RESUMEN
Medullary thyroid carcinoma (MTC) accounts for only 3% of all thyroid carcinomas: 75% as sporadic MTC (sMTC) and 25% as hereditary MTC (hMTC) in the context of multiple endocrine neoplasia type 2 (MEN2). Early diagnosis is possible by determining the tumour marker calcitonin (Ctn) when clarifying nodular goitre and by detecting the mutation in the proto-oncogene RET in the MEN2 families. If the Ctn level is only slightly elevated, up to 30 pg/ml in women and up to 60 pg/ml in men, follow-up checks are advisable. At higher levels, surgery should be considered; at a level of > 100 pg/ml, surgery is always advisable. The treatment of choice is total thyroidectomy, possibly with central lymphadenectomy. In the early stage, cure is possible with adequate surgery; in the late stage, treatment with tyrosine kinase inhibitors is an option. RET A mutation analysis should be performed on all patients with MTC. During follow-up, a biochemical distinction is made between: healed (Ctn not measurably low), biochemically incomplete (Ctn increased without tumour detection) and structural tumour detection (metastases on imaging). After MTC surgery, the following results should be available for classification in follow-up care: (i) histology, Ctn immunohistology if necessary, (ii) classification according to the pTNM scheme, (iii) the result of the RET analysis for categorisation into the hereditary or sporadic variant and (iiii) the postoperative Ctn value. Tumour progression is determined by assessing the Ctn doubling time and the RECIST criteria on imaging. In most cases, "active surveillance" is possible. In the case of progression and symptoms, the following applies: local (palliative surgery, radiotherapy) before systemic (tyrosine kinase inhibitors).
Asunto(s)
Carcinoma Medular , Neoplasia Endocrina Múltiple Tipo 2a , Proto-Oncogenes Mas , Neoplasias de la Tiroides , Humanos , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/diagnóstico , Neoplasias de la Tiroides/patología , Neoplasias de la Tiroides/terapia , Carcinoma Medular/genética , Carcinoma Medular/congénito , Carcinoma Medular/diagnóstico , Carcinoma Medular/patología , Carcinoma Medular/terapia , Neoplasia Endocrina Múltiple Tipo 2a/genética , Neoplasia Endocrina Múltiple Tipo 2a/diagnóstico , Neoplasia Endocrina Múltiple Tipo 2a/patología , Neoplasia Endocrina Múltiple Tipo 2a/terapia , Proteínas Proto-Oncogénicas c-ret/genética , Tiroidectomía , Mutación , Calcitonina/metabolismo , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Carcinoma Neuroendocrino/genética , Carcinoma Neuroendocrino/diagnóstico , Carcinoma Neuroendocrino/patologíaRESUMEN
Medullary thyroid cancer (MTC) is the most frequent manifestation of multiple endocrine neoplasia type 2 (MEN2) that determines the oncological outcome. Germline mutations in the rearranged during transfection (RET) protooncogene, a tumor suppressor gene on chromosome 10q11.2, were identified 30 years ago as the genetic basis of MEN2 and published in 1993 and 1994. These seminal findings gave rise to the concept of prophylactic thyroidectomy for asymptomatic gene mutation carriers based on a positive RET gene test, which has become the standard of care ever since. Clinical genetic investigations showed genotype-phenotype correlations with respect to the individual gene mutation regarding the penetrance and onset of MTC and to a lesser extent also with respect to the other components of MEN2, pheochromocytoma and primary hyperparathyroidism. From this a clinically relevant risk stratification could be derived. Initially, the optimal timing of prophylactic thyroidectomy was primarily based on the RET genotype alone, which was not sufficient for a precise age recommendation and subsequently required additional consideration of calcitonin serum levels for fine tuning. Calcitonin levels first show the risk of lymph node metastasis when they exceed the upper normal limit of the assay independent of carrier age and RET mutation. Routine calcitonin screening of patients with nodular thyroid disease, screening of families on identification of MEN2 index patients, and pre-emptive thyroidectomy in carriers of gene mutations with normal calcitonin levels have led to the fact that nowadays, 30 years after the first description of the gene mutations causing the disease, the life-threatening hereditary MTC has become curable: a shining example for the success of translational transnational medical research for the benefit of patients.
