Multiple Endocrine Neoplasia Type 2B Research Articles

Mega-Intestine After Subtotal Colectomy for Constipation

t A male with multiple endocrine neoplasia (MEN) type 2B presented with chronic abdominal distention and onstipation. He had previously undergone total thyroidectomy or medullary thyroid carcinoma, and a subtotal colectomy with leosigmoidostomy for megacolon. Examination revealed a maranoid body habitus, neuromas on the tip of the tongue, pectus xcavatum, and severe abdominal distention. Laboratory studies ere unremarkable, including negative urine catecholamines creening for pheochromocytoma. Abdominal x-ray showed muliple dilated loops of small bowel (Figure A). At laparotomy, ilated loops of small bowel with maximum diameter of 8 cm were oted (Figure B). The patient underwent sigmoid resection with nd ileostomy. On microscopic examination, the sigmoid and erminal ileum revealed hyperplasia of the nerve plexuses and an ncreased density of ganglia, many of which showed dysplastic hanges (Figure C, inset, yellow arrow). Hyperplastic subserosal erve fibers were also identified (Figure C, inset, black arrow). Intestinal ganglioneuromatosis associated with MEN type 2B as confirmed by the identification of dysplastic ganglion cells in oth resected sigmoid and terminal ileum. Intestinal ganglioneuomatosis (gangliocytic dysplasia) is characterized by hyperplasia f myenteric or submucosal nerve plexuses with increased number nd size of dysplastic ganglia, and hyperplastic subserosal nerves.1 MEN 2B results from an autosomal dominant mutation with a high degree of penetrance. The mutation involves a gain of function of the RET (rearranged during transfection) proto-oncogene (that encodes a tyrosine kinase receptor) on chromosome 10. The mutation appears to induce growth and differentiation in several developing tissues including those derived from the neural crest.2 In a 28-patient series, 93% of patients with MEN 2B had gastrointestinal symptoms 1 to 24 years before the diagnosis of MEN 2B. Symptoms included flatulence (86%), abdominal distention or being underweight as a child (64%), abdominal pain (54%), constipation or diarrhea (43%), difficulty swallowing (39%), vomiting (14%), and 29% underwent surgery.2 In a series of 16 patients, 90% had colonic disturbances, typically chronic constipation from birth. Megacolon developed in 14 patients, and 8 required colonic surgery.3 Postoperatively, the patient received oral pyridostigmine 60 mg 4 times a day, and supplemental parenteral nutrition. One month later, he was asymptomatic, on regular (full) oral diet and pyridostigmine, and intestinal loops were not dilated on abdominal radiograph. Management of abdominal distension and constipation in MEN 2B is usually conservative with laxatives; however some patients require total colectomy and oral prokinetic agents. Our patient responded to acetyl cholinesterase inhibition (pyridostigmine). The potential efficacy of 5-hydroxytryptamine (5HT)4 agonists, other prokinetics, and stem cell therapy for intesinal ganglioneuromatosis associated with MEN 2B are unclear.

Multiple Endocrine Neoplasia Type 2B with a RET Proto-Oncogene A883F Mutation Displays a More Indolent Form of Medullary Thyroid Carcinoma Compared with a RET M918T Mutation

Most cases of multiple endocrine neoplasia type 2B (MEN-2B) are attributable to a germline methionine to threonine mutation at codon 918 (M918T) of the RET proto-oncogene; very few cases of a germline alanine to phenylalanine mutation at codon 883 (A883F) are reported without a clear description of the clinical course. Nevertheless, RET-A883F is currently considered to be among the highest risk mutations, and prophylactic thyroidectomy is recommended as early as 6 months of life. Further characterization of the clinical behavior of RET-A883F mutation is warranted. We present the clinical data for a family with MEN-2B associated with RET-A883F mutation. The proband, a 39-year-old woman, had multifocal medullary thyroid carcinoma (MTC) with cervical lymphadenopathy, but no evidence of distant metastases. She was disease free after surgical resection. She also had bilateral pheochromocytomas and mucosal neuromas leading to the clinical diagnosis of MEN-2B. Genetic testing showed that the woman and her three children (3-5 years old) had the RET-A883F mutation. The children had near-normal calcitonin levels, and none had sonographic evidence of suspicious thyroid nodules or cervical lymphadenopathy. A family with MEN-2B due to RET-A883F mutation displayed a less aggressive form of MTC than what is usually seen in patients with RET-M918T mutation. RET-A883F mutation could be a lower-risk mutation than previously thought and the current recommendation of prophylactic thyroidectomy in the first year of life may not be warranted. Further reports will help clarify the natural history of MTC caused by this mutation.

