Sporadic Medullary Thyroid Carcinoma Research Articles

Preoperative Clinical and Ultrasonographic Predictors for Aggressive Behaviors in Sporadic Medullary Thyroid Carcinomas.

Objective: To explore the clinical and ultrasonographic predictors for aggressive behaviors preoperatively in sporadic medullary thyroid carcinomas (MTCs). Materials and Methods: The preoperative clinical and ultrasonographic characteristics of patients diagnosed with MTCs between January 2009 and May 2022 were retrospectively reviewed. MTCs were described and categorized according to the American College of Radiology (ACR) thyroid imaging reporting and data system classification by 2 radiologists. Interobserver agreement was evaluated by kappa test. Univariate and multivariate analyses were performed to identify predictors of aggressive behaviors in MTCs. The log-rank test was utilized to compare differences in Kaplan-Meier (K-M) curves for postoperative disease-free survival (PDFS). Results: A total of 120 patients were enrolled in the final study. Male sex was significant risk factor for metastasis, perithyroidal invasion, and lateral cervical lymph node (LCLN) metastasis [odds ratio (OR): 3.109, P = .019; OR: 5.316, P = .018; OR: 5.154 P = .012, respectively]. The kappa values for all ultrasonic characteristics were high (ranged from 0.811 to 0.941). Size, focality, and margin of the nodule were independent risk factors for metastasis, as well as for LCLN metastasis. Whereas margin (P < .001) and a subcapsular location (P = .021) were risk factors for perithyroidal invasion. According to K-M analysis, PDFS of patients differed significantly between groups with/without metastasis (P < .001), groups with/without perithyroidal extension (P < .001) and groups with/without LCLN metastasis (P < .001). Conclusions: Male sex is an independent risk factor for metastasis, perithyroidal invasion, and LCLN metastasis. The large size (≥2.55 cm for metastasis, ≥2.15 cm for LCLN metastasis, respectively), multifocality, and irregular margin of nodules were independent risk factors for both metastasis and LCLN metastasis. Extrathyroidal extension and a subcapsular location were risk factors for perithyroidal invasion. Moreover, patients with metastasis/perithyroidal extension/LCLN metastasis exhibited worse PDFS.

Molecular characterization of circulating tumor cells (CTCs) in sporadic medullary thyroid carcinoma (spMTC) patients

Molecular characterization of circulating tumor cells (CTCs) in sporadic medullary thyroid carcinoma (spMTC) patients

Clinical presentation of sporadic and familial medullary thyroid carcinoma: is there a real difference?

Clinical presentation of sporadic and familial medullary thyroid carcinoma: is there a real difference?

Timing and Ideal Patient for an Appropriate Search for Somatic RET Mutation in Medullary Thyroid Cancer.

RET somatic mutation analysis in sporadic MTC should be guided by postoperative evaluation results.

Next-Generation Sequencing in Sporadic Medullary Thyroid Cancer Patients: Mutation Profile and Disease Aggressiveness.

Next-generation sequencing (NGS) analysis of sporadic medullary thyroid carcinoma (sMTC) has led to increased detection of somatic mutations, including RET M918T, which has been considered a negative prognostic indicator. This study aimed to determine the association between clinicopathologic behavior and somatic mutation identified on clinically motivated NGS. In this retrospective cohort study, patients with sMTC who underwent NGS to identify somatic mutations for treatment planning were identified. Clinicopathologic factors, time to distant metastatic disease (DMD), disease-specific survival (DSS), and overall survival (OS) were compared between somatic mutations. Somatic mutations were identified in 191 sMTC tumors, including RET M918T (53.4%), other RET codons (10.5%), RAS (18.3%), somatic RET indels (8.9%), and RET/RAS wild-type (WT) status (8.9%). The median age at diagnosis was 50 years (range, 11-83); 46.1% were female. When comparing patients with RET M918T, RET-Other, and RET WT (which included RAS and RET/RAS WT), there were no differences in sex, TNM category, systemic therapy use, time to DMD, DSS, or OS. On multivariate analysis, older age at diagnosis (HR 1.05, P < .001; HR 1.06, P< .001) and M1 stage at diagnosis (HR 3.17, P = .001; HR 2.98, P = .001) were associated with decreased DSS and OS, respectively, but mutation cohort was not. When comparing RET M918T to RET indels there was no significant difference in time to DMD, DSS, or OS between the groups. Somatic RET mutations do not portend compromised DSS or OS in a cohort of sMTC patients who underwent clinically motivated NGS.

