RESUMO
OBJECTIVE: Ectopic Cushing's syndrome (ECS) induced by medullary thyroid cancer (MTC) is rare, and data on clinical characteristics, treatment and outcome are limited. DESIGN: Retrospective cohort study in three German and one Swiss referral centres. PATIENTS: Eleven patients with MTC and occurrence of ECS and 22 matched MTC patients without ECS were included. MEASUREMENTS: The primary endpoint of this study was the overall survival (OS) in MTC patients with ECS versus 1:2 matched MTC patients without ECS. RESULTS: The median age at diagnosis of ECS was 59 years (range: 35-81) and the median time between initial diagnosis of MTC and diagnosis of ECS was 29 months (range: 0-193). Median serum morning cortisol was 49 µg/dl (range: 17-141, normal range: 6.2-18). Eight (73%) patients received treatment for ECS. Treatment of ECS consisted of bilateral adrenalectomy (BADX) in four (36%) patients and adrenostatic treatment in eight (73%) patients. One patient received treatment with multityrosine kinase inhibitor (MKI) to control hypercortisolism. All patients experienced complete resolution of symptoms of Cushing's syndrome and biochemical control of hypercortisolism. Patients with ECS showed a shorter median OS of 87 months (95% confidence interval [95% CI]: 64-111) than matched controls (190 months, 95% CI: 95-285). Of the nine deaths, four were related to progressive disease (PD). Four patients showed PD as well as complications and comorbidities of hypercortisolism before death. CONCLUSION: This study shows that ECS occurs in advanced stage MTC and is associated with a poor prognosis. Adrenostatic treatment and BADX were effective systemic treatment options in patients with MTC and ECS to control their hypercortisolism. MKI treatment achieved complete remission of hypercortisolism and sustained tumour control in one treated case.
Assuntos
Carcinoma Neuroendócrino , Síndrome de Cushing , Neoplasias da Glândula Tireoide , Carcinoma Neuroendócrino/complicações , Criança , Pré-Escolar , Síndrome de Cushing/diagnóstico , Humanos , Estudos Retrospectivos , Neoplasias da Glândula Tireoide/complicaçõesRESUMO
OBJECTIVES: Procalcitonin (PCT) has been suggested as a tumor marker in patients with medullary thyroid carcinoma (MTC). Clinical application data in long term follow-up are missing. METHODS: 210 serum samples of 169 consecutive patients with MTC (92 sporadic, 77 hereditary, 158 postoperative follow-up, 11 preoperative) were collected between 2018 and 2020. Postoperative patients were stratified into three groups according to their disease status at the end of follow-up: cured (n=51, calcitonin (CT) levels < limit of quantitation), minimal residual disease (n=55, detectable CT and no metastases provable by imaging methods), metastatic disease (n=52). In five patients CT and PCT were measured while on therapy with tyrosine kinase inhibitors (TKI). CT was analyzed by the Roche ECLIA, PCT by three assays from Roche, PES, Abbott. RESULTS: The mean ± SD values seen with the three PCT assays in the MTC response groups, cured: <0.06, 0.016 ± 0.007, 0.014 ± 0.007 ng/mL, minimal residual disease: 0.511 ± 0.800, 0.389 ± 0.687, 0.341 ± 0.614 ng/mL, metastatic disease 109 ± 202, 60.4 ± 110, 63.3 ± 115 ng/mL correlate well with the CT results in these groups: cured <1.0 pg/mL, minimal residual disease 91.3 ± 121.5 pg/mL, metastatic disease 14,489 ± 30,772 pg/mL. There was a significant correlation (p<0.001) between the three PCT assays (Roche/PES r=0.970, Roche/Abbott r=0.976, Abbott/PES r=0.995). In the course of treatment with TKI both CT and PCT reflected clinical state. Preoperative PCT in hereditary MTC has the same diagnostic validity than CT. CONCLUSIONS: PCT measured with three different immunoassays is as good as the standard tumor marker CT in the follow-up of MTC but has a superior analytical stability.
Assuntos
Carcinoma Neuroendócrino , Neoplasias da Glândula Tireoide , Biomarcadores Tumorais , Carcinoma Neuroendócrino/diagnóstico , Seguimentos , Humanos , Pró-Calcitonina , Neoplasias da Glândula Tireoide/patologiaRESUMO
The aim of this study was to investigate in a longitudinal approach whether levothyroxine (LT4) substitution has a different impact on quality of life (QoL) and thyroid related QoL in younger (<40 years) and older subjects (>60 years) with elevated thyroid-stimulating hormone (TSH) concentrations. The study included male and female patients with newly diagnosed, untreated subclinical hypothyroidism defined by TSH>8 mU/l. Patients were recruited throughout Germany from 2013-2016 and evaluated by clinical assessment, blood sampling and questionnaires for health related QoL and thyroid-disease thyroid-related QoL (ThyPRO) at time of diagnosis and six months after initiation of LT4 treatment. We found significantly lower QoL in both young and old patients with subclinical hypothyroidism compared to age-matched healthy individuals. Higher scores on follow-up were found in all patients irrespective of age, indicating better QoL on LT4 therapy. Analysis of the ThyPRO questionnaire showed that old patients experienced less Emotional Susceptibility, Tiredness, and Impaired Day Life on LT4, while young patients reported less Cognitive Complaints, Emotional Susceptibility, and Impaired Day Life compared to baseline assessment. Hypothyroidism with TSH concentrations>8 mU/l is associated with impairment in general and ThyPRO QoL in young and old age. Older patients benefited from LT4 therapy and remarkably show similar degree of improvement as younger patients, albeit with some thematic variation in ThyPRO QoL. Our data confirm current recommendations on initiation of LT4 substitution and suggest that this should not be withheld in elderly with TSH concentration above 8-10 mU/l.