An Unusual Presentation of Ganglioneuromatosis of Gallbladder in Absence of MEN Type 2b

Purpose: Neuronal hyperplasia or ganglioneuromatosis are very rare tumors which may present as components of multiple endocrine neoplasia type 2b (MEN2b). They may evolve from differentiating neuroblastoma or originate as a primary ganglioneuroma. Ganglioneuromas are usually incidental findings. As far as we know, this is a second case report in a literature presenting as an incidental ganglioneuromatosis of gallbladder after elective cholecystectomy for cholelithiasis. Case report: A 36 year old Hispanic female with history of hypothyroidism due to subtotal thyroidectomy for multinodular goiter and cyst was referred to gastroenterology clinic for a symptomatic elevation of liver enzymes. Patient denied history of sweating, palpitation, hypertension, alcohol intake or intravenous drug use. She had marfanoid features on physical examination. Labs revealed ALT 303, AST 167, ALP 224, GGT 103 and TSH 122.22. Antinuclear antibody, anti smooth muscle antibody, sprue serology, iron studies, ceruloplasmin and alpha 1 antitrypsin were unremarkable. Hepatitis serology was negative for Hepatitis A antibody, Hepatitis C antibody and hepatitis B surface antigen. Liver biopsy was also unremarkable. Ultrasound of the abdomen revealed gallstones in gallbladder. Patient subsequently had laparoscopic cholecystectomy and pathology report of the gallbladder specimen showed diffuse subepithelial spindle cell proliferation with rare ganglion cells in the lamina propria. Immunohistochemical stains revealed that spindle cells are positive for S100 and ganglion cells were positive for synaptophysin. The spindle cell proliferation was also present in the cystic duct margin. The staining pattern supported the diagnosis of ganglioneuroma of the gallbladder wall. Patient is being followed up in GI clinic intermittently. Discussion: Ganglioneuromas are asymptomatic regardless of their size, however, may present with abdominal pain, dyspepsia, dyspnea, cough and abdominal mass. Some may be hormonally active and hypertension, diarrhea, flushing and virilization may occur from catecholamine, vasoactive intestinal peptide or androgenic hormone secretion. Tests that can be done if ganglioneuroma is suspected include; CT scan and MRI. Blood and urine testing can also be done for hormonally active tumor. However, the definitive diagnosis is made by tissue biopsy. Treatment is surgical resection of the tumor and prognosis after resection seems to be excellent. Conclusion: Even though Ganglionueromas are benign they may present as a part of MEN type 2b with potentially lethal endocrine neoplasm. Every attempt should be made to look for MEN type 2b with incidental findings of ganglioneuromatosis.

Multiple endocrine neoplasia type 2B associated with malignant melanoma

Multiple endocrine neoplasia type 2B associated with malignant melanoma

Multiple Endocrine Neoplasia-2B Presenting with Orthodontic Relapse

The multiple endocrine neoplasia (MEN) syndromes are a relatively uncommon group of genetic disorders characterized by the development of tumors in various endocrine organs. MEN type 2B is of particular interest to the dental profession because of its oral manifestations, which are often some of the earliest clinically detectable signs of the disorder. Early identification of this syndrome is critical because affected patients often develop a characteristic malignancy, medullary carcinoma of the thyroid, at a very early age. We describe a 17-year-old male whose initial diagnosis of MEN-2B was triggered by his orthodontist's request for an oral and maxillofacial pathology consultation to evaluate the patient's oral abnormalities.

Multiple Endocrine Neoplasia Type 2B: Early Diagnosis by Multiple Mucosal Neuroma and Its DNA Analysis

Multiple endocrine neoplasia type 2B (MEN 2B) is a rare disease caused by germline mutations in the RET proto-oncogene and is transmitted in an autosomal dominant fashion. It is characterized by medullary thyroid carcinoma, pheochromocytoma and mucosal neuroma developing in the tongue, lip, intestinal tract, palate etc. Among these neoplasias, mucosal neuroma generally develops from early childhood. Therefore, early detection and proper treatment can minimize the disease course. Here we describe a 9-year-old male who presented with multiple verrucous papules and nodules on his lips, tongue and gingiva that were there since birth. Histologic findings of his lips and tongue showed well-defined nerve bundles and DNA analysis revealed a M918T mutation at codon 918 of the RET oncogene. He was diagnosed early as having MEN 2B according to his genetic and phenotypic features.