Changes of biochemical factors and the effect on recurrence of medullary thyroid carcinoma after surgery

ObjectiveMedullary thyroid carcinoma (MTC) is a rare malignancy secreting calcitonin (Ctn). We aimed to analyze the relationship between Ctn levels at different time points in patients with MTC, and evaluate its predictive effect on recurrence. MethodsA retrospective study of patients diagnosed with MTC in a large medical center were conducted in northern China. The interrelationships between preoperative Ctn, normalization of postoperative serum Ctn at the first month (NPS), and long-term biochemical cure as well as their predicting roles on structural recurrence were assessed. ResultsA total of 212 patients were included in this study. The median follow-up time was 59.5 months. The 5- and 10-year cumulative disease-free survival rates were 81.5 % and 66.8 %, respectively. NPS (OR: 216.33, 95 % CI: 28.69–1631.09, P < 0.001) and absence of structural recurrence (OR: 61.71, 95 % CI: 3.90–975.31; P = 0.003) were associated with biochemical cure. Non-biochemical cure (OR: 28.76; 95 % CI: 2.84–290.86; P = 0.004, HR: 14.63, 95 % CI: 2.27–94.07, P = 0.005), larger tumor size (OR: 8.79, 95 % CI: 2.12–36.40, P = 0.003, HR: 5.41, 95 % CI: 2.04–14.37, P = 0.001), and multifocality (OR: 4.02, 95 % CI: 1.06–15.17, P = 0.040, HR: 3.00, 95 % CI: 1.18–7.60, P = 0.021) were unfavorable independent predictors of structural recurrence and disease-free survival. For sporadic MTC confined to the thyroid lobe, there was no difference in biochemical or structural prognosis between the different surgeries in the subgroup analysis. ConclusionsNPS, rather than preoperative Ctn, predicted long-term biochemical cure for MTC. Non-biochemical cure, larger tumor burden including larger tumor size and multifocality at initial surgery, served as worse prognostic predictors.

Not Only RET but NF1 and Chromosomal Instability Are Seen in Young Patients with Sporadic Medullary Thyroid Carcinoma.

Genetic analysis of sporadic medullary thyroid carcinoma (MTC) has revealed somatic variants in RET, RAS, and occasionally other genes. However, around 20% of patients with sporadic MTC lack a known genetic driver. To uncover potential new somatic or germline drivers, we analyze a distinct cohort of patients with sporadic, very early-onset, and aggressive MTC. Germline and somatic DNA exome sequencing was performed in 19 patients, previously tested negative for germline RET variants. Exome sequencing of 19 germline samples confirmed the absence of RET and identified an NF1 pathogenic variant in 1 patient. Somatic sequencing was successful in 15 tumors revealing RET variants in 80%, predominantly p.Met918Thr, which was associated with disease aggressiveness. In RET-negative tumors, pathogenic variants were found in HRAS and NF1. The NF1 germline and somatic variants were observed in a patient without a prior clinical diagnosis of neurofibromatosis type 1, demonstrating that the loss of heterozygosity of NF1 functions as a potential MTC driver. Somatic copy number alterations analysis revealed chromosomal alterations in 53.3% of tumors, predominantly in RET-positive cases, with losses in chromosomes 9 and 22 being the most prevalent. This study reveals that within a cohort of early-onset nonhereditary MTC, RET remains the major driver gene. In RET-negative tumors, NF1 and RAS are drivers of sporadic MTC. In addition, in young patients without a RET germline mutation, a careful clinical evaluation with a consideration of germline NF1 gene analysis is ideal to exclude Neurofibromatosis type 1 (NF1).

