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

Context: 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. Objective: To uncover potential new somatic or germline drivers, we analyze a distinct cohort of patients with sporadic, very early-onset, and aggressive MTC. Methods: Germline and somatic DNA exome sequencing was performed in 19 patients, previously tested negative for germline RET variants. Results: 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. Conclusion: 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).

Correlation of 18F-sodium fluoride uptake and radiodensity in extraosseous metastases of medullary thyroid carcinoma.

Objective: Although 18F-sodium fluoride (18F-NaF) uptake is frequently observed in extraosseous metastases of medullary thyroid carcinoma (MTC) with calcification, itcan also occur in metastatic sites without visible calcium deposition, leading to the hypothesis that visually undetectable calcium accumulation may be responsible for this uptake. The aim of this study was to indirectly support this hypothesis by analyzing the correlation between the degree of 18F-NaF uptake and radiodensity in extraosseous MTC metastases, since calcium deposition can increase attenuation even when not visually detectable. Subjects and methods: Extraosseous metastatic lesions of 15 patients with MTC were evaluated using 18F-NaF positron-emission tomography (PET)/computed tomography (CT)and segmented by levels of standardized uptake value (SUV). The correlation between mean SUV and mean Hounsfield unit (HU) values was assessed for the entire group of segments and for two subgroups with different mean HU values. Results: Very high correlations were observed between mean SUV and mean HU values for both the entire group of segments and the subgroup with a mean HU value greater than 130 (p = 0.92 and p = 0.95, respectively; p < 0.01). High correlation (p = 0.71) was also observed in the subgroup with mean HU values ranging from 20 to 130 (p < 0.01). Conclusion: The findings of the present study suggest that there is an association between 18F-NaF uptake and calcium deposition in extraosseous metastasesof MTC, supporting the hypothesis that visually undetectable calcium accumulation may be responsible for 18F-NaF uptake in regions without visible calcium deposition.

Optimizing Diagnostic Accuracy of Fine Needle Aspiration Biopsy Calcitonin Measurements in Detecting Medullary Thyroid Carcinoma.

Background: The optimal cutoff value of calcitonin (Ctn) levels measured using an electrochemiluminescence immunoassay (ECLIA) obtained from the washout fluid of fine needle aspiration (FNA-Ctn) for the diagnosis of medullary thyroid carcinoma (MTC) is currently not established. We evaluated the diagnostic accuracy and clinical utility of FNA-Ctn for the diagnosis and location of MTC in patients with nodular or multinodular goiters. Methods: This was a case-control study nested on a prospective multicenter cohort of patients with nodular or multinodular goiter, normal or elevated serum Ctn, and thyroidectomy indications. Ctn and FNA-Ctn were measured using ECLIA methodology before surgery. From this nested cohort, MTC cases and controls (non-medullary pathology) were identified from the final pathological analysis. Cumulative incidence sampling of controls was randomly performed at a ratio of 1:2. Sensitivity, specificity, and area under the receiver operator curve (AUROC) were calculated for patients and the total number of thyroid nodules. Results: From 1272 patients included in the prospective cohort, 50 MTC cases and 105 controls were included. In this study, 286 thyroid nodules were evaluated (63 MTC and 223 non-MTCs). The median serum Ctn value was significantly higher in cases (525 pg/mL [interquartile range (IQR), 162.5-1.200]) than in controls (1.6 pg/mL [IQR, 0.5-5.6]; p < 0.001). The median FNA-Ctn value was significantly higher in MTC nodules (3.100 pg/mL [IQR, 450-45,200]) than in non-MTC nodules (0.5 pg/mL [IQR, 0.5-0.5]; p < 0.0001). In 11 MTC patients with multinodular goiter, the FNA-Ctn value was significantly higher in non-medullary nodules located in the same lobe where an MTC nodule was diagnosed (p = 0.0002). Overall, the FNA-Ctn AUROC was 0.99 [95% confidence interval, 0.98-1.0], and a threshold of ≥220 pg/mL showed 100% sensitivity and 98% specificity for MTC diagnosis. Conclusions: The use of FNA-Ctn measured by ECLIA showed adequate diagnostic accuracy for MTC diagnosis. Moreover, it may be clinically useful for localization in multinodular goiter when lobectomy is considered. Clinical Trial Registration: Clinicaltrials.gov NCT06067594.