Assuntos
Hipotireoidismo/tratamento farmacológico , Qualidade de Vida , Tiroxina/administração & dosagem , Adulto , Fatores Etários , Idoso , Humanos , Hipotireoidismo/fisiopatologia , Hipotireoidismo/psicologia , Masculino , Pessoa de Meia-Idade , Glândula Tireoide/fisiopatologia , Adulto JovemRESUMO
Medullary thyroid carcinoma (MTC) is a rare neuroendocrine tumor originating from the thyroid C cells producing mainly calcitonin (CTN) used as tumor marker. MTC occurs either sporadic (75%) or in a hereditary form (multiple endocrine neoplasia type 2, MEN2), due to germline mutations in the RET proto-oncogene. The discovery of an MTC in a patient has several diagnostic implications involving a specific strategy: preoperative evaluation of the tumor marker CTN and the extent of the disease, classification of MTC as sporadic or hereditary by DNA testing, and screening for associated endocrinopathies in hereditary MTC. Elevated CTN is a highly sensitive and specific tumor marker for diagnosis and follow-up of MTC. CTN is directly related to the tumor mass. In patients with nodular thyroid disease, diagnosis of MTC could be made by CTN determination as an indicator of tumor burden in conjunction with fine-needle aspiration. Patients with confirmed sporadic or hereditary MTC should have a total thyroidectomy and depending on the preoperative CTN value and the extent of disease additional dissection of the lymph nodes in the central and lateral neck compartment. In MEN 2 patients diagnosed by screening, the time of prophylactic thyroidectomy depends on RET mutation and CTN level.
Assuntos
Carcinoma Neuroendócrino/diagnóstico , Carcinoma Neuroendócrino/epidemiologia , Neoplasia Endócrina Múltipla Tipo 2a/diagnóstico , Neoplasia Endócrina Múltipla Tipo 2a/epidemiologia , Neoplasia Endócrina Múltipla Tipo 2b/diagnóstico , Neoplasia Endócrina Múltipla Tipo 2b/epidemiologia , Neoplasias da Glândula Tireoide/diagnóstico , Neoplasias da Glândula Tireoide/epidemiologia , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinoma Neuroendócrino/genética , Carcinoma Neuroendócrino/metabolismo , Carcinoma Neuroendócrino/terapia , Citodiagnóstico , Diagnóstico por Imagem , Predisposição Genética para Doença , Humanos , Neoplasia Endócrina Múltipla Tipo 2a/genética , Neoplasia Endócrina Múltipla Tipo 2a/metabolismo , Neoplasia Endócrina Múltipla Tipo 2a/terapia , Neoplasia Endócrina Múltipla Tipo 2b/genética , Neoplasia Endócrina Múltipla Tipo 2b/metabolismo , Neoplasia Endócrina Múltipla Tipo 2b/terapia , Estadiamento de Neoplasias , Fenótipo , Valor Preditivo dos Testes , Proto-Oncogene Mas , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/metabolismo , Neoplasias da Glândula Tireoide/terapia , Tireoidectomia , Resultado do TratamentoRESUMO
During the last two decades, there has been a marked expansion of our knowledge of both the basic and clinical aspects of multiple endocrine neoplasia type 2 (MEN2). There are two clinically distinct types of MEN2 syndrome, termed MEN2A and MEN2B. Within MEN2A, there are four variants: (i) classical MEN2A, represented by the uniform presence of MTC and the less frequent occurrence of pheochromocytoma, or primary hyperparathyroidism, or both; (ii) MEN2A with cutaneous lichen amyloidosis; (iii) MEN2A with Hirschsprung's disease; and (iv) familial medullary thyroid carcinoma (FMTC), i.e., families or individuals with only MTC. MEN2B is associated with MTC, pheochromocytoma, and mucosal neuromas. Hereditary MTC is caused by autosomal dominant gain of function mutations in the RET proto-oncogene. Specific RET mutations may suggest a predilection toward a particular phenotype and clinical course with a strong genotype-phenotype correlation. Based upon these genotype-phenotype correlations, RET mutations are now stratified into three risk levels, i.e., highest, high, and moderate risk, based on the penetrance and aggressiveness of the MTC. Children in the highest risk category should undergo thyroidectomy in their first year of life, and perhaps even in their first months of life. Children in the high-risk category should have ultrasound of the neck and calcitonin (CTN) measurement performed prior to thyroidectomy. Thyroidectomy should typically be performed at the age of 5 or earlier, depending on the presence of elevated serum CTN levels. However, heterogeneity in disease expression and progression within these groups varies considerably. To personalize disease management, the decision regarding the age of prophylactic thyroidectomy is no longer based upon genotype alone but is currently driven by additional clinical data, the most important being serum CTN levels; specifically, the decision to perform thyroidectomy should err on the safe side if the CTN level is elevated but below 30 pg/ml, especially in the moderate risk group. Personalized management also includes decisions about the best age to begin biochemical screening for pheochromocytoma and primary hyperparathyroidism.