Constitutive Ret signaling is protective for dopaminergic cell bodies but not for axonal terminals

Ret is the canonical signaling receptor for glial cell line-derived neurotrophic factor (GDNF), which has been shown to have neuroprotective effects when administered prior to neurotoxic challenge. A missense Meth918Thr mutation causes the constitutive activation of Ret, resulting in multiple endocrine neoplasia type 2 B (MEN2B). To clarify the role of Ret signaling in neuroprotection, we studied the effects of the neurotoxins 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 6-hydroxydopamine (6-OHDA) on the dopaminergic system of mice carrying the MEN2B mutation. We found that MEN2B mice were significantly more resistant to nigral tyrosine hydroxylase (TH)-positive cell loss induced by unilateral striatal 6-OHDA than Wt mice. However, 6-OHDA caused profound dopamine (DA) depletion in the striatum of both MEN2B and Wt mice. Systemic MPTP caused similar DA depletion and a decrease in TH-immunostaining in the striatum of MEN2B and Wt mice. Neither neurotoxin induced a compensatory increase in striatal metabolite/DA ratios in the MEN2B mice, possibly contributing to an increased amphetamine-induced turning behavior observed in behavioral assessments of these mice. Thus, our data suggest that activated Ret protects DA cell bodies in the substantia nigra pars compacta, but does not protect DA axons in the striatum.

Medullary thyroid carcinoma identified within the first year of life in children with hereditary multiple endocrine neoplasia type 2A (codon 634) and 2B

Early prophylactic thyroidectomy in patients with multiple endocrine neoplasia (MEN) type 2 offers the best chance for a normal life expectancy. To analyze the results of thyroidectomy performed during the first year of life in six patients with MEN 2A (codon 634) or MEN 2B (codon 918) syndrome. A university hospital-based prospective study from 2001 to 2008. Six family members affected either by MEN 2A (n=3) or MEN 2B (n=3) syndrome were identified through neonatal genetic screening. Total thyroidectomy was performed at a median age of 0.8 year in the six patients, with central lymph node dissection in five. Bilateral millimetric medullary thyroid carcinoma (MTC) was found in all patients, with a unilateral lymph node micrometastasis in two of the three MEN 2B patients. Before thyroidectomy, MEN 2B patients had much higher basal serum calcitonin levels than those with MEN 2A and controls. After thyroidectomy, with a median follow-up of 3.3 years, the six patients had no evidence of persistent MTC. Bilateral millimetric MTC may be present during the first year of life in these patients, with lymph node metastases also occurring in MEN 2B patients. These results support a total thyroidectomy at the age of about one year in MEN 2A (codon 634) children with an abnormal serum calcitonin level, and a total thyroidectomy with central neck dissection within the first weeks of life in MEN 2B patients.

Diabetes insipidus and panhypopituitarism due to intrasellar metastasis from medullary thyroid cancer

Medullary thyroid cancer (MTC) commonly metastasizes to lymph nodes in the central and lateral neck, but spread to distant organs also occurs, typically involving lung, liver, and bone. Metastases to pituitary gland are rare for this tumor. We describe an unusual case and peculiar presentation of pituitary metastasis from MTC. We report clinical, genetic, and laboratory data of this patient. A young woman with multiple endocrine neoplasia type 2B was seen with recent onset of classic symptoms and signs of panhypopituitarism, mild diabetes insipidus, and optic chiasmatic compression. Transphenoidal resection of an intrapituitary mass confirmed the presence of metastatic MTC. MTC recurrence may present solely with subacute pituitary symptomatology, even in the context of a very lengthy interval after initial surgery, atypically low calcitonin plasma levels, carcinoembryonic antigen doubling times, and the concomitant absence of other tell-tale signs of disseminated metastatic disease.