Asunto(s)
Neoplasia Endocrina Múltiple Tipo 2a , Proteínas Proto-Oncogénicas c-ret , Neoplasias de la Tiroides , Tiroidectomía , Investigación Biomédica Traslacional , Humanos , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/cirugía , Neoplasias de la Tiroides/patología , Neoplasias de la Tiroides/prevención & control , Proteínas Proto-Oncogénicas c-ret/genética , Neoplasia Endocrina Múltiple Tipo 2a/genética , Neoplasia Endocrina Múltiple Tipo 2a/cirugía , Neoplasia Endocrina Múltiple Tipo 2a/patología , Carcinoma Medular/genética , Carcinoma Medular/cirugía , Carcinoma Medular/congénito , Carcinoma Medular/patología , Procedimientos Quirúrgicos Profilácticos , Carcinoma Neuroendocrino/genéticaRESUMEN
BACKGROUND: In clinical practice, genetic testing has become standard for many cancerous diseases. While a diagnosis of a single hereditary syndrome is not uncommon, the coexistence of two genetic diseases, even with partially common symptoms, remains unusual. Therefore, targeted next-generation sequencing (NGS), along with genetic consultation and imaging studies, is essential for every patient with confirmed paraganglioma. In this report, we present two sisters diagnosed with multiple endocrine neoplasia type 2 (MEN2A) and familial paraganglioma syndrome type 1 (FPGL1). CASE PRESENTATION: After presenting to the clinic with neck tumors persisting for several months, both patients underwent tumor removal procedures following imaging and laboratory studies. Pathological reports confirmed the diagnosis of paragangliomas. Subsequently, genetic testing, including NGS, revealed a mutation in the rearranged during transfection (RET) gene: the heterozygous change (c.2410G > A), (p.Val804Met), and a variant of the succinate dehydrogenase complex subunit D (SDHD) gene: (c.64 C > T), (p.Arg22Ter). Subsequently, thyroidectomy procedures were scheduled in both cases. CONCLUSION: To the best of our knowledge, this is the first report presenting these two mutations in two related patients, resulting in distinctive genetic syndromes with similar manifestations. This underscores that although infrequent, multiple hereditary disorders may co-occur in the same individual.
Asunto(s)
Neoplasia Endocrina Múltiple Tipo 2a , Hermanos , Succinato Deshidrogenasa , Humanos , Femenino , Neoplasia Endocrina Múltiple Tipo 2a/genética , Neoplasia Endocrina Múltiple Tipo 2a/cirugía , Neoplasia Endocrina Múltiple Tipo 2a/patología , Neoplasia Endocrina Múltiple Tipo 2a/diagnóstico , Succinato Deshidrogenasa/genética , Adulto , Proteínas Proto-Oncogénicas c-ret/genética , Pronóstico , Tiroidectomía , Mutación , Pruebas Genéticas , Linaje , Paraganglioma/genética , Paraganglioma/cirugía , Paraganglioma/diagnóstico , Paraganglioma/patología , Secuenciación de Nucleótidos de Alto RendimientoRESUMEN
CONTEXT: Sporadic medullary thyroid carcinoma (sMTC) rarely occurs in childhood and no studies have specifically focused on this entity. OBJECTIVE: 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). METHODS: Retrospective study of 144 patients diagnosed with MTC between 1961 and 2019 at an age ≤â¯21 years and evaluated at a tertiary referral center. RESULTS: In contrast to hMTC (n = 124/144, 86%), patients with sMTC (n = 20/144, 14%) are older (P < .0001), have larger tumors (P < .0001), a higher initial stage grouping (P = .001) and have more structural disease (P = .0045) and distant metastases (DM) (P = .00084) at last follow-up, but are not more likely to die from MTC (P = .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 = .27), presence of DM at diagnosis (P = 1.0), disease status at last follow-up (P = .13), overall survival (P = .57), or disease-specific survival (P = .87). Of the 12 sMTC tumors that underwent somatic testing, 11 (91%) had an identifiable alteration: 10 RET gene alterations and 1 ALK fusion. CONCLUSION: 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.
Asunto(s)
Carcinoma Neuroendocrino , Neoplasias de la Tiroides , Humanos , Neoplasias de la Tiroides/patología , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/mortalidad , Neoplasias de la Tiroides/epidemiología , Neoplasias de la Tiroides/diagnóstico , Masculino , Femenino , Niño , Estudios Retrospectivos , Adolescente , Adulto Joven , Carcinoma Neuroendocrino/patología , Carcinoma Neuroendocrino/genética , Carcinoma Neuroendocrino/mortalidad , Preescolar , Adulto , Estudios de Seguimiento , Pronóstico , Neoplasia Endocrina Múltiple Tipo 2a/genética , Neoplasia Endocrina Múltiple Tipo 2a/patología , Carcinoma Medular/genética , Carcinoma Medular/patología , Carcinoma Medular/mortalidad , Carcinoma Medular/congénito , Carcinoma Medular/diagnóstico , LactanteRESUMEN
Genetic testing for germline RET pathogenic variants, which cause the Multiple Endocrine Neoplasia Type 2 (MEN2) syndrome, has become crucial in managing patients with medullary thyroid carcinoma (MTC). Classically, RET heterozygous missense pathogenic variants are transmitted in a Mendelian autosomal dominant pattern, of which germline/gonadal mosaicism has never been reported. We report the novel occurrence of a MEN2A patient's family in which the siblings inherited three different RET 634 genotypes: wild type (p.Cys634), p.Cys634Gly or p.Cys634Arg heterozygous pathogenic variants. We hypothesized that germline/gonadal mosaicism, derived from an inherited + early somatic mutation in the mother or a double de novo mutation during maternal embryogenesis, led to this rare event in the RET gene. Exome analysis of the proband's deceased mother's paraffin-embedded thyroid tissue confirmed the three nucleotides in the same 634 codon position. For the first time, we describe germline/gonadal mosaicism in RET, generating a second pathogenic amino acid change in the same codon causing MEN2A. Our finding shows that RET parental mosaicism, confirmed by somatic exome sequencing, might explain discrepant genotype cases in siblings with inherited cancers.