Correlation of 18F-sodium fluoride uptake and radiodensity in extraosseous metastases of medullary thyroid carcinoma

ABSTRACT Objective: Although 18F-sodium fluoride (18F-NaF) uptake is frequently observed in extraosseous metastases of medullary thyroid carcinoma (MTC) with calcification, it can also occur in metastatic sites without visible calcium deposition, leading to the hypothesis that visually undetectable calcium accumulation may be responsible for this uptake. The aim of this study was to indirectly support this hypothesis by analyzing the correlation between the degree of 18F-NaF uptake and radiodensity in extraosseous MTC metastases, since calcium deposition can increase attenuation even when not visually detectable. Subjects and methods: Extraosseous metastatic lesions of 15 patients with MTC were evaluated using 18F-NaF positron-emission tomography (PET)/computed tomography (CT) and segmented by levels of standardized uptake value (SUV). The correlation between mean SUV and mean Hounsfield unit (HU) values was assessed for the entire group of segments and for two subgroups with different mean HU values. Results: Very high correlations were observed between mean SUV and mean HU values for both the entire group of segments and the subgroup with a mean HU value greater than 130 (p = 0.92 and p = 0.95, respectively; p < 0.01). High correlation (p = 0.71) was also observed in the subgroup with mean HU values ranging from 20 to 130 (p < 0.01). Conclusion: The findings of the present study suggest that there is an association between 18F-NaF uptake and calcium deposition in extraosseous metastases of MTC, supporting the hypothesis that visually undetectable calcium accumulation may be responsible for 18F-NaF uptake in regions without visible calcium deposition.

Carcinoma medular esporádico de tiroides / Sporadic Medullary Thyroid Carcinoma

Introducción: El carcinoma medular de tiroides, representa aproximadamente entre el 5 - 10 por ciento de todos los carcinomas tiroideos, aparece con más frecuencia entre los 25 y 60 años y en el sexo femenino. Se distinguen dos tipos: el esporádico (no hereditario) y el familiar (hereditario). La localización más frecuente es la unión del tercio superior de lóbulo tiroideo con el tercio medio, que es la zona de mayor concentración de células C. Objetivo: Presentar el caso de paciente masculino operado de carcinoma medular de tiroides, tipo esporádico, en la provincia de Cienfuegos. Caso clínico: Paciente masculino de 60 años de edad, piel blanca, que acudió a la consulta; refiere aumento de volumen del cuello acompañado de disfonía y disfagia a los alimentos sólidos. Al examen físico se constató la presencia del nódulo tiroideo. Se le realizó ultrasonido que corrobora la presencia de un nódulo en el lóbulo derecho del tiroides. La biopsia por aspiración con aguja fina informó el nódulo como sospechoso de malignidad. Se le realizó tiroidectomía total, informándose por la biopsia por parafina de la pieza como un carcinoma medular del tiroides. En la actualidad lleva 6 meses de operado con evolución favorable. Conclusiones: El carcinoma medular de tiroides constituye una entidad rara y agresiva más frecuente en los pacientes mayores de 45 años, cuyo tratamiento de elección es la cirugía(AU)

Introduction: Medullary thyroid carcinoma accounts for approximately 5-10 percent of all thyroid carcinomas. It appears more frequently at ages 25-60 years and in females. Two types are distinguished: sporadic (nonhereditary) and familial (hereditary). The most common location is the union of the upper third of the thyroid lobe to the middle third, the area with the highest concentration of C cells. Objective: To present the case of a male patient operated on for medullary thyroid carcinoma, of sporadic type, in the Cienfuegos Province. Clinical case: A 60-year-old male patient of white skin attended consultation. He reported an increase in neck volume accompanied by dysphonia and dysphagia for solid food. The physical examination revealed the presence of the thyroid nodule. Ultrasound was performed, which confirmed the presence of a nodule in the right lobe of the thyroid. Fine needle aspiration biopsy reported the nodule as suspicious for malignancy. A total thyroidectomy was performed, after which, paraffin biopsy of the specimen permitted to report a medullary carcinoma of the thyroid. At present, he has been operating for six months, with favorable evolution. Conclusions: Medullary thyroid carcinoma is a rare and aggressive entity, more frequent in patients over 45 years of age, whose treatment of choice is surgery(AU)

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

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 (AIFM3p = 0.01 and DLK1p = 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.