Assuntos
Biomarcadores Tumorais/genética , Carcinoma Neuroendócrino/genética , Neoplasia Endócrina Múltipla Tipo 2a/genética , Neoplasia Endócrina Múltipla Tipo 2b/genética , Mutação , Proteínas Proto-Oncogênicas c-ret/genética , Neoplasias da Glândula Tireoide/genética , Carcinoma Neuroendócrino/patologia , Carcinoma Neuroendócrino/cirurgia , Análise Mutacional de DNA , Predisposição Genética para Doença , Hereditariedade , Humanos , Neoplasia Endócrina Múltipla Tipo 2a/patologia , Neoplasia Endócrina Múltipla Tipo 2a/cirurgia , Neoplasia Endócrina Múltipla Tipo 2b/patologia , Neoplasia Endócrina Múltipla Tipo 2b/cirurgia , Linhagem , Fenótipo , Valor Preditivo dos Testes , Prognóstico , Proto-Oncogene Mas , Fatores de Risco , Neoplasias da Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/cirurgia , TireoidectomiaRESUMO
After surgery, patients with medullary thyroid carcinoma (MTC) should be assessed regarding the presence of residual disease, the localization of metastases, and the identification of progressive disease. Postoperatively, patients with MTC are staged to separate those at low risk from those at high risk of recurrence. The TNM staging system is based on tumor size, extra-thyroidal invasion, nodal metastasis, and distant spread of cancer. In addition, the number of lymph-node metastases, the number of compartments involved, and the postoperative calcitonin (CTN) and carcinoembryonic antigen (CEA) levels should be documented. The postoperative normalization of the serum CTN level is associated with a favorable outcome. When patients have basal serum CTN levels less than 150 pg/ml after a thyroidectomy, any persistent or recurrent disease is nearly always confined to lymph nodes in the neck. When the postoperative serum CTN level exceeds 150 pg/ml, patients should be evaluated with imaging procedures, including computed tomography (CT) of the neck and chest, contrast-enhanced magnetic resonance imaging (MRI) and ultrasound (US) of the liver, bone scintigraphy, MRI of the bone, and positron emission tomography (PET)/CT. One can estimate the growth rate of MTC metastases by quantifying increases in tumor size over time from sequential imaging studies analyzed with response evaluation criteria in solid tumors (RECIST), and by determining the tumor marker doubling time from sequential measures of serum CTN or CEA levels over multiple time points. One of the main challenges remains to find effective adjuvant and palliative options for patients with metastatic disease. Patients with persistent or recurrent MTC localized to the neck following thyroidectomy are candidates for neck operations, depending on the tumor extension. Once metastases appear, the clinician must decide which patients require therapy. This requires a balance between the (often) slow rate of tumor progression, which is associated with a good quality of life, and the limited efficacy and potential toxicities of local and systemic therapies. Considering that metastatic MTC is incurable, the management goals are to provide loco-regional disease control, palliate symptoms of hormonal excess, such as diarrhea, palliate symptomatic metastases, like pain or bone fracture, and control metastases that threaten life, such as bronchial obstruction or spinal cord compression. This can be achieved with palliative surgery, external beam radiation therapy (EBRT), or systemic therapy with tyrosine kinase inhibitor (TKI).
Assuntos
Carcinoma Neuroendócrino/cirurgia , Neoplasias da Glândula Tireoide/cirurgia , Tireoidectomia , Biomarcadores Tumorais/sangue , Calcitonina/sangue , Carcinoma Neuroendócrino/sangue , Carcinoma Neuroendócrino/genética , Carcinoma Neuroendócrino/secundário , Quimioterapia Adjuvante , Diagnóstico por Imagem , Progressão da Doença , Intervalo Livre de Doença , Predisposição Genética para Doença , Humanos , Mutação , Recidiva Local de Neoplasia , Estadiamento de Neoplasias , Neoplasia Residual , Cuidados Paliativos , Fenótipo , Valor Preditivo dos Testes , Proteínas Proto-Oncogênicas c-ret/genética , Radioterapia Adjuvante , Fatores de Risco , Neoplasias da Glândula Tireoide/sangue , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/patologia , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: Menopausal estrogen depletion increases the risk of cardiovascular disease and of osteoporosis. Both of these risks can be increased by thyroid dysfunction as well. This cumulation of risks will be presented. METHODS: This review is based on publications retrieved by a selective search in PubMed (publications dated January 2000 to October 2022) for clinical trials, meta-analyses, randomized controlled trials, and systematic reviews containing the keywords "menopause and thyroid disorders." RESULTS: Hyperthyroidism and menopause have similar symptoms. Decreased levels of thyroid-stimulating hormone (TSH) are found in 8-10% of women in their fifth and sixth decades. TSH is decreased in 21.6-27.2% of women treated with L-thyroxine; decreased TSH is associated with increased cardiovascular mortality (hazard ratio [HR] 3.3, 95% confidence interval [CI]: [1.3; 8.0]) and increased mortality of all causes (HR 2.1; 95% CI: [1.2; 3.8]). Menopausal estrogen depletion accelerates the risk of cardiovascular disease and causes a disproportionate loss of bone density. In hyperthyroidism, bone density is decreased, and the risk of vertebral fractures is increased (HR 3.57; 95% CI: [1.88; 6.78]). CONCLUSION: The risk of heart diseases and bone diseases accelerates around the time of the menopause. Early detection and treatment of hyperthyroidism, which can further elevate the risk of both of these diseases is therefore required. In perimeno - pausal and postmenopausal women who are being treated for hypothyroidism, TSH suppression must be avoided. Thyroid dysfunction is common in women; its manifestations are less obvious with advancing age, making clinical diagnosis more difficult, yet it can have major deleterious effects. Thus, the indications for measuring TSH in perimenopausal women should be kept broad, rather than restrictive.