Asunto(s)
Mutación de Línea Germinal , Mosaicismo , Neoplasia Endocrina Múltiple Tipo 2a , Linaje , Proteínas Proto-Oncogénicas c-ret , Humanos , Neoplasia Endocrina Múltiple Tipo 2a/genética , Neoplasia Endocrina Múltiple Tipo 2a/patología , Proteínas Proto-Oncogénicas c-ret/genética , Mutación de Línea Germinal/genética , Femenino , Masculino , Adulto , Sustitución de Aminoácidos , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/patología , Genotipo , Secuenciación del ExomaRESUMEN
PURPOSE: Multiple endocrine neoplasia Type 2A (MEN2A) can occur with Hirschsprung disease (HD) due to mutation in the RET proto-oncogene, with the majority developing medullary thyroid carcinoma (MTC). Given the comorbidity, many parents have contacted us to share concerns and unfortunate experiences about the prevalence rates of MEN2A/MTC in patients with HD. The aim is to determine the prevalence rate of patients with HD and MEN2A or medullary thyroid carcinoma, respectively. METHODS: This is a cross-sectional study of the COSMOS database from January 01, 2017, to March 08, 2023. The database was searched for patients diagnosed with MEN2A, MTC, and HD. IRB exemption was provided (COMIRB #23-0526). RESULTS: The database contained 183,993,122 patients from 198 contributing organizations. The prevalence of HD and MEN2A was 0.00002%, and for HD and MTC was 0.000009%. One in 66 patients (1.5%) with MEN2A also had HD. One in 319 patients (0.3%) in the HD group had MEN2A. One in 839 patients (0.1%) within the HD population had MTC. CONCLUSION: The prevalence of MTC and HD or MEN2A and HD in the study population was low. Considering that almost all MEN2A patients have a positive family history, this data does not support the general genetic testing of HD patients.
Asunto(s)
Enfermedad de Hirschsprung , Neoplasia Endocrina Múltiple Tipo 2a , Neoplasias de la Tiroides , Humanos , Neoplasia Endocrina Múltiple Tipo 2a/genética , Neoplasia Endocrina Múltiple Tipo 2a/patología , Enfermedad de Hirschsprung/epidemiología , Enfermedad de Hirschsprung/genética , Incidencia , Estudios Transversales , Proteínas Proto-Oncogénicas c-ret/genética , Neoplasias de la Tiroides/epidemiología , Neoplasias de la Tiroides/genéticaRESUMEN
CONTEXT: Early genetic association studies yielded too high risk estimates for multiple endocrine neoplasia (MEN2A), suggesting a need for extended surgery. OBJECTIVE: The objective was to delineate temporal changes in MEN2A presentation by birth cohort analyses. METHODS: Birth cohort analyses (10-year increments; ≤1950 to 2011-2020) of carriers of rearranged during transfection (RET) mutations who underwent surgery for MEN2A. RESULTS: Included in this study were 604 carriers (155 index, 445 nonindex, 4 additional patients), with 237 carriers harboring high-risk mutations, 165 carriers moderate-high risk mutations, and 202 carriers low-moderate risk mutations. With increasing recency of birth cohorts, there was a continual decline in index patients from 41-74% to 0% (P < .001) and of medullary thyroid cancer (MTC) from 96-100% to 0-33% (P < .001). Node metastases diminished from 62-70% to 0% (P ≤ .001; high and low-moderate risk mutations), whereas biochemical cure after thyroidectomy surged from 17-33% to 100% (P ≤ .019; high and low-moderate mutations). Surgical interventions for MEN2A-related tumors were performed increasingly earlier, causing median carrier age to fall: from 51-63 to 3-5 years at thyroidectomy (P < .001); from 46-51 to 24-25 years at first adrenalectomy (P ≤ .013; high and moderate-high risk mutations); and from 43.5-66 to 16.5-32 years at parathyroidectomy. MTC diameters were more effectively decreased from 14-32 to 1-4 mm (P ≤ 002) than pheochromocytoma diameters (nonsignificant). CONCLUSION: These insights into MEN2A presentation, adjusted by birth year, illustrate the shift from reactive to preventative medicine, enabling less extensive risk-reducing surgery.
