Total parathyroidectomy in a large cohort of cases with hyperparathyroidism associated with multiple endocrine neoplasia type 1: experience from a single academic center

Most cases of sporadic primary hyperparathyroidism present disturbances in a single parathyroid gland and the surgery of choice is adenomectomy. Conversely, hyperparathyroidism associated with multiple endocrine neoplasia type 1 (hyperparathyroidism/multiple endocrine neoplasia type 1) is an asynchronic, asymmetrical multiglandular disease and it is surgically approached by either subtotal parathyroidectomy or total parathyroidectomy followed by parathyroid auto-implant to the forearm. In skilful hands, the efficacy of both approaches is similar and both should be complemented by prophylactic thymectomy. In a single academic center, 83 cases of hyperparathyroidism/ multiple endocrine neoplasia type 1 were operated on from 1987 to 2010 and our first surgical choice was total parathyroidectomy followed by parathyroid auto-implant to the non-dominant forearm and, since 1997, associated transcervical thymectomy to prevent thymic carcinoid. Overall, 40% of patients were given calcium replacement (mean intake 1.6 g/day) during the first months after surgery, and this fell to 28% in patients with longer follow-up. These findings indicate that several months may be needed in order to achieve a proper secretion by the parathyroid auto-implant. Hyperparathyroidism recurrence was observed in up to 15% of cases several years after the initial surgery. Thus, long-term follow-up is recommended for such cases. We conclude that, despite a tendency to subtotal parathyroidectomy worldwide, total parathyroidectomy followed by parathyroid auto-implant is a valid surgical option to treat hyperparathyroidism/multiple endocrine neoplasia type 1. Larger comparative systematic studies are needed to define the best surgical approach to hyperparathyroidism/multiple endocrine neoplasia type 1.

Glucose-dependent insulinotropic peptide receptor overexpression in adrenocortical hyperplasia in MEN1 syndrome without loss of heterozygosity at the 11q13 locus

BACKGROUND: The molecular mechanisms involved in the genesis of the adrenocortical lesions seen in MEN1 syndrome (ACL-MEN1) remain poorly understood; loss of heterozygosity at 11q13 and somatic mutations of MEN1 are not usually found in these lesions. Thus, additional genes must be involved in MEN1 adrenocortical disorders. Overexpression of the glucose-dependent insulinotropic peptide receptor has been shown to promote adrenocortical tumorigenesis in a mice model and has also been associated with ACTH-independent Cushing syndrome in humans. However, to our knowledge, the status of glucose-dependent insulinotropic peptide receptor expression in adrenocortical lesions in MEN1 has not been previously investigated. OBJECTIVE: To evaluate glucose-dependent insulinotropic peptide receptor expression in adrenocortical hyperplasia associated with MEN1 syndrome. MATERIALS/METHODS: Three adrenocortical tissue samples were obtained from patients with previously known MEN1 germline mutations and in whom the presence of a second molecular event (a new MEN1 somatic mutation or an 11q13 loss of heterozygosity) had been excluded. The expression of the glucose-dependent insulinotropic peptide receptor was quantified by qPCR using the DDCT method, and b-actin was used as an endogenous control. RESULTS: The median of glucose-dependent insulinotropic peptide receptor expression in the adrenocortical lesions associated with MEN1 syndrome was 2.6-fold (range 1.2 to 4.8) higher than the normal adrenal controls (p = 0.02). CONCLUSION: The current study represents the first investigation of glucose-dependent insulinotropic peptide receptor expression in adrenocortical lesions without 11q13 loss of heterozygosity in MEN1 syndrome patients. Although we studied a limited number of cases of MEN1 adrenocortical lesions retrospectively, our preliminary data suggest an involvement of glucose-dependent insulinotropic peptide receptor overexpression in the etiology of adrenocortical hyperplasia. New prospective studies will be able to clarify the exact role of the glucose-dependent insulinotropic peptide receptor in the molecular pathogenesis of MEN1 adrenocortical lesions.

Timectomia na abordagem cirúrgica do hiperparatireoidismo na neoplasia endócrina múltipla do tipo 1 / Thymectomy in the surgical approach to hyperparathyroidism in type 1 multiple endocrine neoplasia

Introdução: O hiperparatireoidismo (HPT) é comum na neoplasia endócrina múltipla do tipo I (NEM 1). O tratamento definitivo é cirúrgico. Objetivo: Analisar os resultados da timectomia no tratamento do HPT associado à NEM 1. Método: Estudo retrospectivo de 24 pacientes com NEM 1 submetidos a paratireoidectomia entre 1988 e 2003. Analisaram-se a ocorrência de recidivas e a necessidade de re-operações em pacientes com e sem a timectomia. Resultados: A média etária foi de 37,6 anos, com 12 homens e 12 mulheres. Vinte foram submetidos à primeira cirurgia já com o diagnóstico de NEM1 e quatro pacientes foram operados inicialmente sem esse diagnóstico no pré-operatório (dois em outros Serviços). Nos 20 casos com diagnóstico préoperatório, a calcemia média no pré-operatório que era de 11,5 mg/dL reduziu-se para 8,37 mg/dL nos primeiros dias após a cirurgia e medidas com 6 e 12 meses de pós-operatório; 9,2 e 9,4 mg/dL, respectivamente. Os 13 pacientes com exérese de 4 glândulas: 10 (76,9%) encontravam-se euparatireoideos; 1 paciente (7,7%) apresentou HPT recorrente (retirada de uma glândula intratímica após 10 anos e recidiva do enxerto após 14 anos); e 2 (15,4%) pacientes evoluíram com hipoparatireoidismo. Dos 20 pacientes com diagnóstico pré-operatório, em 17 foi realizada timectomia na primeira cirurgia. Nos 3 pacientes não submetidos a esse procedimento, um apresentou recidiva por glândula intratímica, outro evoluiu com tumor carcinoide tímico e o terceiro está euparatireoideo. Conclusão: O tratamento do HPT na NEM 1 é mais complexo. A realização de timectomia associou-se a melhores resultados no seguimento.