Comparison of 18F-NaF PET/CT with Other Imaging Methods in the Detection of Bone Metastases in Patients with Medullary Thyroid Cancer: a Report of a Series of 31 Cases.

PURPOSE: To compare the 18F-NaF PET/CT studies (18F-NaF) with other imaging methods in the detection of skeletal metastases (SM) in patients with medullary thyroid cancer (MTC). METHODS: We retrospectively analyzed 31 patients with MTC who performed 18F-NaF to assess SM. The results of the 18F-NaF were compared with other imaging methods performed for metastasis detection: 99Tc-MDP bone scan (BS), magnetic resonance imaging (MRI), contrast-enhanced CT (CT), and 68Ga-Dotatate and 18F-FDG PET/CT studies. A qualitative analysis comparing the 18F-NaF findings with the ones of the other methods was performed, and the results were classified as superior (>), equal (=), and inferior (<). RESULTS: Eleven patients had no bone metastases detected on any of the imaging methods used. Twenty patients presented SM depicted on 18F-NaF. Of these 20 patients, 12 performed bone scan (in 9 18F-NaF > BS and in 3 18F-NaF = BS), 1 performed 18F-FDG (18F-NaF > 18F-FDG), 4 performed 68Ga-Dotatate (in 2 18F-NaF > 68Ga-Dotatate and in 2 18F-NaF = 68Ga-Dotatate), 20 performed CT of at least one body segment (in 15 18F-NaF = CT and in 5 18F-NaF > CT), and 16 performed MRI of at least one body segment, and in all of them, the 18F-NaF was equal to the MRI. Beside this, the 18F-NaF detected SM in body segments not routinely scanned in MRI and CT. CONCLUSION: In patients with MTC, the 18F-NaF seems to be equal or superior to other imaging modalities in the detection of SM and allows the analysis of the whole skeletal in a single study.

The tissue expression pattern of CA 19.9 is associated with oncological features in medullary thyroid carcinoma.

PURPOSE: Elevated serum levels of carbohydrate antigen 19.9 (CA19.9), a well-established tumor marker in pancreatic neoplasms, has been proposed as a prognostic marker of tumor aggressiveness in medullary thyroid carcinoma (MTC). A hypothesis of C-cell dedifferentiation has been raised. Here, we evaluated the expression of CA19.9 and CD133, a stem cell marker, in MTC tissues. METHODS: MTC samples from patients attending a university-based hospital were evaluated for CA19.9 and CD133 expression by immunohistochemistry. Clinical data were retrieved from medical records. RESULTS: Tumor specimens from 70 MTC patients (57.1% hereditary) were evaluated. The age at diagnosis was 36.1 ± 16.3 years, and 58.6% were female; 53% of patients had cervical and 20% distant metastases. CA19.9 staining was detected in 87% of the samples, but no association was observed with biochemical markers, tumor size, local or distant metastases (All P > 0.05). Remarkable, CA19.9 expression was higher in the metastasis than in primary tumor samples (P = 0.0002). CD133 was expressed in 90.5% samples, but no correlation was found with CA19.9. Interestingly, we identified three distinct expression patterns to CA19.9: individual, focal, and diffuse cells. Sporadic MTC was associated with the individual cell pattern (70.6%), while the hereditary form with the focal expression pattern (63.9%; P = 0.04). Remarkably, the diffuse pattern was associated with larger tumor size and distant metastases (P = 0.032). CONCLUSIONS: The majority of samples stained for CA19.9, suggesting it is an MTC cell-intrinsic feature. Three distinct expression patterns were identified, which were associated with the hereditary or sporadic form, larger tumor size, and presence of metastases.

A novel combined transoral and transcervical surgical approach for recurrent metastatic medullary thyroid cancer to the parapharyngeal space.