Assuntos
Doenças Cardiovasculares , Hipertireoidismo , Feminino , Humanos , Pós-Menopausa , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/complicações , Hipertireoidismo/epidemiologia , Hipertireoidismo/complicações , Tireotropina , EstrogêniosRESUMO
BACKGROUND: Based on reports of higher frequencies among patients with sporadic medullary thyroid cancer (MTC) relative to external controls, the RET (REarranged during Transfection) variants G691S, L767L, S836S and S904S have been considered disease modifiers, suggesting greater lifetime risks of MTC. Other studies, employing different external controls, failed to confirm this association. Using a complementary approach, this study aimed at exploring differences in clinico-pathological characteristics among patients with sporadic MTC carrying no (wildtype), one (heterozygotes) or both (homozygotes) homologue RET variants in the germline, with wildtype cases acting as internal controls. METHODS: Included in this investigation were 150 patients with complete genetic information on G691S, L769L, S836S and S904S RET alleles operated on for sporadic MTC at a tertiary referral centre. RESULTS: Not one statistically significant dose-response relationship was identified between any RET variant (wildtype vs RET heterozygotes vs homologue RET homozygotes) and patient age at MTC diagnosis, gender, primary tumour size, extrathyroidal extension, numbers of involved and removed lymph nodes, or distant metastasis. L769L and S836S homozygotes, unlike G691S and S904S homozygotes, were either rare or absent, limiting the analyses to comparisons of heterozygosity versus wildtype. On time-to-event analysis, G691S, L769L, S836S or S904S carriers and noncarriers developed MTC at similar rates. CONCLUSIONS: In carriers and noncarriers of the RET variants G691S, L767L, S836S and S904S, sporadic MTC appeared clinically and pathologically indistinguishable. This observation, along with the inconclusive evidence of previous association studies, calls for larger longitudinal association studies with age- and sex-matched external controls and additional functional studies of RET biology.
Assuntos
Carcinoma Medular/genética , Mutação de Sentido Incorreto , Proteínas Proto-Oncogênicas c-ret/genética , Neoplasias da Glândula Tireoide/genética , Substituição de Aminoácidos , Análise de Variância , Carcinoma Medular/patologia , Feminino , Frequência do Gene , Heterozigoto , Homozigoto , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Neoplasias da Glândula Tireoide/patologiaRESUMO
BACKGROUND: RET (rearranged during transfection) variants are the most prevalent oncogenic events in medullary thyroid cancer (MTC). In advanced disease, multi-tyrosine kinase inhibitors (MKIs) cabozantinib and vandetanib are the approved standard treatment irrespective of RET status. The actual outcome of patients with RET-positive MTC treated with MKIs is ill described. METHODS: We here retrospectively determined the RET oncogene variant status with a targeted DNA Custom Panel in a prospectively collected cohort of 48 patients with advanced MTC treated with vandetanib and/or cabozantinib at four German referral centers. Progression-free survival (PFS) and overall survival (OS) probabilities were estimated using the Kaplan-Meier method. RESULTS: In total, 44/48 (92%) patients had germline or somatic RET variants. The M918T variant was found in 29/44 (66%) cases. In total, 2/32 (6%) patients with a somatic RET variant had further somatic variants, while in 1/32 (3%) patient with a germline RET variant, additional variants were found. Only 1/48 (2%) patient had a pathogenic HRAS variant, and no variants were found in 3 cases. In first-line treatment, the median OS was 53 (95% CI (95% confidence interval), 32-NR (not reached); n = 36), and the median PFS was 21 months (12-39; n = 33) in RET-positive MTC patients. In second-line treatment, the median OS was 18 (13-79; n = 22), and the median PFS was 3.5 months (2-14; n = 22) in RET-positive cases. CONCLUSIONS: RET variants were highly prevalent in patients with advanced MTC. The treatment results in RET-positive cases were similar to those reported in unselected cohorts.
RESUMO
Multiple endocrine neoplasia type 2 is characterized by germline mutations in RET. For exon 10, comprehensive molecular and corresponding phenotypic data are scarce. The International RET Exon 10 Consortium, comprising 27 centers from 15 countries, analyzed patients with RET exon 10 mutations for clinical-risk profiles. Presentation, age-dependent penetrance, and stage at presentation of medullary thyroid carcinoma (MTC), pheochromocytoma, and hyperparathyroidism were studied. A total of 340 subjects from 103 families, age 4-86, were registered. There were 21 distinct single nucleotide germline mutations located in codons 609 (45 subjects), 611 (50), 618 (94), and 620 (151). MTC was present in 263 registrants, pheochromocytoma in 54, and hyperparathyroidism in 8 subjects. Of the patients with MTC, 53% were detected when asymptomatic, and among those with pheochromocytoma, 54%. Penetrance for MTC was 4% by age 10, 25% by 25, and 80% by 50. Codon-associated penetrance by age 50 ranged from 60% (codon 611) to 86% (620). More advanced stage and increasing risk of metastases correlated with mutation in codon position (609â620) near the juxtamembrane domain. Our data provide rigorous bases for timing of premorbid diagnosis and personalized treatment/prophylactic procedure decisions depending on specific RET exon 10 codons affected.