Asunto(s)
Neoplasias de las Glándulas Suprarrenales , Carcinoma Neuroendocrino , Neoplasia Endocrina Múltiple Tipo 2a , Neoplasias de la Tiroides , Humanos , Neoplasia Endocrina Múltiple Tipo 2a/genética , Neoplasia Endocrina Múltiple Tipo 2a/cirugía , Neoplasia Endocrina Múltiple Tipo 2a/patología , Neoplasias de la Tiroides/diagnóstico , Neoplasias de la Tiroides/epidemiología , Neoplasias de la Tiroides/genética , Neoplasias de las Glándulas Suprarrenales/epidemiología , Neoplasias de las Glándulas Suprarrenales/genética , Neoplasias de las Glándulas Suprarrenales/cirugíaRESUMEN
BACKGROUND: Val804Met RET is one of the most common genetic alterations in Multiple Endocrine Neoplasia 2 and is considered to confer only a moderate risk for familial medullary thyroid carcinoma (MTC). The associated phenotype can however be much more complex in some cases. METHODS: A clinical, genetic, and pathological analysis was conducted on a family cluster of thyroid neoplasms associated with Val804Met RET mutation. RESULTS: All the kindreds who are carriers of the mutated RET received total thyroidectomy + /- VI level dissection. The proband presented with a pT1bN0 MTC, her 29-yo brother showed a concomitant papillary thyroid carcinoma (PTC) and MTC, their father had a pT1a PTC plus a follicular adenoma, while the uncle of the proband showed C-cell hyperplasia. None had clinical or biochemical evidence of parathyroid disorders or pheochromocytoma. CONCLUSIONS: In the presence of Val804Met RET several types of thyroid premalignant and malignant should be screened for, and without limiting to MTC.
Asunto(s)
Neoplasias de las Glándulas Suprarrenales , Neoplasia Endocrina Múltiple Tipo 2a , Neoplasias de la Tiroides , Masculino , Femenino , Humanos , Proteínas Proto-Oncogénicas c-ret/genética , Neoplasia Endocrina Múltiple Tipo 2a/genética , Neoplasia Endocrina Múltiple Tipo 2a/patología , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/patología , Mutación/genéticaRESUMEN
BACKGROUND: Significant genotype-phenotype variability among multiple endocrine neoplasia type 2A patients with a RET V804M mutation has been reported. METHODS: Patients with a RET V804M mutation treated at a single center were identified (January 1996-December 2020). The baseline characteristics, operative details, pathology, biochemical, and long-term data were analyzed. RESULTS: There were 79 patients; none developed pheochromocytoma or hyperparathyroidism or died in the study period. The mean age was 41.5 years (range = 1.0-81.0 years); 46.8% were men. Of 68 surgical patients, 53 (77.9%) underwent total thyroidectomy and 15 (22.1%) underwent total thyroidectomy with central neck dissection with or without lateral neck dissection. Twenty-four patients had elevated preoperative calcitonin, of whom 12 underwent total thyroidectomy (median = 7.5; range = 5.0-237.0 pg/mL), 10 underwent total thyroidectomy + central neck dissection (median = 27.6; range = 5.1-147.0 pg/mL), and 2 underwent total thyroidectomy + central neck dissection + lateral neck dissection (median = 3182.0; range = 361.0-6003.0 pg/mL). Pathology was benign (27.9%), papillary thyroid cancer alone (1.5%), C-cell hyperplasia (23.5%), and medullary thyroid cancer (47.1%; median tumor size = 3.0 mm). Three patients had elevated calcitonin postoperatively (median follow-up time = 60.0 months). In adjusted modeling, a preoperative calcitonin >5 pg/mL was associated with having medullary thyroid cancer on final pathology (odds ratio = 13.3; 95% confidence interval, 3.2-56.3; P < .001). CONCLUSION: In this large United States cohort of surgical patients with a RET V804M mutation, most had indolent disease and were without classic multiple endocrine neoplasia type 2A features. Calcitonin >5 pg/mL may serve as a meaningful value to guide surveillance and timing of surgery.
Asunto(s)
Neoplasias de las Glándulas Suprarrenales , Carcinoma Medular , Neoplasia Endocrina Múltiple Tipo 2a , Neoplasias de la Tiroides , Humanos , Neoplasia Endocrina Múltiple Tipo 2a/genética , Neoplasia Endocrina Múltiple Tipo 2a/cirugía , Neoplasia Endocrina Múltiple Tipo 2a/patología , Carcinoma Medular/genética , Carcinoma Medular/cirugía , Carcinoma Medular/patología , Calcitonina , Proteínas Proto-Oncogénicas c-ret/genética , Proto-Oncogenes Mas , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/cirugía , Neoplasias de la Tiroides/patología , Tiroidectomía , Mutación , Neoplasias de las Glándulas Suprarrenales/cirugíaRESUMEN
AIM: To define the role of prophylactic parathyroidectomy in the surgical treatment of medullary thyroid carcinoma (MTC) in multiple endocrine neoplasia type IIa (MEN2A) syndrome through a literature review.