Pediatric Medullary Thyroid Carcinoma: Clinical Presentations and Long-term Outcomes in 144 Patients Over Six Decades.

Sporadic medullary thyroid carcinoma (sMTC) rarely occurs in childhood and no studies have specifically focused on this entity. To describe the clinical presentations and long-term outcomes of a large cohort of children and young adults with sMTC compared with hereditary MTC (hMTC). Retrospective study of 144 patients diagnosed with MTC between 1961-2019 at an age ≤21 years and evaluated at a tertiary referral center. In contrast to hMTC (n=124/144, 86%), patients with sMTC (n=20/144, 14%) are older (p<0.0001), have larger tumors (p<0.0001), a higher initial stage grouping (p=0.001) and have more structural disease (p=0.0045) and distant metastases (DM) (p=0.00084) at last follow up, but are not more likely to die from MTC (p=0.42). Among 77 patients diagnosed clinically, not by family history (20/20 sMTC and 57/124 hMTC), there was no difference in the initial stage (p=0.27), presence of DM at diagnosis (p=1.0), disease status at last follow-up (p=0.13), overall survival (p=0.57), or disease specific survival (p=0.87). Of the twelve sMTC tumors that underwent somatic testing, eleven (91%) had an identifiable alteration: ten RET gene alterations and one ALK fusion. sMTC is primarily a RET-driven disease that represents 14% of childhood-onset MTC in this cohort. Pediatric sMTC patients are older, present with clinical disease at a more advanced TNM classification, and have more persistent disease at last follow up compared with hMTC, but these differences disappear when comparing those presenting clinically. Somatic molecular testing should be considered in sMTC patients who would benefit from systemic therapy.

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

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

A novel somatic genetic alteration in sporadic medullary thyroid carcinoma

A novel somatic genetic alteration in sporadic medullary thyroid carcinoma

Central (N1A) and latero-cervical (N1B) lymph nodes metastases in sporadic medullary thyroid carcinoma patients: clinical impact on disease specific and recurrence free survival

Central (N1A) and latero-cervical (N1B) lymph nodes metastases in sporadic medullary thyroid carcinoma patients: clinical impact on disease specific and recurrence free survival

Molecular analysis of multiple foci of sporadic medullary thyroid carcinoma suggests that they are intrathyroidal metastases from the same primary tumor

Molecular analysis of multiple foci of sporadic medullary thyroid carcinoma suggests that they are intrathyroidal metastases from the same primary tumor

Clinical application of grading system in sporadic medullary thyroid carcinoma patients

Clinical application of grading system in sporadic medullary thyroid carcinoma patients

Partial preservation of the normal thyroid gland based on tumor diameter may be possible in small medullary thyroid carcinoma: a two-center 15-year retrospective study.

At present, there are some controversies in the formulation of surgical protocol for small medullary thyroid carcinoma(s-MTC). We wanted to explore the feasibility of normal thyroid gland retention in small medullary thyroid carcinoma based on different tumor diameters and its prognostic impact on the tumor. The data of patients with stage T1 MTC treated at Tianjin Cancer Hospital and Sichuan Cancer Hospital from 2006 to 2021 were analyzed. The tumor diameters of 0.5 cm and 1.0 cm were used as dividing points. The outcomes were tumor recurrence, metastasis, or patient death. Survival was estimated by the Kapan-Meier curve. A total of 121 T1 s-MTC patients were included, including 55 with total thyroidectomy (TT) and 66 with subthyroidectomy (Sub-TT). There were eleven cases of tumor recurrence and metastasis, and four patients died. When the tumor diameter was 1.0 cm as the cut-off point, tumor diameter (p = 0.010), TT (p = 0.028), unilateral and bilateral type (p = 0.009), and TNM staging (p = 0.007) had significant effects on progression-free survival (PFS). The tumor diameter, unilateral and bilateral type, and TT were risk factors for the prognosis of T1 MTC (p < 0.05). The tumor diameter of 1.0 cm can be used as a cut-off point for stage T1 MTC. Alt-hough there was no significant difference in overall survival (OS) between T1a and T1b in patients, tumor diameter significantly influenced PFS. TT is not necessary for patients with sporadic MTC with T1a.