Assuntos
Éxons , Mutação em Linhagem Germinativa/genética , Neoplasia Endócrina Múltipla Tipo 2a/genética , Penetrância , Proteínas Proto-Oncogênicas c-ret/genética , Proteínas Proto-Oncogênicas c-ret/metabolismo , Adolescente , Neoplasias das Glândulas Suprarrenais/genética , Neoplasias das Glândulas Suprarrenais/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Neuroendócrino , Criança , Pré-Escolar , Códon/genética , Feminino , Humanos , Hiperparatireoidismo/genética , Hiperparatireoidismo/patologia , Masculino , Pessoa de Meia-Idade , Neoplasia Endócrina Múltipla Tipo 2a/patologia , Estadiamento de Neoplasias , Feocromocitoma/genética , Feocromocitoma/patologia , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/patologia , Adulto JovemRESUMO
OBJECTIVE: Primary hyperparathyroidism (HPT) is characterised by autonomous secretion of PTH from enlarged parathyroid glands leading, in most patients, to asymptomatic hypercalcaemia. Familial hypocalciuric hypercalcaemia (FHH) is an autosomal dominant disorder caused by inactivating mutations in the calcium-sensing receptor (CaSR) gene; it is characterised by lifelong and usually asymptomatic hypercalcaemia. Establishing the correct diagnosis is important because surgery can be curative in HPT, but ineffective in FHH. There is overlap in the diagnostic criteria for the two disorders and some patients carrying inactivating mutations in the CaSR gene, which is suggestive of FHH, also have HPT with hyperplastic parathyroid glands or adenomas. DESIGN AND PATIENTS CaSR gene mutations were analysed and clinical and biochemical parameters evaluated in 139 consecutive outpatients presenting with hypercalcaemia and suspected of having HPT. RESULTS: Six different mutations of the CaSR gene were found in eight patients. In four patients, classical FHH was suspected based on clinical and biochemical results and was confirmed by the CaSR mutations. In the other four patients, HPT was diagnosed based on the biochemical profile or symptoms; in these four patients, the parathyroids were operated on and single adenomas were histologically confirmed. In all four patients, serum calcium decreased postoperatively; and in three patients, serum calcium normalised postoperatively. The CaSR mutations in these patients were R25X, E250K and Q926R. CONCLUSION: The coexistence of HPT and FHH in four of 139 patients suggests a pathogenetic role of CaSR mutations in HPT. Despite also having a CaSR mutation, these patients benefited from parathyroid surgery.
Assuntos
Adenoma/genética , Hipercalcemia/congênito , Hiperparatireoidismo Primário/genética , Neoplasias das Paratireoides/genética , Receptores de Detecção de Cálcio/genética , Adenoma/cirurgia , Adulto , Idoso , Criança , Comorbidade , Humanos , Hipercalcemia/epidemiologia , Hipercalcemia/genética , Hiperparatireoidismo Primário/epidemiologia , Hiperparatireoidismo Primário/cirurgia , Masculino , Pessoa de Meia-Idade , Mutação/genética , Neoplasias das Paratireoides/cirurgia , Adulto JovemRESUMO
OBJECTIVE: Autosomal dominant hypocalcaemia or hypoparathyroidism is caused by activating mutations of the calcium-sensing receptor (CaSR). Treatment with calcium and vitamin D often worsens hypercalciuria and nephrocalcinosis, and renal impairment can result. Our aim was to describe the phenotypic variance of this rare disorder in a large series and to evaluate the outcome after long-term treatment. DESIGN: Nationwide retrospective collaborative study. PATIENTS: We describe 25 patients (14 men and 11 women), 20 belonging to 11 families and five single cases. MEASUREMENTS: Activating CaSR mutations and clinical and biochemical findings were evaluated. RESULTS: Nine different missense mutations of the CaSR, including one novel variant (M734T), were found. Twelve patients (50%) were symptomatic, 9 (36%) had basal ganglia calcifications and 3 (12%) had nephrocalcinosis. Serum calcium was decreased (1·87 ± 0·13 mm), and PTH was decreased (n = 19) or inappropriately low (n = 4). The occurrence of hypocalcaemic symptoms at diagnosis was related to the degree of hypocalcaemia. The occurrence of features like calcification of basal ganglia or kidney calcification did not correlate with the severity of hypocalcaemia or the age at diagnosis. The most common treatment was calcitriol (median dosage 0·6 µg/day), and the mean duration of therapy was 7·1 years (max. 26 years). Hypercalcaemic episodes rarely occurred, and the rate of kidney calcifications was remarkably low (12%). CONCLUSION: This series increases the limited knowledge of mutations and phenotypes of this rare disorder. Mutation analysis of the CaSR gene facilitates patient and family management. Low dosages of calcitriol resulted in less frequent renal calcifications.
Assuntos
Hipocalcemia/genética , Mutação , Receptores de Detecção de Cálcio/genética , Adolescente , Adulto , Criança , Pré-Escolar , Estudos de Coortes , Análise Mutacional de DNA , Coleta de Dados , Feminino , Genes Dominantes , Alemanha/epidemiologia , Humanos , Hipocalcemia/epidemiologia , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Mutação/fisiologia , Fenótipo , Receptores de Detecção de Cálcio/química , Estudos Retrospectivos , Adulto JovemRESUMO
CONTEXT: Long-term data are scarce on large cohorts with sporadic (sMTC) and hereditary medullary thyroid carcinoma (hMTC). OBJECTIVES: To compare long-term disease-specific survival (DSS) and outcomes between sMTC and hMTC groups. DESIGN: Retrospective analysis. SETTING: German tertiary referral center. PATIENTS: A total of 673 patients with MTC that underwent surgery from January 1974 to July 2019. INTERVENTION: None (observational study). MAIN OUTCOME MEASURE: Differences between sMTC and hMTC in long-term, stage-dependent survival and outcomes. RESULTS: Surgery was performed at median ages of 49 years for sMTC (n = 477, 44% male) and 29 years for hMTC (n = 196, 43% male; P < 0.0001). The mean follow-up times were 9.2 ± 8.0 (sMTC) and 14.6 ± 10.3 years (hMTC). Age and tumor stage at diagnosis were significantly different between the 2 groups (P < 0.0001). The sMTC and hMTC groups had different overall DSS (log rank, P = 0.0183), but similar stage-dependent DSS (log rank, P = 0.1242-0.8981). In a multivariate analysis, sMTC and hMTC did not differ in DSS (hazard ratio [HR] = 1.56; 95% CI, 0.94-2.57), but in both groups, a worse DSS was significantly associated with age at diagnosis (HR = 1.04; 95% CI, 1.02-1.05), male sex (HR = 0.49; 95% CI, 0.32-0.76), and stages III and IV at diagnosis (HR = 20.00; 95% CI, 2.74-145.91 and HR = 97.47; 95% CI, 13.07-726.67, respectively). The groups had significantly different (P < 0.0001) outcomes (i.e., cured, minimal residual disease, structural detectable disease, and death), but similar stage-dependent outcomes (P = 0.9449-0.0511), except for stage III (P = 0.0489). CONCLUSION: Patients with sMTC and hMTC had different ages of onset, but similar stage-dependent DSS and outcomes after the MTC diagnosis. This finding suggested that tumor behavior was similar in sMTC and hMTC.
