Functioning glucagonoma associated with primary hyperparathyroidism: multiple endocrine neoplasia type 1 or incidental association?

BACKGROUND: Diagnosis of multiple endocrine neoplasia type 1 (MEN1) is commonly based on clinical criteria, and confirmed by genetic testing. In patients without known MEN1-related germline mutations, the possibility of a casual association between two or more endocrine tumors cannot be excluded and subsequent management may be difficult to plan. We describe a very uncommon case of functioning glucagonoma associated with primary hyperparathyroidism (pHPT) in which genetic testing failed to detect germline mutations of MEN-1 and other known genes responsible for MEN1. CASE PRESENTATION: The patient, a 65-year old woman, had been suffering for more than 1 year from weakness, progressive weight loss, angular cheilitis, glossitis and, more recently, skin rashes on the perineum, perioral skin and groin folds. After multidisciplinary investigations, functioning glucagonoma and asymptomatic pHPT were diagnosed and, since family history was negative, sporadic MEN1 was suspected. However, genetic testing revealed neither MEN-1 nor other gene mutations responsible for rarer cases of MEN1 (CDKN1B/p27 and other cyclin-dependent kinase inhibitor genes CDKN1A/p15, CDKN2C/p18, CDKN2B/p21). The patient underwent distal splenopancreatectomy and at the 4-month follow-up she showed complete remission of symptoms. Six months later, a thyroid nodule, suspected to be a malignant neoplasia, and two hyperfunctioning parathyroid glands were detected respectively by ultrasound with fine needle aspiration cytology and 99mTc-sestamibi scan with SPECT acquisition. Total thyroidectomy was performed, whereas selective parathyroidectomy was preferred to a more extensive procedure because the diagnosis of MEN1 was not supported by genetic analysis and intraoperative intact parathyroid hormone had revealed "adenoma-like" kinetics after the second parathyroid resection. Thirty-nine and 25 months after respectively the first and the second operation, the patient is well and shows no signs or symptoms of recurrence. CONCLUSIONS: Despite well-defined diagnostic criteria and guidelines, diagnosis of MEN1 can still be challenging. When diagnosis is doubtful, appropriate management may be difficult to establish.

Asymptomatic insulinoma: a case report and autopsy series.

AIMS: We investigated the prevalence and characterization of asymptomatic pancreatic tumors in response to our experience of asymptomatic insulinoma. METHODS: A patient with a moderately low glucose level and pancreatic incidentaloma detected by CT was examined. Pancreas specimens from 423 autopsy cases were also pathologically examined systematically by hematoxylin-eosin staining. RESULTS: The examined patient showed no profile characteristic of insulinoma by fasting or loading tests, however, ASVS led to diagnosis of insulin-producing tumor. The tumor was resected with the pancreatic body and tail and revealed to be 10 mm in diameter, with 98.5% of the cells positive for insulin. Pathological evaluation confirmed a well-differentiated endocrine pancreatic tumor, which was suggestive of an incidentally detected asymptomatic insulinoma. Microscopic evaluations of pancreatic specimens from 423 autopsy cases revealed pancreatic monotonous lesions in 6 cases (1.42%). In 4 autopsy specimens large enough for immuno-histochemical evaluation, the lesions were positive for glucagon but negative for insulin. CONCLUSIONS: As concerns the present study, retrospective immunohistochemical investigation in autopsy cases revealed the presence of asymptomatic glucagonoma but no asymptomatic insulinoma. Advances in diagnostic imaging, however, might raise the probability of detecting early asymptomatic stages of insulinoma incidentally. ASVS appears to be sensitive even for asymptomatic incidental insulinomas.

Erupciones cutáneas y masa pancreática / No disponible

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Pancreatic glucagonoma presenting as a pulmonary mass.

Glucagonoma is an uncommon disease, a neuroendocrine tumour that develops from glucagon-producing pancreatic cells. They are usually slow-growing, but generally advanced at diagnosis, and metastatic disease is virtually incurable. Liver is the most common site of metastatic disease. We present the case of a 48-year-old man with a glucagonoma being diagnosed from a pulmonary mass. This case had no liver affection in the whole evolution of the disease, and showed a particularly aggressive course, with very little response to all therapies administered, and a survival from diagnosis of just 16 months.