The survival outcomes of prophylactic lateral neck dissection for medullary thyroid carcinoma, a retrospective cohort study.

The purpose of this study was to evaluate the benefits of prophylactic lymph node dissection in medullary thyroid carcinoma (MTC) patients without radiographically lateral neck metastases. Retrospective cohort study. Tianjin Medical University Cancer Institute and Hospital. Patients who underwent primary surgery for MTC between 2011 and 2019 and without structural disease of the lateral neck preoperatively. Locoregional recurrence, disease-free survival (DFS), and overall survival (OS) were examined. The patients were divided into two groups: the central lymph node dissection (CLND) only group and the prophylactic lateral lymph node dissection (PLND) group, which included CLND and ipsilateral lateral lymph node dissection (LLND). A total of 89 patients were included: 71 patients in the CLND group and 18 patients in the PLND group. Although there were no significant differences in age, gender, multifocality, capsule invasion or TNM stage between the two groups, the tumour size and preoperative median calcitonin levels were different. The recurrence rate was 4.2% for the CLND group and 5.6% for the PLND group (p > 0.05). DFS among the CLND and PLND groups was 95.4% and 94.4%, and OS among the groups was 100% and 94.1% (p > 0.05) at 5 years. The biochemical cure rates were similar. PLND in the absence of structural disease of the lateral neck preoperatively is not associated with improved survival in patients with sporadic MTC.

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

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

NF1 Gene Inactivation Acts as Tumor Driver in RET/RAS Negative Medullary Thyroid Carcinomas.

20% of sporadic MTC has no RET/RAS somatic alterations or other known gene alterations. Aim of this study was to investigate RET/RAS negative MTC for the presence of NF1 alterations. we studied 18 sporadic RET/RAS negative MTC cases: Next generation sequencing of tumoral and blood DNA was performed using a custom panel including the entire coding region of the NF1 gene. The effect of NF1 alterations on the transcripts were characterized by RT-PCR and the loss of heterozygosity of the other NF1 allele was investigated with Multiplex Ligation-dependent Probe Amplification. Two cases showed bi-allelic inactivation of NF1 with a prevalence of about 11% of RET/RAS negative cases. In a patient affected by neurofibromatosis there was a somatic intronic point mutation determining the transcript alteration in one allele and a germline loss of heterozygosity (LOH) in the other. In the other case described both the point mutation and the LOH were somatic events; this latter finding shows, for the first time, a driver role of NF1 inactivation in MTC independent of RET/RAS alterations and the presence of neurofibromatosis. About 11% of our series of sporadic RET/RAS negative MTC harbor biallelic inactivation of NF1 suppressor gene also regardless neurofibromatosis status. According to our results, NF1 alterations should be searched in all RET/RAS negative MTC as possible driver. Moreover, this finding reduces the number of negative sporadic MTCs and may have important clinical implications in the management of these tumors.

Abstract #1399687: Precision Oncology in the Management of Medullary Thyroid Cancer in an Adolescent with MEN2B, 1-year Follow-up