Assuntos
Carcinoma Medular/congênito , Neoplasia Endócrina Múltipla Tipo 2a/mortalidade , Neoplasia Endócrina Múltipla Tipo 2a/cirurgia , Neoplasias da Glândula Tireoide/mortalidade , Neoplasias da Glândula Tireoide/cirurgia , Adolescente , Adulto , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Carcinoma Medular/genética , Carcinoma Medular/mortalidade , Carcinoma Medular/cirurgia , Criança , Pré-Escolar , Feminino , Seguimentos , Alemanha/epidemiologia , Humanos , Lactente , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Neoplasia Endócrina Múltipla Tipo 2a/genética , Estadiamento de Neoplasias , Estudos Retrospectivos , Fatores Sexuais , Análise de Sobrevida , Neoplasias da Glândula Tireoide/genética , Tireoidectomia , Resultado do Tratamento , Adulto JovemRESUMO
Background: Management of patients with advanced medullary thyroid cancer (MTC) remains a therapeutic challenge. The multi-tyrosine kinase inhibitors (TKIs) vandetanib and cabozantinib have been approved for the treatment of progressive MTC based on prolonged progression-free survival (PFS) in phase 3 clinical trials. Patients and Methods: To evaluate clinical characteristics, treatment regimens, efficacy, and treatment emergent adverse events (TEAEs) of vandetanib and cabozantinib in MTC patients outside clinical trials at four German tertiary care centers. Forty-eight patients diagnosed between 1990 and 2018 were included. PFS and overall survival (OS) probabilities were estimated using the Kaplan-Meier method and compared by log-rank test. Results: The median age at diagnosis was 46 years (15-80 years); a germ line RET (rearranged during transfection) mutation was known in 6 (13%) patients. Thirty-two (67%) patients showed progressive disease before TKI initiation. Forty-seven (98%) patients were treated with vandetanib and 23 (48%) patients with cabozantinib. Vandetanib was first-line treatment in 41 (85%) patients and cabozantinib in 7 (15%) patients. Partial response was the best response in 12 (26%) patients treated with vandetanib and in 5 (22%) patients treated with cabozantinib. Sixteen (34%) patients treated with vandetanib and 3 (13%) patients treated with cabozantinib had stable disease ≥24 weeks. The median PFS for vandetanib and cabozantinib was 17 months [95% confidence interval, CI, 9.3-24.6 months] and 4 months [CI 3.1-4.9 months], respectively. The 6- and 12-month survival rates were 98% and 86% for vandetanib and 78% and 70% for cabozantinib, respectively. The median OS for vandetanib and cabozantinib was 53 months [CI 43.7-62.3 months] and 24 months [CI 5.9-42.1 months], respectively. In vandetanib-treated patients, the PFS and OS were significantly longer in patients aged ≤60 years at TKI initiation and in patients with ≥5 TEAEs. Additionally, the PFS was longer in the absence of bone metastases. In cabozantinib-treated patients, the PFS was significantly longer in patients experiencing TEAEs and in patients aged ≤60 years, and the OS was significantly longer in patients who had TEAEs and in patients with ≥5 TEAEs. Conclusions: Vandetanib and cabozantinib are effective treatment options in the majority of MTC patients. We hypothesize that the poorer prognosis of cabozantinib-treated patients in our retrospective analysis is most likely due to its use as second-line treatment after treatment failure on vandetanib. However, different degrees of efficacy of the two drugs are possible.
Assuntos
Anilidas/uso terapêutico , Antineoplásicos/uso terapêutico , Carcinoma Neuroendócrino/tratamento farmacológico , Piperidinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas/uso terapêutico , Quinazolinas/uso terapêutico , Neoplasias da Glândula Tireoide/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anilidas/efeitos adversos , Antineoplásicos/efeitos adversos , Carcinoma Neuroendócrino/genética , Carcinoma Neuroendócrino/mortalidade , Carcinoma Neuroendócrino/patologia , Feminino , Alemanha , Humanos , Masculino , Pessoa de Meia-Idade , Piperidinas/efeitos adversos , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/efeitos adversos , Piridinas/efeitos adversos , Quinazolinas/efeitos adversos , Sistema de Registros , Estudos Retrospectivos , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/mortalidade , Neoplasias da Glândula Tireoide/patologia , Fatores de Tempo , Adulto JovemRESUMO
Background: Multiple endocrine neoplasia type 2 (MEN2) is an autosomal dominant disorder caused by mutations in the RET proto-oncogene. MEN2 is classified into two subtypes, MEN 2A and 2B. MEN2B is characterized by early-onset and aggressive medullary thyroid carcinoma (MTC), pheochromocytoma, and characteristic physical features. Patient Findings: We present a 39-year-old male with early-onset metastatic MTC diagnosed at the age of 13 years and physical features typical for MEN2B such as marfanoid habitus, mucosal neuromas, and thickened eyelids. The patient has two first-degree relatives (mother and maternal uncle) with MTC and pheochromocytoma. The mother has similar facial features. RET sequencing revealed a novel tandem RET E768D/L790F germline mutation in exon 13. The patient's mother has the same RET variant. For functional in vitro characterization, wild-type RET, RET E768D, RET L790F, the double RET E768D/L790F mutant, and RET M918T were expressed in HEK293 cells. The novel double RET E768D/L790F mutant increased ligand-independent RET phosphorylation, activation of the mitogen-activated protein kinase (MAPK)-pathway, and colony formation similar to the classical MEN2B RET M918T mutation. Summary: In this male patient with a MEN2B-like phenotype, we identified a novel double RET germline mutation, E768D/L790F. Functional characterization of the double mutant shows similar transforming capacity as RET M918T.