Asunto(s)
Carcinoma Neuroendocrino , Neoplasia Endocrina Múltiple Tipo 2a , Neoplasias de la Tiroides , Humanos , Neoplasia Endocrina Múltiple Tipo 2a/cirugía , Neoplasia Endocrina Múltiple Tipo 2a/patología , Tiroidectomía , Paratiroidectomía , Neoplasias de la Tiroides/cirugíaRESUMEN
The Multiple Endocrine Neoplasia type 2 (MEN2) RET proto-oncogene database, originally published in 2008, is a comprehensive repository of all publicly available RET gene variations associated with MEN2 syndromes. The variant-specific genotype/phenotype information, age of earliest reported medullary thyroid carcinoma (MTC) onset, and relevant references with a brief summary of findings are cataloged. The ACMG/AMP 2015 consensus statement on variant classification was modified specifically for MEN2 syndromes and RET variants using ClinGen sequence variant interpretation working group recommendations and ClinGen expert panel manuscripts, as well as manuscripts from the American Thyroid Association Guidelines Task Force on Medullary Thyroid Carcinoma and other MEN2 RET literature. The classifications for the 166 single unique variants in the MEN2 RET database were reanalyzed using the MEN2 RET specifically modified ACMG/AMP classification guidelines (version 1). Applying these guidelines added two new variant classifications to the database (likely benign and likely pathogenic) and resulted in clinically significant classification changes (e.g., from pathogenic to uncertain) in 15.7% (26/166) of the original variants. Of those clinically significant changes, the highest percentage of changes, 46.2% (12/26), were changes from uncertain to benign or likely benign. The modified ACMG/AMP criteria with MEN2 RET specifications will optimize and standardize RET variant classifications.
Asunto(s)
Carcinoma Medular , Neoplasia Endocrina Múltiple Tipo 2a , Neoplasias de la Tiroides , Humanos , Neoplasia Endocrina Múltiple Tipo 2a/genética , Neoplasia Endocrina Múltiple Tipo 2a/patología , Carcinoma Medular/genética , Proteínas Proto-Oncogénicas c-ret/genética , Síndrome , Neoplasias de la Tiroides/diagnóstico , Neoplasias de la Tiroides/genética , Adenosina MonofosfatoRESUMEN
Precision medicine is a reality in some diseases; it supports the development of accurate and specific diagnostic methods, new drugs and molecules. Our research team in Mexico, made up of clinical and biomedical researchers, has been performing free RET gene mutational diagnosis for medullary thyroid cancer and multiple endocrine neoplasia (MEN) 2 and 3 for 20 years. RET pathogenic variants in the Mexican population are consistent with reported data: most common mutations are 634/NEM2 and 918/NEM3. Currently, new nanobiotechnology methods are being developed for this type of determination in order to obtain faster, simpler, more sensitive and specific results applicable in all types of laboratories.
La medicina de precisión en algunas enfermedades es una realidad; respalda el desarrollo de métodos diagnósticos certeros y específicos, de nuevas drogas y moléculas. Nuestro equipo de investigación en México, conformado por investigadores clínicos y biomédicos, desde hace 20 años realiza de forma gratuita el diagnóstico mutacional del gen RET y su relación con el cáncer medular de tiroides y la neoplasia endocrina múltiple (NEM) 2 y 3. Las variantes patogénicas de RET en la población mexicana coinciden con los datos reportados: la mayoría con 634/NEM2 y 918/NEM3. Actualmente se están desarrollando nuevos métodos de nanobiotecnología para este tipo de determinaciones, de tal forma que puedan obtenerse resultados más rápidos, simples, sensibles y específicos aplicables en todo tipo de laboratorio.
Asunto(s)
Carcinoma Medular , Neoplasia Endocrina Múltiple Tipo 2a , Neoplasias de la Tiroides , Carcinoma Medular/genética , Humanos , México , Neoplasia Endocrina Múltiple Tipo 2a/diagnóstico , Neoplasia Endocrina Múltiple Tipo 2a/genética , Neoplasia Endocrina Múltiple Tipo 2a/patología , Medicina de Precisión , Proteínas Proto-Oncogénicas c-ret/genética , Neoplasias de la Tiroides/patologíaRESUMEN
Medullary thyroid carcinoma (MTC) is an uncommon malignancy of neuroendocrine origin derived from the parafollicular C cells. Although infrequent, the interest in this cancer exceeds its incidence owing to its distinctive features and its characteristic association with other endocrine tumors. Although the majority of MTCs are sporadic, hereditary varieties occur in isolation or as a part of multiple endocrine neoplasia type 2 syndrome (MEN 2). Currently, complete surgical resection of the tumor and nodal metastases with a curative intent remains the mainstay of therapy. The role of adjuvant therapy is limited, although radiotherapy and newer targeted therapies are routinely used for metastatic disease. The lack of consensus in the available guidance regarding the most appropriate diagnostic, therapeutic and follow-up strategies has caused substantial variability in clinical practice. Therefore, this review summarizes the latest available evidence and guidelines on the management of MTC with an emphasis on diagnosis, surgical treatment and follow-up.