Medullary thyroid cancer (MTC) represents less than 1% of all thyroid cancers. Complete surgical resection remains the mainstay of treatment for locoregional disease. Unfortunately, patients with recurrence may present with metastasis to challenging anatomic locations. We describe the first case of a recurrent MTC metastatic to the parapharyngeal space (PPS) that was managed using a combined transoral robotic surgery (TORS) and transcervical (TC) approach. We review the presentation, natural history, diagnosis and management of recurrent MTC, and describe a novel combined TORS-TC surgical approach for the treatment of PPS metastasis. A 66-year-old male with history of MTC treated with total thyroidectomy in 2000 and a liver resection in 2011 for metastatic MTC was referred to our Head and Neck Surgery Clinic in October 2016 due to increased calcitonin and CEA levels. Exam was significant for mild right tonsillar/pharyngeal bulging and induration. Imaging with PET-CT and MRI showed an enlarging ovoid mass centered within the right PPS without the presence of another systemic metastasis. FNA was consistent with MTC. The patient was taken to the operating room for a combined TORS-TC approach. Final pathology was consistent with metastatic MTC. Until recently, PPS tumors have been managed using highly morbid and cosmetically disfiguring open surgical approach. TORS provides a safe and effective alternative.

CA19-9 as a Predictor of Worse Clinical Outcome in Medullary Thyroid Carcinoma.

OBJECTIVE: Medullary thyroid carcinoma (MTC) is a rare disease, and its classic tumor marker is calcitonin. However, recently, very aggressive cases have been reported to also secrete carbohydrate antigen 19-9 (CA19-9), and its role as a marker of worse prognosis has been questioned. The aim of this study was to analyze the relationship between CA19-9 serum levels and MTC outcomes. METHODS: We retrospectively reviewed 122 MTC patients followed in a tertiary cancer center from 1985 to 2017. Clinical-pathologic characteristics, therapeutic approaches, and outcomes were recorded and CA19-9 was collected. RESULTS: Of the 122 patients included in the study, 48 had distant metastases, and at the end of follow-up 18.1% had structural persistent disease and 32.7% had progressive disease. CA19-9 was significantly higher in those who had disease progression than in those who had not (21.4 [14.3-110.9] vs. 7.27 [0.6-44.75] U/mL, p = 0.01) and was also higher in patients who died from MTC (18.4 [14.3-110.9] vs. 7.59 [0.6-67.8] U/mL, p < 0.001). Furthermore, using a ROC curve analysis, the cutoff point for CA19-9 in MTC patients was lower than that observed in pancreatic tumors. CONCLUSION: CA19-9 might have a role as a prognostic factor in addition to calcitonin and carcinoembryonic antigen in metastatic MTC.

[Routine serum calcitonin measurement in thyroid nodules]. / Medición rutinaria de calcitonina sérica en nódulos tiroideos.

There is much controversy about the benefits of the use of serum calcitonin (CT) in the initial evaluation of patients with thyroid nodules. The objective of the study was to early identify medullary thyroid carcinoma (MTC) through the routine measurement of CT in thyroid nodular pathology in a large cohort of patients from Buenos Aires, Argentina. Consecutive patients with nodular thyroid disease (n=1017) were studied. CT was measured by chemiluminescence, normal value: up to 18 pg/ml in men and 12 pg/ml in women. In two patients, hypercalcitoninemia was confirmed in repeated measurements. Fine needle aspiration with CT measurement in the needle wash fluid identified MTC in nodules with citology abnormalities. The genetic study was positive in one patient (mutation exon 14, Val804Met, MTC familiar). The other presented a polymorphism (exon 13 L769L heterozygous - exon 15 S904S heterozygous). In both cases, CT was normalized 3 months after surgery and remained normal after 6 years of follow-up. The routine measurement of CT in thyroid nodular pathology was useful to detect two cases of MTC, one of them sporadic and the other familiar in this cohort. The prevalence of MTC was 0.2%.