Assuntos
Biomarcadores Tumorais/genética , Carcinoma Neuroendócrino/genética , Neoplasia Endócrina Múltipla Tipo 2b/genética , Mutação , Proteínas Proto-Oncogênicas c-ret/genética , Neoplasias da Glândula Tireoide/genética , Adulto , Biomarcadores Tumorais/metabolismo , Carcinoma Neuroendócrino/diagnóstico , Carcinoma Neuroendócrino/metabolismo , Feminino , Predisposição Genética para Doença , Células HEK293 , Hereditariedade , Humanos , Sistema de Sinalização das MAP Quinases , Masculino , Pessoa de Meia-Idade , Neoplasia Endócrina Múltipla Tipo 2b/diagnóstico , Neoplasia Endócrina Múltipla Tipo 2b/metabolismo , Linhagem , Fenótipo , Proto-Oncogene Mas , Proteínas Proto-Oncogênicas c-ret/metabolismo , Neoplasias da Glândula Tireoide/diagnóstico , Neoplasias da Glândula Tireoide/metabolismoRESUMO
Medullary thyroid carcinoma (MTC) is a rare malignancy and compromises only 3â% of all thyroid carcinomas. MTC cells secret calcitonin, which serves as a sensitive tumor marker for screening and follow-up of MTC. Calcitonin screening in patients with nodular goiter allows for early diagnosis of MTC and surgical curative treatment. In 25â% of patients MTC occurs as an integral part of multiple endocrine neoplasia type 2 (MEN2), an autosomal dominant inherited tumor syndrome. It is caused by germline mutations in the RET protooncogene. In gene carriers early diagnosis and treatment through prophylactic thyroidectomy is possible. MTC is a slowly growing tumor with a good prognosis and 5 and 10 year survival rates up to 80 and 60â%. In the follow-up a dynamic risk stratification allows for a personalized disease management. In symptomatic and progressive metastasizing MTC tyrosine kinase inhibitors are an effective therapy.
Assuntos
Carcinoma Neuroendócrino , Neoplasia Endócrina Múltipla Tipo 2a , Neoplasias da Glândula Tireoide , Biomarcadores Tumorais/sangue , Calcitonina/sangue , HumanosRESUMO
CONTEXT: The clinical relevance of bone metastases (BM) in advanced medullary thyroid carcinoma (MTC) is poorly described. OBJECTIVE: The objectives of this work are to describe the prevalence of BM, frequency of skeletal related events (SREs), and impact of BM morphology and SREs on prognosis, and to assess the role of antiresorptive treatment (ART). DESIGN: A retrospective cohort study was conducted. SETTING: This study was conducted at 4 German referral centers. PATIENTS: A total of 1060 MTC patients were included. MAIN OUTCOME MEASURE: Main outcome measures include descriptive statistics, overall survival (OS) by the Kaplan-Meier method, and risk factors by Cox proportional hazards modeling. RESULTS: A total of 120 of 416 patients (29%) with metastatic MTC had BM, of which 97% had concurrent nonosseous metastases. BM occurred 2.1 years (median, range -0.1 to 20.6 years) after initial diagnosis, were multifocal in 79%, and were located preferentially in the spine (86%) and pelvis (60%). BM morphology was osteolytic in 32%, osteoblastic in 25%, and mixed in 22% of cases (unknown: 21%). Within a median observation period of 26.6 months (range, 0-188 months) after BM diagnosis, 47% of patients experienced one or more SREs (bone radiation 50%, pathological fractures 32%), of which 42% occurred in osteolytic and 17% in osteoblastic BM (Pâ =â .047). Presence of osteolytic metastases (hazard ratio 3.85, 95% CI 1.52-9.77, Pâ =â .005) but not occurrence of SREs was associated with impaired OS. Among the 36 patients who received ART (no ART: nâ =â 71), SREs were significantly less frequent than in untreated patients (Pâ =â .04). CONCLUSION: BM are common in metastatic MTC and most often with an osteolytic morphology and an unfavorable prognosis. The majority of SREs occur in osteolytic metastases and may be prevented by ART.
Assuntos
Neoplasias Ósseas/secundário , Carcinoma Neuroendócrino/patologia , Fraturas Espontâneas/patologia , Osteólise/patologia , Neoplasias da Glândula Tireoide/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Ósseas/terapia , Carcinoma Neuroendócrino/terapia , Terapia Combinada , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Morbidade , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida , Neoplasias da Glândula Tireoide/terapia , Adulto JovemRESUMO
Multiple endocrine neoplasia type 2 (MEN2) is an autosomal dominant tumour syndrome caused by germline activating mutations of the RET proto-oncogene. It has a strong penetrance of medullary thyroid carcinoma (MTC) and can be associated with bilateral pheochromocytoma and primary hyperparathyroidism (MEN2A) within a single patient or family. Based on the phenotype three distinct clinical forms have been described: (1) classical MEN2A, (2) MEN2B, an association of MTC, pheochromocytoma and mucosal neuroma and (3) familial MTC (FMTC), which is associated with a very low incidence of other endocrinopathies. Each variant of MEN2 results from a different RET gene mutation, with a good genotype-phenotype correlation with regard to aggressiveness of MTC, time of onset of MTC and the presence or absence of other endocrine tumours. Recommendations on the timing of prophylactic thyroidectomy and extent of surgery are based on a classification of RET mutations into three risk levels using the genotype-phenotype correlations. MEN2 provides a unique model for early prevention and cure of cancer and for stratified roles of mutation-based diagnosis of carriers.