Introduction: Hyperparathyroidism (HPT) is common in type I Multiple Endocrine Neoplasia (MEN 1). Surgery is the definitive treatment. Objective: To analyze the results of thymectomy in the surgical treatment of MEN 1 HPT. Method: Retrospective study of 24 MEN 1 patients submitted to parathyroidectomy between 1988 and 2003. Recurrences and the need of re-operative intervention were evaluated according to the type of operation. Results: Mean age was 37.6 years. Twelve were men. Twenty patients were operated on with the preoperative diagnosis of MEN 1 and four, not (two of them at another facilities). In the 20 cases with preoperative diagnosis, mean preoperative calcemia was 11.5 mg/dL and it dropped to 8.37 mg/dL in the early moment. At six and 12 months means were 9.2 and 9.4 mg/dL, respectively. In 13 patients with four gland excision, 10 (76.9%) were normocalcemic; one patient (7.7%) recurred twice (an intratimic fifth parathyroid after 10 years and autograft recurrence after 14 years); and two (15.4%) presented hypoparathyroidism. Of 20 patients with MEN 1 preoperative diagnosis, thymectomy was performed at the first operation in 17. In the three cases without prophylatic thymectomy, one recurred in a fifht thymic parathyroid, one developed thymic carcinoid and one was normocalcemic. Conclusion: Treatment of HPT in MEN 1 is more complex. Concomitant thymectomy was associated with better results.

The impact of clinical and genetic screenings on the management of the multiple endocrine neoplasia type 1

PURPOSE: To perform clinical and genetic screening for multiple endocrine neoplasia type 1 (MEN1) in patients at the Academic Hospital of the University of São Paulo School of Medicine, and to analyze its impact on clinical management of patients with MEN1. METHODS: The clinical diagnosis of MEN1 was made in accordance with the Consensus on multiple endocrine neoplasias. Mutation analysis of the entire MEN1 tumor suppressor gene and genetic screening of at-risk family members were performed by direct sequencing. To analyze the implementation of genetic diagnosis, the studied patients were separated into 3 groups: MEN1 index cases (group I), clinically diagnosed MEN1 cases (group II), and genetically diagnosed MEN1 cases (group III). RESULTS: In total, 154 individuals were clinically and genetically studied. We identified 12 different MEN1 mutations. Fifty-two MEN1 cases were identified: 13 in group I, 28 in group II, and 11 in group III. The mean age in group III (27.0 years) was significantly lower than in groups I (39.5 years) and II (42.4 years; P = 0.03 and P = 0.01, respectively). Patients in groups I and II mostly presented 2 or 3 MEN1-related tumors, while 81.8 percent of those in group III presented 1 or no MEN1-related tumor. Additionally, in group III, 45.4 percent of cases were asymptomatic, and no metastasis or death was verified. Surveillance for MEN1 mutations allowed the exclusion of 102 noncarriers, including a case of MEN1 phenocopy. CONCLUSION: Our data supports the benefits of clinical and genetic screening for multiple endocrine neoplasia type 1 in the management of this syndrome.

OBJETIVOS: Realizar rastreamentos clínico e gênico para Neoplasia Endócrina Múltipla tipo 1 (NEM1) e analisar seu impacto no seguimento clínico desses pacientes no Hospital das Clínicas, SP. MÉTODOS: O diagnóstico clínico de NEM1 foi realizado de acordo com o Consenso sobre neoplasias endócrinas múltiplas. A análise genética para identificação de mutações foi realizada por sequenciamento automático de todas as regiões codificadoras e fronteiras exon/intron do gene MEN1. Os casos afetados foram sub-divididos em 3 grupos e analisados separadamente: casos-índices (grupo I), familiares diagnosticados clinicamente (grupo II) e genicamente (grupo III). RESULTADOS: Um total de 154 casos participou desse estudo, sendo 52 diagnosticados com NEM1: 13 do grupo I, 28 do grupo II e 11 do grupo III. A idade média ao diagnóstico no grupo III (27 anos) foi significativamente menor que a dos grupos I (39,5 anos; p = 0,03) e II (42,4 anos; p = 0,01). A maioria dos pacientes dos grupos I e II apresentou 2 ou 3 tumores, enquanto que 81,8 por cento dos casos do grupo III apresentavam 1 ou nenhum tumor relacionado à NEM1. Além disto, 45,4 por cento dos casos do grupo III eram assintomáticos, não sendo observados nenhuma metástase ou óbito. Os demais 102 familiares sob-risco estudados não herdaram mutação MEN1 e foram excluídos do rastreamento clínico. Um caso de fenocópia NEM1 foi também localizado. DISCUSSÃO: Nossos dados demonstraram importantes benefícios no seguimento dos pacientes NEM1, obtidos pela implementação dos rastreamentos clínico e gênico para essa doença.