Existe mucha controversia sobre los beneficios de la medición de la calcitonina sérica (CT) durante la evaluación inicial de pacientes con nódulos tiroideos. El objetivo del estudio fue evaluar la identificación temprana del carcinoma medular de tiroides (CMT) a través de la medición rutinaria de CT sérica en una cohorte de Buenos Aires, Argentina. Se estudiaron consecutivamente a los pacientes con enfermedad nodular de la tiroides (n=1017). La CT se midió por quimioluminiscencia (valor normal: hasta 18 pg/ml en hombres y 12 pg/ml en mujeres). En dos pacientes, la hipercalcitoninemia se confirmó en mediciones repetidas. La aspiración con aguja fina con medición de CT en el líquido obtenido identificó la presencia del CMT. El estudio genético fue positivo en uno (mutación exón 14, Val804Met, CMT familiar). El otro presentó un polimorfismo (heterocigoto exón 13 L769L - heterocigoto exón 15 S904S). En ambos casos, la CT se normalizó 3 meses después de la cirugía y se mantuvo en valores normales después de 6 años de seguimiento. La medición rutinaria de la CT en nódulos tiroideos fue útil para detectar dos casos de CMT, uno de ellos esporádico y el otro familiar en la cohorte seguida. La prevalencia de CMT fue de 0.2%.

Medición rutinaria de calcitonina sérica en nódulos tiroideos / Routine serum calcitonin measurement in thyroid nodules

Existe mucha controversia sobre los beneficios de la medición de la calcitonina sérica (CT) durante la evaluación inicial de pacientes con nódulos tiroideos. El objetivo del estudio fue evaluar la identificación temprana del carcinoma medular de tiroides (CMT) a través de la medición rutinaria de CT sérica en una cohorte de Buenos Aires, Argentina. Se estudiaron consecutivamente a los pacientes con enfermedad nodular de la tiroides (n=1017). La CT se midió por quimioluminiscencia (valor normal: hasta 18 pg/ml en hombres y 12 pg/ml en mujeres). En dos pacientes, la hipercalcitoninemia se confirmó en mediciones repetidas. La aspiración con aguja fina con medición de CT en el líquido obtenido identificó la presencia del CMT. El estudio genético fue positivo en uno (mutación exón 14, Val804Met, CMT familiar). El otro presentó un polimorfismo (heterocigoto exón 13 L769L - heterocigoto exón 15 S904S). En ambos casos, la CT se normalizó 3 meses después de la cirugía y se mantuvo en valores normales después de 6 años de seguimiento. La medición rutinaria de la CT en nódulos tiroideos fue útil para detectar dos casos de CMT, uno de ellos esporádico y el otro familiar en la cohorte seguida. La prevalencia de CMT fue de 0.2%.

There is much controversy about the benefits of the use of serum calcitonin (CT) in the initial evaluation of patients with thyroid nodules. The objective of the study was to early identify medullary thyroid carcinoma (MTC) through the routine measurement of CT in thyroid nodular pathology in a large cohort of patients from Buenos Aires, Argentina. Consecutive patients with nodular thyroid disease (n=1017) were studied. CT was measured by chemiluminescence, normal value: up to 18 pg/ml in men and 12 pg/ml in women. In two patients, hypercalcitoninemia was confirmed in repeated measurements. Fine needle aspiration with CT measurement in the needle wash fluid identified MTC in nodules with citology abnormalities. The genetic study was positive in one patient (mutation exon 14, Val804Met, MTC familiar). The other presented a polymorphism (exon 13 L769L heterozygous - exon 15 S904S heterozygous). In both cases, CT was normalized 3 months after surgery and remained normal after 6 years of follow-up. The routine measurement of CT in thyroid nodular pathology was useful to detect two cases of MTC, one of them sporadic and the other familiar in this cohort. The prevalence of MTC was 0.2%.

Retroposed copies of RET gene: a somatically acquired event in medullary thyroid carcinoma.