Pancreatic glucagonoma presenting as a pulmonary mass

Glucagonoma is an uncommon disease, a neuroendocrine tumour that develops from glucagon-producing pancreatic cells. They are usually slow-growing, but generally advanced at diagnosis, and metastatic disease is virtually incurable. Liver is the most common site of metastatic disease. We present the case of a 48-year-old man with a glucagonoma being diagnosed from a pulmonary mass. This case had no liver affection in the whole evolution of the disease, and showed a particularly aggressive course, with very little response to all therapies administered, and a survival from diagnosis of just 16 months (AU)

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Síndrome del glucagonoma y seudoglucagonoma / Glucagonoma and pseudoglucagonoma syndrome

Introducción. El síndrome del glucagonoma puede ser verdadero -asociado a un tumor pancreático secretor de glucagón- o un seudoglucagonoma, asociado a otro tipo de enfermedad. Es una enfermedad extremadamente infrecuente con una prevalencia actual estimada de 1/20.000.000.Material y métodos. Se ha realizado una revisión retrospectiva de casos de glucagonoma y seudoglucagonoma entre enero de 1998 y diciembre de 2003 en 3 hospitales. Se han tratado 5 casos: 3 con tumoración pancreática demostrable y 2 sin neoplasia asociada. Se han analizado la edad, el sexo, el diagnóstico inicial, los síntomas asociados, las enfermedades concomitantes, los procedimientos diagnósticos de imagen empleados, los datos analíticos existentes, los procedimientos terapéuticos empleados, la cirugía y el seguimiento. Resultados. Se encontró hiperglucemia en todos los casos y elevación de valores de glucagón plasmático. En 3 casos había hipoaminoacidemia y descenso de ácidos grasos totales. No se observaron alteraciones de los valores de cinc. La ultrasonografía abdominal no ofreció resultados concluyentes. La tomografía axial computarizada demostró tumoración pancreática en 3 pacientes que fueron intervenidos, por lo que fue posible la resección curativa. El eritema necrolítico migratorio ha sido la clave diagnóstica en todos los casos. La hiperglucagonemia estaba presente en todos ellos. El tratamiento quirúrgico ha sido curativo con seguimientos de 7, 36 y 56 meses en los casos de glucagonoma verdadero. Conclusiones. La prevalencia real del síndrome del glucagonoma puede ser mayor que la estimada actualmente. En nuestra serie ha sido de 13,5/20.000.000 habitantes/año (AU)

A nutrient-regulated cytosolic calcium oscillator in endocrine pancreatic glucagon-secreting cells.

We investigated the influence of nutrients on spontaneous cytosolic calcium oscillations in InR1-G9 glucagonoma cells, a model for pancreatic alpha-cells. The oscillations depended on calcium release from stores and on calcium influx, partly through voltage-dependent calcium channels. Oscillations required the presence of at least 1 mM glucose, 50 microM alanine, or 50 microM glutamine, but were terminated by higher nutrient concentrations (40 mM glucose, or above 2 mM alanine or glutamine). The effects depended on the metabolism of the nutrients. Glutamine and alanine hyperpolarized the cells. This effect was inhibited (glutamine) or attenuated (alanine) by 1 mM ouabain. Our findings suggest that [Ca2+]i regulation in alpha-cells is dominated by slow oscillations induced by a lack of metabolic energy, resulting in decreased calcium export and storage, as well as increased calcium influx, partly due to depolarization caused by reduced sodium pump activity. These processes, leading to an elevated cytosolic calcium concentration, may mediate oscillations by calcium-induced calcium release from intracellular stores.

Endocrine diffuse system. Histological and functional aspects interrelated with tumoral pathology.

It was first believed that all these endocrine cells are deriving from the neural crests; in time were discovered more than 40 different types of such cells with different origins and only 6 or 7 are deriving from the neural crests. Serotonin-secreting cells show yellow fluorescence, while those secreting cathecolamines show a green fluorescence, with formaldehyde. The most usual method for the stain of the cells of the endocrine diffuse system is the silver salts impregnation. In the electron microscopy the cells show dense granules, which are modified in appearance in the malignancies developed from such cells. Most of the hormones secreted in the intestine were found also to be hormones secreted in the central nervous system. The border between benign proliferation and malignant tumors arising from these endocrine cells is not well defined. DNES--diffuse neuroendocrine system.

