Cancer: A Randomized, Double-Blind Phase III Trial

There is no effective therapy for patients with advanced medullary thyroid carcinoma (MTC). Vandetanib, a once-daily oral inhibitor of RET kinase, vascular endothelial growth factor receptor, and epidermal growth factor receptor signaling, has previously shown antitumor activity in a phase II study of patients with advanced hereditary MTC. Patients with advanced MTC were randomly assigned in a 2:1 ratio to receive vandetanib 300 mg/d or placebo. On objective disease progression, patients could elect to receive open-label vandetanib. The primary end point was progression-free survival (PFS), determined by independent central Response Evaluation Criteria in Solid Tumors (RECIST) assessments. Between December 2006 and November 2007, 331 patients (mean age, 52 years; 90% sporadic; 95% metastatic) were randomly assigned to receive vandetanib (231) or placebo (100). At data cutoff (July 2009; median follow-up, 24 months), 37% of patients had progressed and 15% had died. The study met its primary objective of PFS prolongation with vandetanib versus placebo (hazard ratio [HR], 0.46; 95% CI, 0.31 to 0.69; P < .001). Statistically significant advantages for vandetanib were also seen for objective response rate (P < .001), disease control rate (P = .001), and biochemical response (P < .001). Overall survival data were immature at data cutoff (HR, 0.89; 95% CI, 0.48 to 1.65). A final survival analysis will take place when 50% of the patients have died. Common adverse events (any grade) occurred more frequently with vandetanib compared with placebo, including diarrhea (56% v 26%), rash (45% v 11%), nausea (33% v 16%), hypertension (32% v 5%), and headache (26% v 9%). Vandetanib demonstrated therapeutic efficacy in a phase III trial of patients with advanced MTC (ClinicalTrials.gov NCT00410761).

Chromosome 10 and RET gene copy number alterations in hereditary and sporadic Medullary Thyroid Carcinoma

About 30% of hereditary Medullary Thyroid Carcinoma (MTC) have been demonstrated to harbour imbalance between mutant and wild-type RET alleles. We studied the RET copy number alterations ( RET CNA) in 65 MTC and their correlation with RET mutation and patients’ outcome. Fluorescence in situ Hybridization and Real-time PCR revealed RET CNA in 27.7% MTC but only in a variable percentage of cells. In sporadic MTC, RET CNA were represented by chromosome 10 aneuploidy while in hereditary MTC by RET amplification. A significant higher prevalence of RET CNA was observed in RET mutated MTC ( P = 0.003). RET CNA was also associated to a poorer outcome ( P = 0.005). However, the multivariate analysis revealed that only RET mutation and advanced clinical stage correlated with the worst outcome. In conclusion, 30% MTC harbour RET CNA in variable percentage of cells suggesting cell heterogeneity. RET CNA can be considered a poor prognostic factor potentiating the poor prognostic role of RET mutation.

Simultaneous Medullary and Papillary Thyroid Cancer: A Novel Entity?

The causes underlying the phenomenon of simultaneous medullary (MTC) and papillary thyroid cancer (PTC) are unclear. This study of 26 patients with simultaneous MTC and PTC aimed at clarifying clinical and histopathologic characteristics and trends of this unusual condition among MTC and PTC patients who were operated on at a tertiary referral center in Germany. A total of 26 patients revealed simultaneous MTC and PTC, yielding the following rates: 2.6% (26 patients) among all 1019 PTC patients, 2.6% (6 patients) among all 235 hereditary MTC patients, 4.1% (20 patients) among all 492 sporadic MTC patients, and 3.6% (26 patients) among all 727 MTC patients. Simultaneous MTC and PTC were consistently smaller than nonsimultaneous MTC (6 vs. 13mm for hereditary MTC, P=.16; 12 vs. 23mm for sporadic MTC, P=.009; and 11 vs. 20mm for any MTC, P=.008) and PTC (8 vs. 20mm, P<.001). Simultaneous MTC and PTC increased among MTC and PTC patients over time: from 0% to 4.3% (PTC), from 0% to 4.6% (hereditary MTC), from 0% to 8.1% (sporadic MTC), and from 0% to 7.0% (any MTC). For sporadic MTC, these rates virtually doubled every 5years. Of 6 patients with simultaneous hereditary MTC and PTC, 5 revealed late-onset REarranged during Transfection (RET) mutations (1 L790F carrier; 2 V804L and 2 S891A carriers). Greater pathologic scrutiny, in addition to environmental changes, explains the surge of simultaneous MTC and PTC in Germany. More data are needed from additional geographic areas and populations to delineate individual contributions of these factors.