A ganglioneuroma of the sigmoid colon presenting as leading point of intussusception in a child: a case report

We present a case of intestinal ganglioneuroma (GN) of the sigmoid colon in a 5-year-old girl, which caused intermittent colocolic intussusception. Ganglioneuromas are rare benign tumors of the autonomic nervous system composed of mature ganglion cells and satellite cells. Colonic GNs are uncommon. The unusual intramural proliferation of neural elements in this case resembled the diffuse intestinal ganglioneuromatosis, which is known to be associated with multiple endocrine neoplasia type 2B. However, the specific mutations of multiple endocrine neoplasia type 2B were not found by genetic sequencing. This is the first pediatric case described in the literature of a solitary polypoid GN presenting as a colocolic intussusception. We present a brief overview of intestinal ganglioneuromatous lesions and associated conditions.

Identification of tyrosine 806 as a molecular determinant of RET kinase sensitivity to ZD6474

ZD6474 (vandetanib, Zactima, Astra Zeneca) is an anilinoquinazoline used to target the receptor tyrosine kinase RET in familial and sporadic thyroid carcinoma (IC(50): 100 nM). The aim of this study was to identify molecular determinants of RET sensitivity to ZD6474. Here, we show that mutation of RET tyrosine 806 to cysteine (Y806C) induced RET kinase resistance to ZD6474 (IC(50): 933 nM). Y806 maps close to the gate-keeper position at the RET kinase nucleotide-binding pocket. Although tyrosine 806 is a RET auto-phosphorylation site, its substitution to phenylalanine (Y806F) did not markedly affect RET susceptibility to ZD6474 (IC(50): 87 nM), suggesting that phosphorylation of Y806 is not required for compound binding. Accordingly, the introduction of a phosphomimetic residue (Y806E) also caused resistance to ZD6474, albeit of a lesser degree (IC(50): 512 nM) than the cysteine mutation. Y806C/E RET mutants were also resistant to ZD6474 with respect to intracellular signalling and activation of an AP1-responsive promoter. We conclude that Y806 is a molecular determinant of RET sensitivity to ZD6474. Y806C is a natural RET mutation identified in a patient affected by multiple endocrine neoplasia type 2B. Based on its rare occurrence, it is unlikely that Y806C will be a frequent cause of refractoriness to ZD6474; however, it may be envisaged that mutations at this site can mediate secondary resistance formation in patients treated with the compound.

Transcriptome analysis in mouse tumors induced by Ret-MEN2/FMTC mutations reveals subtype-specific role in survival and interference with immune surveillance

Activating mutations in the Ret proto-oncogene are responsible for occurrence of multiple endocrine neoplasia (MEN) type 2A and 2B, and familial medullary thyroid carcinoma (FMTC). A striking genotype-phenotype correlation between the mutated RET codon and clinical manifestation implies that tumorigenesis is conditioned by the type of mutation. We investigated gene expression profiles between and within distinct MEN2 subtypes through whole-genome microarray analysis in tumors induced by NIH-3T3 cells transformed with defined RET-MEN2A (C609Y, C634R), MEN2B, (A883F, M918T), and FMTC (Y791F) mutations. Expression profiling identified a statistically significant modification of 1494 genes, 628 down- and 866 upregulated in MEN2B compared with MEN2A/FMTC tumors. By contrast, no obvious alterations were observed among individual MEN2B and MEN2A type mutations, or between MEN2A and FMTC. Functional clustering of differential genes revealed RET-MEN2B specific upregulation of genes associated with novel growth and survival pathways. Intriguingly, RET-MEN2A/FMTC-specific tumors were characterized by a considerable number of genes involved in the host antitumor immune response via stimulation of natural killer/T-cell proliferation, migration, and cytotoxicity, which were completely absent in RET-MEN2B related cancers. QPCR on tumors versus cultured NIH-RET cell lines demonstrated that they are largely attributed to the host innate immune system, whereas expression of CX3CL1 involved in leukocyte recruitment is exclusively RET-MEN2A/FMTC tumor cell dependent. In correlation, massive inflammatory infiltrates were apparent only in tumors carrying MEN type 2A/FMTC mutations, suggesting that RET-MEN2B receptors specifically counteract immune infiltration by preventing chemokine expression, which may contribute to the different clinical outcome of both subtypes.