Eritema necrolítico migratorio: presentación de un caso y revisión de la literatura / Necrolytic migratory erythema: case and literature review

El eritema necrolítico migratorio es una erupción cutánea característica, con hallazgos histopatológicos específicos que se relacionan frecuentemente con un tumor pancreático, el glucagonoma. Los pacientes con este síndrome son generalmente mal diagnosticados. Se presenta un paciente de 54 años de edad con una erupción cutánea recurrente, pérdida de peso, glositis e hiperglucemia de cuatro meses de duración. Esta importante, pero rara enfermedad, puede ser diagnosticada tempranamente, basándonos en el cuadro cutáneo

Eritema necrolítico migratorio: presentación de un caso y revisión de la literatura / Necrolytic migratory erythema: case and literature review

El eritema necrolítico migratorio es una erupción cutánea característica, con hallazgos histopatológicos específicos que se relacionan frecuentemente con un tumor pancreático, el glucagonoma. Los pacientes con este síndrome son generalmente mal diagnosticados. Se presenta un paciente de 54 años de edad con una erupción cutánea recurrente, pérdida de peso, glositis e hiperglucemia de cuatro meses de duración. Esta importante, pero rara enfermedad, puede ser diagnosticada tempranamente, basándonos en el cuadro cutáneo (AU)

Potent inhibitory effects of transplantable rat glucagonomas and insulinomas on the respective endogenous islet cells are associated with pancreatic apoptosis.

Effects of transplantable rat insulinomas (IN) and glucagonomas (GLU) on the endogenous pancreas were analyzed using morphometry, immunocytochemistry, in situ hybridization, and staining for apoptotic cells. Hyperinsulinemia (IN-rats) and hyper-GLP-1/glucagonemia (GLU-rats) were both associated with marked islet atrophy (67 and 76% of control average planimetrical islet area, respectively). Selective islet B cell inhibition of proinsulin (I and II) genes as well as of expression of the insulin gene transcription factor, IPF1/STF1, was found in IN-rats. Moreover, these islets were characterized by significant B cells apoptosis in the absence of infiltrating lymphocytes. In GLU-rats selective islet A cell inhibition was observed at the level of glucagon mRNA. These islets contained small, highly condensed but clearly active B cells with prominent IPF1/STF1-positive nuclei, surrounded by densely packed glucagon-negative cells with reduced cytoplasm. Furthermore, an active apoptotic process was found exclusively in the exocrine pancreas of GLU-rats. Thus, in IN-rats, islet B cell mass reduction is distinguished by non-immune-mediated programmed cell death, while GLU-rats exhibit A cell mass reduction by cytoplasmic retraction and selective exocrine apoptosis.

Transplantable glucagonomas derived from pluripotent rat islet tumor tissue cause severe anorexia and adipsia.

From pluripotent pancreatic rat islet tumor tissue we have previously reported the isolation of stable transplantable glucagonoma tumor phenotypes in rats characterized by acute onset of anorexia. We now report that these tumors also cause severe adipsia. Food and water intake is reduced by more than 95% and is immediately cured upon tumor removal. Four anorectic tumor lines were all characterized as glucagonomas with high levels of proglucagon mRNA, and of two tested both were associated with highly elevated plasma levels of glucagon as well as of Glp-1(7-36amide) in the host rat. This fetal processing pattern of proglucagon may be indirectly linked to the anorectic phenotype, since we have now isolated a non-anorectic glucagonoma with similar levels of proglucagon mRNA. Lack of anorexia/adipsia in SV-40-T-antigen driven glucagonomas in transgenic mice with similar fetal processing as reported by other suggests that our tumors produce a novel anorectic substance. This factor ranges among the most potent of its kind as a peripheral mediator involved in appetite and thirst regulation. In summary, the glucagonomas provide an interesting tool with which to study the nature of severe anorexia as well as adipsia, and the identification of the active substance(s) may provide novel therapeutics for the treatment of obesity-related disorders such as NIDDM.

Eritema necrolítico migratorio asociado a glucagonoma / Necrolytic migratory erythema asociated with glucagonoma

Se estudia y comenta el caso de un hombre de 36 años que presentó lesiones cutáneas qeu clínica e histológiamente fueron diagnosticadas como eriterma necrolítico migratorio, que a su vez determinó el diagnóstico de glucagnoma. Se destaca la rareza de estos casos y la importancia de las lesiones cutáneas como mercadores de este tipo de neoplasia pancreático que puede secretar múltiples hormonas. También se hace hincapié en que es más frecuente en la mujer, sin embargo, en este caso se trata de un hombre que desgraciadamente lleva 10 meses con estaneoplasia no diagnosticada.