Molecular Analysis of the RET Proto-Oncogene Key Exons in Patients with Medullary Thyroid Carcinoma: A Comprehensive Study of the Iranian Population

Germ-line mutations of RET proto-oncogene are the known cause of hereditary medullary thyroid carcinoma (MTC), which account for approximately 25% of all MTC cases and occur as multiple endocrine neoplasia type 2 syndromes. Here, we present the first comprehensive genetic screening and analysis of MTC among Iranian families. A total of 55 patients with MTC (male to female ratio=1:1.6; average age of disease onset = 33 ± 13 years) from 53 independent families participated in this study. All of the patients had undergone total thyroidectomy between 1999 and 2006, and 51 of them were clinically characterized as apparently sporadic cases. Genomic DNA samples were obtained and following highly-specific polymerase chain reaction amplification of the 6 RET key exons (10, 11, 13, 14, 15, and 16) were subjected to direct DNA sequencing without a requirement for a purification step. Sequence analysis revealed that 9 (17.6%) of the apparently sporadic cases (from 8 kindreds) carried an RET germ-line mutation. Of the seven different mutations identified among all of the families studied, five were in the cysteine codons, with Cys634Arg having the highest prevalence (45.5%) among the afflicted families. Mutation carriers have an earlier age of onset (21 ± 6) versus the sporadic cases (37 ± 12). This is the first comprehensive genetic screening and analysis of MTC among Iranian families. The results further confirm the need and advantages of DNA sequencing for identification of hereditary MTC cases. There does not seem to be a meaningful correlation between single nucleotide polymorphism patterns and the average age of disease onset. Geographical distribution of the sporadic cases, however, shows a significant concentration toward the Northern regions of the country, noticeably the provinces situated directly to the south of the Caspian Sea.

Predicting Phenotypic Severity of Uncertain Gene Variants in the RET Proto-Oncogene

Although reported gene variants in the RET oncogene have been directly associated with multiple endocrine neoplasia type 2 and hereditary medullary thyroid carcinoma, other mutations are classified as variants of uncertain significance (VUS) until the associated clinical phenotype is made clear. Currently, some 46 non-synonymous VUS entries exist in curated archives. In the absence of a gold standard method for predicting phenotype outcomes, this follow up study applies feature selected amino acid physical and chemical properties feeding a Bayes classifier to predict disease association of uncertain gene variants into categories of benign and pathogenic. Algorithm performance and VUS predictions were compared to established phylogenetic based mutation prediction algorithms. Curated outcomes and unpublished RET gene variants with known disease association were used to benchmark predictor performance. Reliable classification of RET uncertain gene variants will augment current clinical information of RET mutations and assist in improving prediction algorithms as knowledge increases.

Predominant RET Germline Mutations in Exons 10, 11, and 16 in Iranian Patients with Hereditary Medullary Thyroid Carcinoma

Medullary thyroid carcinoma occurs in both sporadic (75%) and hereditary (25%) forms. The missense mutations of RET proto-oncogene in MTC development have been well demonstrated. To investigate the spectrum of predominant RET germline mutations in exons 10, 11, and 16 in hereditary MTC in Iranian population, 217 participants were included. Genomic DNAs were extracted from the leukocytes using the standard Salting Out/Proteinase K method. Mutation detection was performed through PCR-RFLP and DNA sequencing. In 217 participants, 43 missense mutations were identified in exons 10 (6%), 11 (13%), and 16 (0.9%). Moreover, a novel germline mutation was detected in exon 11 (S686N). Also four different polymorphisms were found in intron 16 in eight patients. The obtained data showed the frequency profile of RET mutations in Iranian individuals with MTC (19.8%). The most frequent mutation in our population was C634G whereas in most population it was C634R. Altogether, these results underline the importance of the genetic background of family members of any patient with MTC.