BACKGROUND: Different pathogenic germline mutations in the RET oncogene are identified in MEN 2, a hereditary syndrome characterized by medullary thyroid carcinoma (MTC) and other endocrine tumors. Although genetic predisposition is recognized, not all RET mutation carriers will develop the disease during their lifetime or, likewise, RET mutation carriers belonging to the same family may present clinical heterogeneity. It has been suggested that a single germline mutation might not be sufficient for development of MEN 2-associated tumors and a somatic bi-allelic alteration might be required. Here we investigated the presence of somatic second hit mutation in the RET gene in MTC. METHODS: We integrated Multiplex Ligation-dependent Probe Amplification (MLPA) and whole exome sequencing (WES) to search for copy number alteration (CNA) in the RET gene in MTC samples and medullary thyroid cell lines (TT and MZ-CR-1). We next found reads spanning exon-exon boundaries on RET, an indicative of retrocopy. We subsequently searched for RET retrocopies in the human reference genome (GRCh37) and in the 1000 Genomes Project data, by looking for reads reporting joined exons in the RET locus or distinct genomic regions. To determine RET retrocopy specificity and recurrence, DNA isolated from sporadic and MEN 2-associated MTC (n = 37), peripheral blood (n = 3) and papillary thyroid carcinomas with RET fusion (n = 10) samples were tested using PCR-sequencing methodology. RESULTS: Through MLPA we have found evidence of CNA in the RET gene in MTC samples and MTC cell lines. WES analysis reinforced the presence of the CNA and hinted for a retroposed copy of RET not found in the human reference genome and 1.000 Genomes Project. Extended analysis confirmed the presence of a somatic MTC-related retrocopy of RET in both sporadic and hereditary tumors. We further unveiled a recurrent (28%) novel point mutation (p.G548 V) found exclusively in the retrocopy of RET. The mutation was also found in cDNA of mutated samples, suggesting it might be functional. CONCLUSION: We here report a somatic specific RET retroposed copy in MTC samples and cell lines. Our results support the idea that generation of retrocopies in somatic cells is likely to contribute to MTC genesis and progression.

Quality of Life and Coping in Multiple Endocrine Neoplasia Type 2.

Scarce data are available on the quality of life and psychosocial distress of patients with multiple endocrine neoplasia type 2 (MEN2), a genetic cancer syndrome caused by RET germline mutations. Carriers of RET mutations can face several challenges, including fear for the future, guilt for transmission of a germline mutation to an offspring, side effects of cancer treatment, coping behaviors in the face of a chronic and frequently incurable cancer, and difficulties in access to adequate health care. We have addressed the effects of genetic testing on the quality of life of patients with MEN2 and the lifelong physical and psychosocial challenges experienced by these patients. We have also suggested strategies to minimize the burden of living with this chronic condition and the perspectives on future studies to improve the health-related quality of life of the patients.

Genotype and phenotype landscape of MEN2 in 554 medullary thyroid cancer patients: the BrasMEN study.

Multiple endocrine neoplasia type 2 (MEN2) is an autosomal dominant genetic disease caused by RET gene germline mutations that is characterized by medullary thyroid carcinoma (MTC) associated with other endocrine tumors. Several reports have demonstrated that the RET mutation profile may vary according to the geographical area. In this study, we collected clinical and molecular data from 554 patients with surgically confirmed MTC from 176 families with MEN2 in 18 different Brazilian centers to compare the type and prevalence of RET mutations with those from other countries. The most frequent mutations, classified by the number of families affected, occur in codon 634, exon 11 (76 families), followed by codon 918, exon 16 (34 families: 26 with M918T and 8 with M918V) and codon 804, exon 14 (22 families: 15 with V804M and 7 with V804L). When compared with other major published series from Europe, there are several similarities and some differences. While the mutations in codons C618, C620, C630, E768 and S891 present a similar prevalence, some mutations have a lower prevalence in Brazil, and others are found mainly in Brazil (G533C and M918V). These results reflect the singular proportion of European, Amerindian and African ancestries in the Brazilian mosaic genome.

A pioneering RET genetic screening study in the State of Ceará, Brazil, evaluating patients with medullary thyroid cancer and at-risk relatives: experience with 247 individuals