Asunto(s)
Carcinoma Medular , Carcinoma Neuroendocrino , Neoplasia Endocrina Múltiple Tipo 2a , Neoplasias de la Tiroides , Carcinoma Medular/diagnóstico , Carcinoma Medular/patología , Carcinoma Medular/terapia , Carcinoma Neuroendocrino/diagnóstico , Carcinoma Neuroendocrino/terapia , Humanos , Neoplasia Endocrina Múltiple Tipo 2a/patología , Neoplasias de la Tiroides/diagnóstico , Neoplasias de la Tiroides/patología , Neoplasias de la Tiroides/terapiaAsunto(s)
Neoplasias de las Glándulas Suprarrenales , Neoplasia Endocrina Múltiple Tipo 2a , Feocromocitoma , Neoplasias de la Tiroides , Neoplasias de las Glándulas Suprarrenales/diagnóstico , Neoplasias de las Glándulas Suprarrenales/patología , Carcinoma Neuroendocrino , Humanos , Neoplasia Endocrina Múltiple Tipo 2a/patología , Feocromocitoma/diagnóstico , Neoplasias de la Tiroides/diagnóstico , Neoplasias de la Tiroides/patología , Neoplasias de la Tiroides/cirugíaRESUMEN
Medullary thyroid cancer (MTC) accounts for only 4% of thyroid carcinomas but 15% of thyroid cancer deaths. MTC is a tumour of the calcitonin secreting parafollicular C cells in the thyroid which can occur sporadically or be hereditary in multiple endocrine neoplasias type 2 syndromes due to germline RET mutations. Sporadic forms of MTC can also be caused by mutations in the RET protooncogene. MTC commonly presents in a late stage, with 70% of patients presenting with local nodal metastasis. Currently, the only curative treatment for MTC is surgical removal. The aim of this paper is to describe the current guidelines and progressions of the surgical management of MTC and to highlight up-and-coming chemotherapies. A database literature review was completed utilizing PubMed to cumulate the extant literature, screening for most recent guidelines and publications regarding the management of MTC. Current guidelines were described by the American Thyroid Association in 2015. Controversial publications continue to present supporting evidence for varying degrees of thyroidectomy and neck dissections. Recently, researchers have been exploring non-surgical options including external beam radiotherapy and multikinase inhibitors such as vandetanib and cabozantinib for the treatment of MTC. Surgical management of MTC remains controversial and varies significantly dependent on the extent of disease. Chemotherapeutic options have undetermined effects on survival to date.
Asunto(s)
Carcinoma Medular , Carcinoma Neuroendocrino , Neoplasia Endocrina Múltiple Tipo 2a , Neoplasias de la Tiroides , Humanos , Carcinoma Medular/genética , Carcinoma Medular/cirugía , Carcinoma Neuroendocrino/genética , Carcinoma Neuroendocrino/cirugía , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/cirugía , Neoplasia Endocrina Múltiple Tipo 2a/genética , Neoplasia Endocrina Múltiple Tipo 2a/patología , Neoplasia Endocrina Múltiple Tipo 2a/cirugía , TiroidectomíaRESUMEN
Multiple endocrine neoplasias are rare hereditary syndromes some of them with malignant potential. Multiple endocrine neoplasia type 2 (MEN 2) is an autosomal dominant hereditary cancer syndrome due to germline variants in the REarranged during Transfection (RET) proto-oncogene. There are two distinct clinical entities: MEN 2A and MEN 2B. MEN 2A is associated with medullary thyroid carcinoma (MTC), phaeochromocytoma, primary hyperparathyroidism, cutaneous lichen amyloidosis and Hirschprung's disease and MEN 2B with MTC, phaeochromocytoma, ganglioneuromatosis of the aerodigestive tract, musculoskeletal and ophthalmologic abnormalities. Germline RET variants causing MEN 2 result in gain-of-function; since the discovery of the genetic variants a thorough search for genotype-phenotype associations began in order to understand the high variability both between families and within family members. These studies have successfully led to improved risk classification of prognosis in relation to the genotype, thus improving the management of the patients by thorough genetic counseling. The present review summarizes the recent developments in the knowledge of these hereditary syndromes as well as the impact on clinical management, including genetic counseling, of both individual patients and families. It furthermore points to future directions of research for better clarification of timing of treatments of the various manifestations of the syndromes in order to improve survival and morbidity in these patients.