Prognostic Factors of Disease-Free Survival after Thyroidectomy in 170 Young Patients with a RET Germline Mutation: A Multicenter Study of the Groupe Français d'Etude des Tumeurs Endocrines

In hereditary medullary thyroid carcinoma (HMTC), prophylactic surgery is the only curative option, which should be properly defined both in time and extent. To identify and characterize prognostic factors associated with disease-free survival (DFS) in children from HMTC families. We conducted a retrospective analysis of a multi-center cohort of 170 patients below age 21 at surgery. Demographic, clinical, genetic, biological data [basal and pentagastrine-stimulated calcitonin (CT and CT/Pg, respectively)], and tumor node metastasis (TNM) status were collected. DFS was assessed based on basal CT levels. Kaplan-Meier curves, Cox regression, and logistic regression models were used to determine factors associated with DFS and TNM staging. No patients with a preoperative basal CT <31 ng/ml had persistent or recurrent disease. Medullary thyroid carcinoma defined by a diameter ≥10 mm [hazard ratio (HR): 6.0; 95% confidence interval (95% CI): 1.8-19.8] and N1 status (HR: 20.8; 95% CI: 3.9-109.8) were independently associated with DFS. Class D genotype [odds ratio (OR): 48.5, 95% CI: 10.6-225.1], preoperative basal CT >30 ng/liter (OR: 43.4, 95% CI: 5.2-359.8), and age >10 (OR: 5.5, 95% CI: 1.4-21.8) were associated with medullary thyroid carcinoma ≥10 mm. No patient with a preoperative basal CT <31 ng/ml had a N1 status. Class D genotype (OR: 48.6, 95% CI: 8.6-274.1), and age >10 (OR: 4.6, 95% CI: 1.1-19.0) were associated with N1 status. In HMTC patients, DFS is best predicted by TNM staging and preoperative basal CT level below 30 pg/ml. Basal CT, class D genotype, and age constitute key determinants to decide preoperatively timely surgery.

Prophylactic thyroidectomy in multiple endocrine neoplasia type 2

Medullary thyroid carcinoma (MTC) is the main component of the autosomal dominant cancer syndrome multiple endocrine neoplasia type 2 (MEN 2). MEN 2 is caused by autosomal dominant gain-of-function mutations in the RET proto-oncogene. In RET-mutation carriers, an age-related progression has been documented from normal C-cells to premalignant C-cell hyperplasia and finally to MTC with or without cervical lymph node metastases. The time required for this neoplastic development as well as penetrance and aggressiveness of disease mainly depends on the specific RET mutation with a strong genotype–phenotype correlation. Recommendations for the timing of prophylactic thyroidectomy are based upon a model that utilizes these genotype–phenotype correlations to stratify mutations into four risk levels. The excellent prognosis for MTC diagnosed at its earliest stage underscores the importance of early diagnosis by RET-mutation analysis for hereditary MTC.

Relative 8q gain is a poor prognostic factor in the diagnosis of prostate biopsies irrespective of the TMPRSS2-ERG fusion status

ETS transcription factor family genes are involved in recurrent genetic rearrangements in prostate carcinoma (PCa). In 50% of PCa patients there is a fusion between the androgen-regulated elements of TMPRSS2 with the ETS transcription factor ERG, causing over-expression of the latter. Other ETS family genes, namely ETV1, ETV4, and ETV5, have more rarely been found to be fused with TMPRSS2 or other 50 partners. We have previously demonstrated that TMPRSS2-ERG is present in pre-malignant prostate lesions in addition to PCa and that relative 8q gain detected in diagnosis needle biopsies is an independent predictor of disease-specific survival. In order to evaluate the prognostic value of these two alterations, we have analyzed a consecutive series of 200 PCa patients by fluorescence in situ hybridization (FISH) assays in paraffin-embedded diagnostic needle biopsies collected from 1997 to 2001. Most of the biopsies displayed Gleason scores (GS) equal to 7 (40.9%) or higher (47%), with the remaining tumors graded with Gleason scores lower than 7 (12.1%). The fusion gene TMPRSS2eERG was detected in 43.2% of PCa cases, being less frequent in higher GS PCa biopsies (54.2%, 50.6%, and 33.3% for GS ! 7, GS 5 7, and GS O 7, respectively; P 5 0.035). On the other hand, relative 8q gain was less frequent in lower GS PCa biopsies (8.3%, 50.6%, 57% for GS ! 7, GS 5 7, and GS O 7, respectively; P ! 0.01). ERG rearrangements alone were not associated with clinical outcome, whereas 8q gain predicted a worse prognosis in PCa patients irrespective of the TMPRSS2eERG fusion status. The prognostic value of relative 8q gain was independent of clinical variables in a multivariate analysis. To the best of our knowledge, this is the first study combining the aforementioned genetic aberrations to assess its prognostic value. The use of genetic prognostic markers in diagnostic prostate biopsies might impact decision making and has, therefore, the potential to become a common procedure in clinical practice. ANALYSIS OF ALTERNATIVE MECHANISMS FOR RET GENE ACTIVATION IN HEREDITARY AND SPORADIC MEDULLARY THYROID CARCINOMA