Assuntos
Neoplasia Endócrina Múltipla Tipo 2a/genética , Neoplasia Endócrina Múltipla Tipo 2b/genética , Carcinoma Medular/genética , Carcinoma Medular/prevenção & controle , Carcinoma Medular/cirurgia , Genótipo , Humanos , Neoplasia Endócrina Múltipla Tipo 2a/diagnóstico , Neoplasia Endócrina Múltipla Tipo 2a/cirurgia , Neoplasia Endócrina Múltipla Tipo 2b/diagnóstico , Fenótipo , Proto-Oncogene Mas , Proteínas Proto-Oncogênicas c-ret/genética , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/prevenção & controle , Neoplasias da Glândula Tireoide/cirurgia , TireoidectomiaRESUMO
CONTEXT: Recent data on long-term outcomes and aggressiveness of medullary thyroid carcinoma (MTC) are lacking for patients with multiple endocrine neoplasia type 2 (MEN2). OBJECTIVES: To analyze the long-term outcomes in MEN2 and compare MTC aggressiveness in three defined RET mutation-risk categories: moderate risk (MOD), high risk (H), and highest risk (HST). DESIGN, SETTING: Retrospective study of 263 operated patients with MEN2 from one German tertiary referral center from 1979 to 2017 comparing demographic, biochemical, genetic, and outcome parameters. INTERVENTION: None (observational study). MAIN OUTCOME MEASURE: Long-term survival and outcomes in three risk groups. RESULTS: Surgery was performed at a mean age of 35.3 ± 18.8 (MOD, n = 122), 23.0 ± 15.7 years (H, n = 120), and 14.9 ± 9.3 (HST, n = 21) years (P < 0.05). The mean follow-up was 12.9 ± 9.8 years. Age and tumor stage at diagnosis differed among the three risk groups (P < 0.0001). Multivariate analysis of disease-specific survival (DSS) showed that increasing age [hazard ratio (HR), 1.06; 95% CI, 1.02 to 1.09], stage III/IV at diagnosis (HR, 7.39; 95% CI, 2.39 to 22.8), and HST group (HR, 14.4; 95% CI, 3.32 to 62.6) were significantly associated with worse DSS; the H group was not (P = 0.175). The DSS rates and outcomes were not different between the MOD and H groups (P = 0.179 and P = 0.893, respectively) but were significantly inferior in the HST group (P < 0.0008 and P < 0.0001, respectively). CONCLUSION: MTC in patients with MEN2 showed a clearly different age of onset in the different risk groups. DSS and outcomes after MTC diagnosis were similar in the MOD and H groups, suggesting similar tumor behavior. The HST group had inferior outcomes and survival vs the MOD and or H groups.
Assuntos
Carcinoma Medular/congênito , Carcinoma Neuroendócrino/patologia , Neoplasia Endócrina Múltipla Tipo 2a/patologia , Proteínas Proto-Oncogênicas c-ret/genética , Neoplasias da Glândula Tireoide/patologia , Adolescente , Adulto , Carcinoma Medular/mortalidade , Carcinoma Medular/patologia , Carcinoma Medular/cirurgia , Carcinoma Neuroendócrino/mortalidade , Carcinoma Neuroendócrino/cirurgia , Criança , Estudos de Coortes , Suscetibilidade a Doenças , Intervalo Livre de Doença , Feminino , Seguimentos , Alemanha , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Neoplasia Endócrina Múltipla Tipo 2a/genética , Neoplasia Endócrina Múltipla Tipo 2a/mortalidade , Neoplasia Endócrina Múltipla Tipo 2a/cirurgia , Análise Multivariada , Mutação , Invasividade Neoplásica/patologia , Estadiamento de Neoplasias , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Medição de Risco , Análise de Sobrevida , Centros de Atenção Terciária , Neoplasias da Glândula Tireoide/mortalidade , Neoplasias da Glândula Tireoide/cirurgia , Tireoidectomia/métodos , Tireoidectomia/mortalidade , Fatores de Tempo , Adulto JovemRESUMO
RET testing in multiple endocrine neoplasia type 2 for molecular diagnosis is the paradigm for the practice of clinical cancer genetics. However, precise data for distinct mutation-based risk profiles are not available. Here, we survey the clinical profile for one specific genotype as a model, TGC to TGG in codon 634 (C634W). By international efforts, we ascertained all available carriers of the RET C634W mutation. Age at diagnosis, penetrance, and clinical complications were analyzed for medullary thyroid carcinoma (MTC), pheochromocytoma, and hyperparathyroidism (HPT), as well as overall survival. Our series comprises 92 carriers from 20 unrelated families worldwide. Sixty-eight subjects had MTC diagnosed at age 3-72 years (mean 29). Lymph node metastases were observed in 16 subjects aged 20-72 and distant metastases in 4 subjects aged 28-69. Forty-one subjects had pheochromocytoma detected at age 18-67 (mean 36). Amongst the 28 subjects with MTC and pheochromocytoma, six developed pheochromocytoma before MTC. Six subjects had HPT diagnosed at age 26-52 (mean 39). Eighteen subjects died; of the 16 with known causes of death, 8 died of pheochromocytoma and 4 of MTC. Penetrance for MTC is 52% by age 30 and 83% by age 50, for pheochromocytoma penetrance is 20% by age 30 and 67% by age 50, and for HPT penetrance is 3% by age 30 and 21% by age 50. These data provide, for the first time, RET C634W-specific neoplastic risk and age-related penetrance profiles. The data may facilitate risk assessment and genetic counseling.