ABSTRACT Objective: Initial diagnosis of medullary thyroid carcinoma (MTC) is frequently associated with advanced stages and a poor prognosis. Thus, the need for earlier diagnoses and detection in relatives at risk for the disease has led to increased use of RET genetic screening. Subjects and methods: We performed RET screening in 247 subjects who were referred to the Brazilian Research Consortium for Multiple Endocrine Neoplasia (BRASMEN) Center in the State of Ceará. Direct genetic sequencing was used to analyze exons 8, 10, 11, and 13-16 in MTC index cases and specific exons in at risk relatives. Afterward, clinical follow-up was offered to all the patients with MTC and their affected relatives. Results: RET screening was performed in 60 MTC index patients and 187 at-risk family members. At the initial clinical assessment of the index patients, 54 (90%) were diagnosed with apparently sporadic disease and 6 (10%) diagnosed with hereditary disease. After RET screening, we found that 31 (52%) index patients had sporadic disease, and 29 (48%) had hereditary disease. Regarding at-risk relatives, 73/187 were mutation carriers. Mutations in RET codon 804 and the rare p.M918V mutation were the most prevalent. Conclusions: Performing RET screening in Ceará allowed us to identify a different mutation profile in this region compared with other areas. RET screening also enabled the diagnosis of a significant number of hereditary MTC patients who were initially classified as sporadic disease patients and benefited their relatives, who were unaware of the risks and the consequences of bearing a RET mutation.

Síndromes de neoplasia endocrina múltiple: revisión radiológica / Multiple Endocrine Neoplasia Syndromes: Radiological Review

Los síndromes de neoplasia endocrina múltiple (MEN), incluyen una serie de enfermedades con alteraciones genéticas que se caracterizan por la presencia de tumores que afectan a dos o más glándulas endocrinas. Son síndromes con una herencia autosómica dominante e incluyen tres patrones: MEN 1 (síndrome de Wermer), MEN 2 (que incluye MEN 2A o síndrome de Sipple y MEN 2B o síndrome de Wagenmann-Froboese) y MEN 4. Los adenomas paratiroideos y el carcinoma medular tiroideo, son los tumores más frecuentes del MEN tipo 1 y 2 respectivamente. Esos síndromes son más comunes en pacientes jóvenes, con patología de afectación bilateral, múltiple o multifocal y, sobre todo, en pacientes con antecedentes familiares. Es necesario el trabajo en equipo de endocrinólogos, cirujanos, oncólogos y radiólogos para optimizar el tratamiento de esos pacientes.

Multiple endocrine neoplasia (MEN) encompasses a serial of familial genetically disorders in wich tumors simultaneusly occur in two or more endocrine organs. MEN síndromes are autosomal-dominant disorders categorized into three main patterns: MEN 1 (Wermer syndrome), MEN 2 (includes MEN 2A o Sipple syndrome and MEN 2B o Wagenmann-Froboese syndrome) and MEN 4. Parathyroid adenomas and medullary thyroid carcinoma are the most frecuent tumors in MEN 1 and MEN 2 respectively. These entities will be suspected in younger patients, bilateral, multiple or multifocal disease and, specially, in patients with family background. Cooperation between endocrinologist, surgeons, oncologists and radiologists is pivotal for optimizing patient treatment.

Medullary thyroid carcinoma - Adverse events during systemic treatment: risk-benefit ratio

ABSTRACT Medullary thyroid carcinoma (MTC) is a rare neuroendocrine tumor originating from parafollicular C cells of the thyroid and associated with mutations in the proto-oncogene REarranged during Transfection (RET). The prognosis of MTC depends on clinical stage, with a 95.6% 10-year survival rate among patients with localized disease and 40% among patients with advanced disease. Standard chemotherapy and radiotherapy have no significant impact on the overall survival of these patients and two tyrosine kinase receptor inhibitors (TKIs), vandetanib and cabozantinib, have been recently approved for the systemic treatment of locally advanced or metastatic MTC. However, since patients with MTC and residual or recurrent disease may have an indolent course with no need for systemic treatment, and since these drugs are highly toxic, it is extremely important to select the patients who will receive these drugs in a correct manner. It is also essential to carefully monitor patients using TKI regarding possible adverse effects, which should be properly managed when occurring.