Asunto(s)
Neoplasia Endocrina Múltiple Tipo 2a , Neoplasia Endocrina Múltiple Tipo 2b , Proteínas Proto-Oncogénicas c-ret/genética , Carcinoma Neuroendocrino/genética , Carcinoma Neuroendocrino/patología , Neoplasias del Sistema Digestivo/genética , Neoplasias del Sistema Digestivo/patología , Ganglioneuroma/genética , Ganglioneuroma/patología , Asesoramiento Genético , Predisposición Genética a la Enfermedad/genética , Pruebas Genéticas , Genotipo , Mutación de Línea Germinal/genética , Humanos , Hiperparatiroidismo/genética , Hiperparatiroidismo/patología , Neoplasia Endocrina Múltiple Tipo 2a/genética , Neoplasia Endocrina Múltiple Tipo 2a/patología , Neoplasia Endocrina Múltiple Tipo 2a/terapia , Neoplasia Endocrina Múltiple Tipo 2b/genética , Neoplasia Endocrina Múltiple Tipo 2b/patología , Neoplasia Endocrina Múltiple Tipo 2b/terapia , Pronóstico , Factores de Riesgo , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/patología , TiroidectomíaRESUMEN
Thyroid cancer (TC) is the eighth most frequently diagnosed cancer worldwide with a rising incidence in the past 20 years. Surgery is the primary strategy of therapy for patients with medullary TC (MTC) and differentiated TC (DTC). In DTC patients, radioactive iodine (RAI) is administered after thyroidectomy. Neck ultrasound, basal and thyroid-stimulating hormone-stimulated thyroglobulin are generally performed every three to six months for the first year, with subsequent intervals depending on initial risk assessment, for the detection of possible persistent/recurrent disease during the follow up. Distant metastases are present at the diagnosis in â¼5 % of DTC patients; up to 15 % of patients have recurrences during the follow up, with a survival reduction (70 %-50 %) at 10-year. During tumor progression, the iodide uptake capability of DTC cancer cells can be lost, making them refractory to RAI, with a negative impact on the prognosis. Significant advances have been done recently in our understanding of the molecular pathways implicated in the progression of TCs. Several drugs have been developed, which inhibit signaling kinases or oncogenic kinases (BRAFV600E, RET/PTC), such as those associated with Platelet-Derived Growth Factor Receptor and Vascular Endothelial Growth Factor Receptor. Tyrosine kinase receptors are involved in cancer cell proliferation, angiogenesis, and lymphangiogenesis. Several tyrosine kinase inhibitors (TKIs) are emerging as new treatments for DTC, MTC and anaplastic TC (ATC), and can induce a clinical response and stabilize the disease. Lenvatinib and sorafenib reached the approval for RAI-refractory DTC, whereas cabozantinib and vandetanib for MTC. These TKIs extend median progression-free survival, but do not increase the overall survival. Severe side effects and drug resistance can develop in TC patients treated with TKIs. Additional studies are needed to identify a potential effective targeted therapy for aggressive TCs, according to their molecular characterization.
Asunto(s)
Adenocarcinoma Folicular/terapia , Carcinoma Medular/congénito , Neoplasia Endocrina Múltiple Tipo 2a/terapia , Inhibidores de Proteínas Quinasas/uso terapéutico , Cáncer Papilar Tiroideo/terapia , Carcinoma Anaplásico de Tiroides/terapia , Neoplasias de la Tiroides/terapia , Tiroidectomía , Adenocarcinoma Folicular/diagnóstico , Adenocarcinoma Folicular/patología , Antineoplásicos/uso terapéutico , Carcinoma Medular/diagnóstico , Carcinoma Medular/patología , Carcinoma Medular/terapia , Humanos , Radioisótopos de Yodo/uso terapéutico , Neoplasia Endocrina Múltiple Tipo 2a/diagnóstico , Neoplasia Endocrina Múltiple Tipo 2a/patología , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Cáncer Papilar Tiroideo/diagnóstico , Cáncer Papilar Tiroideo/patología , Carcinoma Anaplásico de Tiroides/diagnóstico , Carcinoma Anaplásico de Tiroides/patología , Neoplasias de la Tiroides/diagnóstico , Neoplasias de la Tiroides/patologíaRESUMEN
Targeted drug therapies represent a therapeutic breakthrough in the treatment of human cancer. However, the emergence of acquired resistance inevitably compromises therapeutic drugs. Rearranged during transfection (RET) proto-oncogene, which encodes a receptor tyrosine kinase, is a target for several kinds of human cancer such as thyroid, breast, and colorectal carcinoma. A single mutation L881V at the RET kinase domain was found in familial medullary thyroid carcinoma. Nintedanib can effectively inhibit the RET L881V mutant, whereas its analog compound 1 is unable to combat this mutant. However, the underlying mechanism was still unexplored. Here, molecular dynamics (MD) simulations, binding free energy calculations, and structural analysis were performed to uncover the mechanism of overcoming the resistance of RET L881V mutant to nintedanib. Energetic analysis revealed that the L881V mutant remained sensitive to the treatment of nintedanib, whereas it was insensitive to the compound 1. Structural analysis further showed that the distribution of K758, D892, and N879 network had a detrimental effect on the binding of compound 1 to the L881V mutant. The obtained results may provide insight into the mechanism of overcoming resistance in the RET kinase.