Analysis of alternative mechanisms for RET gene activation in hereditary and sporadic Medullary Thyroid Carcinoma

Analysis of alternative mechanisms for RET gene activation in hereditary and sporadic Medullary Thyroid Carcinoma

Medullary Thyroid Carcinoma: Long-Term Outcomes of Surgical Treatment

Medullary thyroid carcinoma (MTC) accounts for 5 to 10% of all thyroid cancers but is responsible for a disproportionate number of deaths. We performed a retrospective review to describe clinical outcomes in patients with medullary thyroid carcinoma, screening a subset of patients for somatic mutations in the RET and p18 genes and performing genotype-phenotype correlation in a tertiary-care referral hospital from 1967 to 2009. We studied a total of 94 patients identified from a prospectively maintained thyroid cancer database. Data gathered included patient demographics, serum calcitonin, clinical outcomes, histopathology, genetic analysis, and status at final follow-up. A subset cohort (n = 50) was screened for somatic mutations in the RET gene and the three exons of the p18 gene. The subset cohort was composed of hereditary medullary thyroid carcinoma (HMTC) (n = 19, index patients = 10, screen detected = 9) and sporadic medullary thyroid carcinoma (SMTC) (n = 31). There were no mutations in the p18 gene in the subset cohort. A total of 67 SMTC and 27 (28.7%) HMTC cases identified. SMTC were older at initial presentation (52 vs. 34, P = 0.003), had higher preoperative serum calcitonin levels (7968 vs. 1346 ng/L, P = 0.008), and had lymph node recurrence (P = 0.001) compared to HMTC. The tumors were smaller in HMTC (P = 0.038). Overall 10-year survival in SMTC versus HMTC was 69 versus 93% (P = 0.12). On multivariate analysis, vascular invasion (hazard ratio 6.4, P = 0.019) was an adverse predictor for disease-free survival. HMTC in the era of RET analysis presents with a smaller primary tumor, lower preoperative serum calcitonin levels, and lower rates of lymph node metastasis. Mutations in the p18 gene were not a major factor in medullary thyroid carcinoma tumorigenesis.

The RET polymorphic allele S836S is associated with early metastatic disease in patients with hereditary or sporadic medullary thyroid carcinoma

The possible role of RET variants in modifying the natural course of medullary thyroid carcinoma (MTC) is still a matter of debate. Here, we investigate whether the RET variants L769L, S836S, and G691S/S904S influence disease presentation in hereditary or sporadic MTC patients. One hundred and two patients with hereditary MTC and 81 patients with sporadic MTC attending our institution were evaluated. The frequencies of RET polymorphisms in hereditary MTC were as follows: L769L, 17.3%; S836S, 7.95%; and S904S/G691S, 18.2%. No associations were observed between these polymorphisms and pheochromocytoma, hyperparathyroidism, lymph node, or distant metastasis. However, patients harboring the S836S variant were younger than those without this allele (17±8.2 vs 28.6±14.4 years, P=0.01), suggesting that these patients had metastases at a young age. Accordingly, the cumulative frequency of local and/or distant metastases as estimated by Kaplan-Meier curves showed that lymph node and distant metastases occurred earlier in patients harboring the S836S variant (P=0.003 and P=0.026 respectively). The S836S allele frequency was higher in sporadic MTC patients than in controls (10.5 vs 3.1%, P=0.01). Individuals harboring the S836S variant were younger (38.6±13.3 vs 48.5±16.7 years, P=0.02) and showed a higher percentage of lymph node and distant metastases (P=0.02 and P=0.04 respectively). Kaplan-Meier estimates of lymph node and distant metastases yielded distinct curves for patients with or without the S836S allele (P=0.002 and P=0.001 respectively). Additional analyses using a COX regression model showed that the S836S variant was independently associated with metastatic disease (hazard ratio 2.82 (95% confidence interval 1.51-5.26), P=0.001). In conclusion, the RET S836S variant is associated with early onset and increased risk for metastatic disease in patients with hereditary or sporadic MTC.