Carcinoma familiar de tiroides no medular: reporte de un caso clínico y revisión de la literatura / Familial non medullary thyroid carcinoma: report of a case and literature review

El carcinoma tiroideo familiar no medular (CFTNM) representa aproximadamente entre el 3,2% y 9,6% de todos los cánceres de tiroides, y se define por la presencia de cáncer diferenciado de tiroides en 2 o más familiares, en ausencia de otros síndromes familiares conocidos o exposición a radiación. Si bien su fisiopatología es aún incierta, algunos investigadores postulan un patrón de herencia dominante con penetrancia incompleta, no habiendo aún un gen específico responsable. Esta entidad suele presentarse a una menor edad y con características más agresivas que en su forma esporádica. Dado el interés por conocer la presentación de esta enfermedad y las recomendaciones para su manejo, se presenta el caso de una paciente diagnosticada con cáncer papilar de tiroides con el antecedente de 4 familiares con la misma patología. Actualmente el tamizaje mediante ecografía cervical y biopsia por punción aspiración con aguja fina de los nódulos tiroideos es el examen de elección ante la presencia del antecedente de CFTNM, ya que aún no hay estudios genéticos disponibles. La tiroidectomía total más disección ganglionar es el tratamiento de elección. Debido al comportamiento más agresivo y peor pronóstico del CFTNM, es necesaria un alto índice de sospecha y una investigación completa en la presencia de un componente familiar.

The non-familial medullary thyroid carcinoma (FNMTC) represents approximately between 3.2 and 9.6% of all thyroid cancers, and is defined by the presence of differentiated thyroid cancer in 2 or more families in the absence of other known familial syndromes or radiation exposure. Although the pathophysiology is still uncertain, some investigators posit a dominant pattern of inheritance with incomplete penetrance, but still there is no specific gene responsible. It occurs at a younger age and with more aggressive characteristics than the sporadic form. Because of the interest in learning about the presentation of this disease and its recommendations, we present the case of a patient diagnosed with papillary thyroid cancer with a history of 4 family with the same pathology. Actually cervical screening by ultrasound and the fine needle aspiration biopsy (FNAB) of thyroid nodules is the examination of choice in the presence of a history of FNMTC, since no genetic studies yet available. Total thyroidectomy with lymph node dissection is the treatment of choice. Because the more aggressive behavior and poor prognosis of FNMTC, a high index of suspicion and a full investigation is required in the presence of a familial component.

68Ga-DOTATATE PET/CT in recurrent medullary thyroid carcinoma: a lesion-by-lesion comparison with 111In-octreotide SPECT/CT and conventional imaging.

PURPOSE: The aim of this study was to prospectively compare the detection rate of 68Ga-DOTATATE PET-CT with 111In-octreotide SPECT-CT and conventional imaging (CI) in medullary thyroid carcinoma (MTC) patients with increased calcitonin (Ctn) levels but negative CI after thyroidectomy. METHODS: Fifteen patients with raised Ctn levels and/or CI evidence of recurrence underwent 68Ga-DOTATATE PET-CT, 111In-octreotide SPECT-CT and CI. Histopathology, CI and biochemical/clinical/imaging follow-up were used as the reference standard. PET/CT, SPECT/CT and CI were compared in a lesion-based and organ-based analysis. RESULTS: PET/CT evidenced recurrence in 14 of 15 patients. There were 13 true positive (TP), 1 true negative (TN), 1 false positive (FP) and no false negative (FN) cases, resulting in a sensitivity and accuracy of 100% and 93%. SPECT/CT was positive in 6 of 15 cases. There were 6 TP, 2 TN, 7 FN and no FP cases, resulting in a sensitivity of 46% and accuracy of 53%. CI procedures detected tumor lesions in 14 of 15 patients. There were 13 TP, 1TN, 1 FP and no FN cases with a sensitivity of 100% and accuracy of 93%. A significantly higher number of lesions was detected by PET/CT (112 lesions, p = 0.005) and CI (109 lesions, p = 0.005) in comparison to SPECT/CT (16 lesions). There was no significant difference between PET/CT and CI for the total number of detected lesions (p = 0.734). PET/CT detected more lesions than SPECT/CT regardless of the organ. PET/CT detected more bone lesions but missed some neck nodal metastases evidenced by CI. The number of lesions per region demonstrated by PET/CT and CI were similar in the other sites. CONCLUSION: 68Ga-DOTATATE PET/CT is superior to 111In-octreotide SPECT/CT for the detection of recurrent MTC demonstrating a significantly higher number of lesions. 68Ga-DOTATATE PET/CT showed a superior detection rate compared to CI in demonstrating bone metastases.