Asunto(s)
Carcinoma Medular/congénito , Resistencia a Antineoplásicos/genética , Neoplasia Endocrina Múltiple Tipo 2a/tratamiento farmacológico , Proteínas Tirosina Quinasas/genética , Proteínas Proto-Oncogénicas c-ret/genética , Neoplasias de la Tiroides/tratamiento farmacológico , Carcinoma Medular/tratamiento farmacológico , Carcinoma Medular/patología , Humanos , Indoles/uso terapéutico , Simulación de Dinámica Molecular , Neoplasia Endocrina Múltiple Tipo 2a/patología , Mutación/genética , Inhibidores de Proteínas Quinasas/uso terapéutico , Neoplasias de la Tiroides/patologíaRESUMEN
RATIONALE: Multiple endocrine neoplasia 2A (MEN2A) is a rare autosomal-dominant genetic syndrome, frequently misdiagnosed or neglected clinically, resulting in delayed therapy to patients. PATIENT CONCERNS: A 47-year-old Chinese male patient underwent laparoscopic right adrenal tumorectomy, and postoperative pathology confirmed the tumor as pheochromocytoma (PHEO). He was readmitted to the department of endocrinology and metabolism due to constant increase in carcinoembryonic antigen (CEA) at 5âmonths after the operation. DIAGNOSIS: The patient was confirmed with medullary thyroid carcinoma (MTC), multiple neck lymph node metastasis, and pituitary microadenoma. The p.Cys611Tyr (c.1832G>A, C611Y) mutation was detected. Therefore, he was diagnosed with MEN2A. INTERVENTIONS: He underwent total thyroidectomy. The gene-sequencing analysis of his family was conducted, and the C611Y mutation was detected in his daughter. OUTCOMES: The level of carcinoembryonic antigen decreased significantly after thyroidectomy in this patient. Long-term follow-up management was conducted. Elevated serum calcitonin and bilateral thyroid nodules were found in his 13-year-old daughter. Thus, MEN2A was highly suspected and she was suggested to undergo total thyroidectomy. CONCLUSION: Patients with MEN2A should be screened regularly and managed by a multidisciplinary team.
Asunto(s)
Neoplasias de las Glándulas Suprarrenales/patología , Antígeno Carcinoembrionario/metabolismo , Neoplasia Endocrina Múltiple Tipo 2a/genética , Feocromocitoma/cirugía , Proteínas Proto-Oncogénicas c-ret/genética , Adolescente , Cuidados Posteriores , Pueblo Asiatico/etnología , Carcinoma Neuroendocrino/complicaciones , Carcinoma Neuroendocrino/diagnóstico , Carcinoma Neuroendocrino/cirugía , Exones , Femenino , Reordenamiento Génico/genética , Humanos , Comunicación Interdisciplinaria , Metástasis Linfática/patología , Masculino , Persona de Mediana Edad , Neoplasia Endocrina Múltiple Tipo 2a/diagnóstico , Neoplasia Endocrina Múltiple Tipo 2a/patología , Mutación , Núcleo Familiar/etnología , Linaje , Neoplasias Hipofisarias/complicaciones , Neoplasias Hipofisarias/diagnóstico , Neoplasias de la Tiroides/complicaciones , Neoplasias de la Tiroides/diagnóstico , Neoplasias de la Tiroides/cirugía , Tiroidectomía/métodos , Resultado del TratamientoRESUMEN
Specific mutations in the RET proto-oncogene are associated with multiple endocrine neoplasia type 2A, a hereditary syndrome characterized by tumorigenesis in multiple glandular elements. In rare instances, MEN2A-associated germline RET mutations have also occurred with non-MEN2A associated cancers. One such germline mutant RET mutation occurred concomitantly in a young adult diagnosed with alveolar rhabdomyosarcoma, a pediatric and young adult soft-tissue cancer with a generally poor prognosis. Although tumor tissue samples were initially unable to provide a viable cell culture for study, tumor tissues were sequenced for molecular characteristics. Through a hierarchical clustering approach, the index case sample was matched to several genetically similar cell models, which were transformed to express the same mutant RET as the index case and used to explore potential therapeutic options for mutant RET-bearing alveolar rhabdomyosarcoma. We also determined whether the RET mutation associated with the index case caused synthetic lethality to select clinical agents. From our investigation, we did not identify synthetic lethality associated with the expression of that patient's RET variant, and overall we did not find experimental evidence for the role of RET in rhabdomyosarcoma progression.