Sue M. Challinor

Identification of multiple endocrine neoplasia type 1 in patients with apparent sporadic primary hyperparathyroidism

BACKGROUND In the evaluation of patients with primary hyperparathyroidism (PHP), specific query for a personal or family history of MEN1 (Hx) is recommended widely, but responses are rarely positiv. We instituted a 6-question panel (6Q) to routinely screen for MEN1 preoperatively. METHODS The clinical database entries of 939 patients explored for apparent sporadic PHP from June 1992 to November 2007 were examined for presenting diagnosis, demographics, anatomic findings, MEN1 analysis, and final diagnosis. To directly compare the results of 6Q and Hx, we also reviewed the charts of 654/939 PHP patients screened systematically from January 2000 to November 2007. RESULTS MEN1 was undiagnosed until the preoperative evaluation in 1.6% of patients referred with apparent sporadic PHP. To date, MEN1 has been diagnosed in 42 of 939 (4.5%) PHP patients. Compared with those who have sporadic PHP, MEN1 patients were often male (38.1% vs 20.2%; P = .005) and young (mean, 38 +/- 17 years vs 60 +/- 13 years; P < .001). When hyperplasia was present at initial parathyroid exploration, the likelihood of MEN1 was 26% (32/123). For the 15 patients diagnosed by a surgeon to have MEN1, Hx was positive in 3 patients (20%) and 6Q in 13 (87%) (P = .0002). In a multivariate analysis of 635 patients with negative Hx, the likelihood of MEN1 increased with (1) younger age at initial parathyroid exploration and (2) number of positive 6Q responses. CONCLUSION MEN1 occurs relatively often and can be missed. Systematic use of a simple 6-question panel helps to identify MEN1 prior to parathyroid exploration. Young male patients with parathyroid hyperplasia and positive 6Q results should be evaluated for MEN1.

Imaging of the pituitary.

In the appropriate clinical setting of pituitary hyperfunction or hypofunction, visual field deficit, or cranial nerve palsy, imaging of the pituitary is necessary. This article reviews the normal appearance of the pituitary and its surroundings, emphasizing magnetic resonance imaging. Typical and variant appearances of pituitary pathology are discussed. Because growth of adenoma into surrounding structures is important to surgical management, cavernous sinus invasion and suprasellar spread as well as adenoma mimics are illustrated. Typical examples of pituitary dysfunction from other entities that secondarily affect the gland, hypophysis, or third ventricle are discussed. Some common errors of interpretation are listed.

Pulses of oxytocin in the cerebrospinal fluid of rhesus monkeys.

Cerebrospinal fluid (CSF) samples were collected at frequent intervals (every 10-15 min) to determine if oxytocin pulses were present in the CSF of monkeys. Temporary indwelling subarachnoid catheters, with the tip of the catheter at the T12-L1 subarachnoid space, were placed in 4 nonlactating and 3 lactating (4 months post partum) female monkeys. Monkeys were maintained on jacket/tether/swivel systems in a constant photoperiod (07.00-19.00 h). CSF was continuously withdrawn at a rate of 1.2 ml/h by peristaltic pump, and CSF was collected in 15-min fractions (from 3 lactating monkeys and 1 nonlactating monkey) or in 10-min fractions (from the other 3 nonlactating monkeys) using a fraction collector. CSF oxytocin was measured by radioimmunoassay. Pulses of oxytocin were analyzed using the computerized Pulsar pulse detection algorithm. A pulsatile pattern of oxytocin concentrations was found in the CSF of lactating and nonlactating monkeys. The ultradian pulses of oxytocin were superimposed upon the diurnal rhythm of oxytocin in CSF. We conclude that frequent sampling of CSF provides a way to monitor moment-to-moment changes in central nervous system concentrations of oxytocin in primates.