Medullary thyroid carcinoma (MTC) is a rare but aggressive thyroid tumor, with 25% of hereditary and 75% of sporadic forms. RET mutations are found in 98% of hereditary MTC and in 55% of sporadic MTC. Targeted therapies are a management option for patients with progressive or symptomatic disease with locoregional or metastatic MTC. We present the case of an adolescent with type 2B multiple endocrine neoplasia (MEN-2B) syndrome with an optimal response to pralsetinib. A 14-year-old adolescent, she was admitted for maxillofacial surgery in September 2019 due to a thyroid nodule and cervical nodes whose FNA reported: MTC; she underwent total thyroidectomy extended to prethyroid muscles + bilateral radical dissection. The pathology reported: multicentric MTC: in LTL tumor of 3.0 x 1.5cm, with invasion of tumor capsule and extraglandular 4mm to the adiposomuscular plane, lymphatic and venous permeation, tumor in isthmus of 1cm and RTL of 0.6cm; Bilateral periglandular and cervical lymph node metastasis (23/58) EC-IVA. Endocrinological evaluation showed a marfanoid phenotype, thick lips, tongue neuromas, diastema, and a history of chronic constipation with segmental colonic dilatation on abdominal radiography. No history of HTA. No similar family history. PET-CT-18FDG: mediastinal lymph nodes suggestive of metastasis. She received cervical-mediastinal radiotherapy: 6000 cGy in April 2020. Follow-up was interrupted due to a pandemic, she was readmitted with mediastinal disease progression according to PET-CT in June 2021. She had access to a genetic NGS tumor study that showed the RET M918T mutation. In December 2021, she started Pralsetinib 200 mg/day, achieving a biochemical and structural response in follow-up sustained to date, without developing major adverse events. The NCCN Guidelines advise performing the RET study at the time of initial diagnosis. Targeted therapies have helped supplant cytotoxic chemotherapy, which has low efficacy against disease progression, but there is still the problem of toxic side effects and frequent development of tumor resistance when using the current treatment regimen. In this case, with the MEN-2B criteria established, the RET M918T mutation detected. and presenting with disease progression (elevated calcitonin and CEA, associated with mediastinal disease progression), she agreed to an expanded program of anti-RET therapy with Pralsetinib, demonstrating safety and efficacy after 1 year of use.

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

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

The Role of 18F-FDOPA PET/CT in Recurrent Medullary Thyroid Cancer Patients with Elevated Serum Calcitonin Levels.

To evaluate the diagnostic performance of 18F-dihydroxyphenylalanine (FDOPA) positron emission tomography/computed tomography (PET/CT) in the detection of medullary thyroid carcinoma (MTC) recurrence in patients with elevated calcitonin levels. The patients who had undergone 18F-FDOPA PET/CT imaging for elevated calcitonin levels after primary surgery of MTC were included in the study. addition, if available 18F-fluorodeoxyglucose (FDG) PET/CT and Gallium-68 (68Ga)- DOTATATE PET/CT images of the patients were evaluated retrospectively. The sensitivity and diagnostic performance of 18F-DOPA PET/CT were investigated. A total of 14 patients (9 F and 5 M; median age: 45) were included in the analysis. Three patients had MEN IIA syndrome and 1 patient had MEN IIB syndrome, 10 patients had a diagnosis of sporadic MTC. Median calcitonin levels of the patients were calculated as 757.5 (min-max: 28.5-7911) pg/mL. Nine patients and 5 patients had undergone ultrasound and contrast-enhanced computed tomography (ceCT) of the neck, respectively, before 18F-FDOPA PET/CT imaging. 18F-FDOPA PET/CT revealed pathological uptake in the thyroid bed, lymph nodes, and distant organs in three, five and two patients, respectively. Median maximum standardized uptake value for the recurrent or metastatic lesions were calculated as 6.4 (min-max: 1.9-18.4). The sensitivity of 18F-FDOPA PET/CT in the detection of recurrent disease was calculated as 64%. Eight patients had 68Ga-DOTATATE PET/CT and 7 of them had 18F-FDG PET/CT within 3 months period before 18F-FDOPA PET/CT. 18F-FDOPA PET/CT revealed recurrent disease in 4 of 5 and 2 of the 5 patients who had negative 18F-FDG PET/CT and negative 68Ga- DOTATATE PET/CT, respectively. 18F-FDOPA PET/CT can detect recurrence in about two- thirds of patients with elevated calcitonin levels after primary surgery for MTC. Due to variable differentiation degree, different receptor status, and clinical behavior of MTC, all three radiopharmaceuticals can be beneficial and are complementary to each other in patient management.