Effect of Naloxone Administration upon the Diurnal Concentrations of Oxytocin in the Cerebrospinal Fluid of Rhesus and Cynomolgus Monkeys

A diurnal pattern in oxytocin concentrations is present in cerebrospinal fluid (CSF) removed from the spinal subarachnoid space of monkeys, with elevated levels occurring in the early light hours. In order to investigate the possible role of endogenous opioid peptides in the generation of this oxytocin rhythm, we administered naloxone (0.4 mg/kg/h x 48 h) to rhesus and cynomolgus monkeys and examined the effects on the diurnal pattern of oxytocin in CSF collected from the lumbar subarachnoid spinal space. Monkeys maintained on jacket/tether/swivel systems and in a 12 h light: 12 h dark cycle (lights on 07.00-19.00 h) were implanted with temporary spinal subarachnoid catheters. CSF was continuously collected from the lumbar subarachnoid space and assayed for oxytocin. Oxytocin concentrations in CSF showed a diurnal variation with peak and nadir concentrations during light and dark hours, respectively. The lumbar CSF concentrations of oxytocin were not significantly different during naloxone vs. saline infusion. Plasma oxytocin concentrations, measured in the same animals, displayed no diurnal variation and were not significantly different during naloxone vs. saline infusion. We conclude that naloxone administration for 48 h does not perturb the diurnal variation in oxytocin concentrations in the CSF of monkeys. Mu opioid receptors are unlikely to be involved in modulating the diurnal rhythm of oxytocin in the CSF of monkeys.

A 23-year-old female with a mixed germ cell tumor of the pituitary infundibulum: the challenge of differentiating neoplasm from lymphocytic infundibuloneurohypophysitis-a case report and literature review.

The pathologic spectrum of diseases that infiltrate the pituitary infundibulum includes a broad variety of clinical entities. There are significant differences in the prevalence of these etiologies depending on the age of presentation. Lymphocytic infundibuloneurohypophysitis (LINH) predominates over other causes of infundibular disease in adults over age 21. Differentiating LINH from other causes of infundibular disease can be difficult because the various etiologies often have similar clinical presentations and radiologic imaging characteristics. We report the first case in an adult of a mixed germ cell tumor comprised of germinoma and embryonal cell carcinoma infiltrating the pituitary infundibulum. In our case, a 23-year-old female was initially misdiagnosed as having LINH. She presented with panhypopituitarism and diabetes insipidus, which is the most common initial presentation in both entities. The two diagnoses are difficult to distinguish based on MRI imaging, CSF findings, and histopathological examination. Our case demonstrates the need for close follow-up of patients with isolated lesions of the pituitary infundibulum and reinforces the need for biopsy of an infundibular lesion when progression of disease is demonstrated. In our case, biopsy with comprehensive immunohistochemical staining was the sole means of making a definitive diagnosis.

Primary RET-mutated lung neuroendocrine carcinoma in MEN2B: response to RET-targeted therapy

Multiple endocrine neoplasias (MENs) are genetic syndromes distinguished by specific patterns of benign and malignant tumors of endocrine glands. MEN2 is caused by autosomal dominant inheritance of a gain-of-function mutation in the RET proto-oncogene on chromosome 10 (Mulligan & Ponder 1995, Santoro et al. 1995) and is further subclassified into three syndromes based on clinical phenotype: MEN2A (medullary thyroid cancer (MTC), pheochromocytoma, primary parathyroid hyperplasia); MEN2B (MTC and pheochromocytoma), and familial medullary thyroid cancer (MTC only). MEN is first suspected when an index patient presents with one or more tumors specific to that syndrome. Of all MEN2B cases, 95% are represented by a germline point mutation affecting codon 918 (exon 16) resulting in a methionine to threonine alteration (M918T), inducing constitutive activation of the intracellular tyrosine kinase domain of the encoded RET receptor tyrosine kinase (RTK) (Alberti et al. 2003). Tumor formation occurs in the neuroendocrine organs where constitutively activated RET is expressed. Although neuroendocrine carcinoma (NEC) of the lung has been described in MEN 1 (Farhandi et al. 1987), it has not been described in the MEN2 syndromes. Treatment of MEN-associated tumors primarily involves surgical excision of the neoplasm. In MEN2, prophylactic thyroidectomy is recommended for family members who carry the germline mutation, ideally within the first year of life in patients with MEN2B due to the high penetrance, morbidity, and mortality of MTC associated with the M918T mutation (Skinner et al. 2005). Standard cytotoxic chemotherapy and radiotherapy are not effective in MTC (Orlandi et al. 2001); however, novel targeted therapies have been developed that inhibit the activated RET RTK, including cabozantinib (Elisei et al. 2013). In 1994, a 40-year-old healthy, nonsmoking, Caucasian male experienced a hypertensive crisis