Early diagnosis of multiple endocrine neoplasia type 2B: a challenge for physicians

The hereditary form of medullary thyroid carcinoma may occur isolated as a familial medullary thyroid carcinoma (FMTC) or as part of Multiple Endocrine Neoplasia 2A (MEN2A) and 2B (MEN2B). MEN2B is a rare syndrome, its phenotype may usually, but not always, be noted by the physician. In the infant none of the MEN2B characteristics are present, except by early gastrointestinal dysfunction caused by intestinal neuromas. When available, genetic analysis confirms the diagnosis and guides pre-operative evaluation and extent of surgery. Here we report four cases of MEN2B in which the late diagnosis had a significant impact in clinical evolution and, potentially, in overall survival. We report four cases, 2 men and 2 women, with differences in their phenotypes and with a late diagnosis. The first case has a history of severe gastrointestinal obstruction requiring a surgery intervention two days after his birth. The second told had nodules in the oral mucosa and constipation since childhood. The third case referred a history of constipation from birth until 5 months of life. The fourth has had a history of chronic constipation since childhood. New concepts have emerged since the RET oncogene was identified in 1993 as the responsible gene for hereditary medullary thyroid carcinoma. The majority of MEN2B individuals have M918T mutation in the exon 16 of RET, with a few cases having a mutation A883F or the association of V804M with E805K, Y806C or S904C mutations. The consensus classifies the RET mutation in codon 918 as of highest risk and recommends total thyroidectomy and central lymph node dissection until 6 months after birth. A fast and precise diagnosis is essential to reach these goals. The identification of early manifestations such as intestinal ganglioneuromatosis and oral mucosal neuromas should prompt the physician to initiate an investigation for multiple endocrine neoplasia type 2B. The diagnosis of MEN2B is very important to allow appropriate investigation of associated diseases and to allow counseling and appropriate screening of relatives for a RET mutation. Even patients with MEN2B, which often have typical physical features, may not be properly recognized and be followed as a sporadic case. Based on this, all suspicious cases of multiple endocrine neoplasia should undergo a molecular genetic test.

Proteomics study of medullary thyroid carcinomas expressing RET germ‐line mutations: Identification of new signaling elements

Proteomics may help to elucidate differential signaling networks underlying the effects of compounds and to identify new therapeutic targets. Using a proteomic-multiplexed analysis of the phosphotyrosine signaling together with antibody-based validation techniques, we identified several candidate molecules for RET (rearranged during transfection) tyrosine kinase receptor carrying mutations responsible for the multiple endocrine neoplasia type 2A and 2B (MEN2A and MEN2B) syndromes in two human medullary thyroid carcinoma (MTC) cell lines, TT and MZ-CRC-1, which express the RET-MEN2A and RET-MEN2B oncoproteins, respectively. Signaling elements downstream of these oncoproteins were identified after treating cells with the indolinone tyrosine kinase inhibitor RPI-1 to knock down RET phosphorylation activity. We detected 23 and 18 affinity-purified phosphotyrosine proteins in untreated TT and MZ-CRC-1 cells, respectively, most of which were shared and sensitive to RPI-1 treatment. However, our data clearly point to specific signaling features of the RET-MEN2A and RET-MEN2B oncogenic pathways. Moreover, the detection of high-level expression of minimally phosphorylated epidermal growth factor receptor (EGFR) in both TT and MZ-CRC-1 cells, together with our data on the effects of EGF stimulation on the proteomic profiles and the response to Gefitinib treatment, suggest the relevance of EGFR signaling in these cell lines, especially since analysis of 14 archival MTC specimens revealed EGFR mRNA expression in all samples. Together, our data suggest that RET/EGFR multi-target inhibitors might be beneficial for therapy of MTC.

Rapid Diagnosis of MEN2B Using Unlabeled Probe Melting Analysis and the LightCycler 480 Instrument

Multiple endocrine neoplasia type 2B (MEN2B) is an autosomal dominant, inherited cancer syndrome. MEN2B patients have a high risk of developing medullary thyroid carcinoma, and prophylactic thyroidectomy is recommended by 6 months of age. Genetic testing can identify MEN2B patients before cancer progression. Two RET proto-oncogene mutations, in exon 15 at codon 883 (GCT>TTT) and in exon 16 at codon 918 (ATG>ACG), account for more than 98% of MEN2B cases. An assay using unlabeled probes and the LightCycler 480 instrument was developed to genotype these two common MEN2B RET mutations. Asymmetric polymerase chain reaction was used to increase ssDNA products followed by melting analysis of the unlabeled probe/ssDNA amplicon duplex. The available samples were either patient DNA of known RET genotype or artificial templates. Analysis of the codon 883 heterozygous mutation demonstrated a DeltaT(m) of 5.70 +/- 0.11 degrees C, while the codon 918 heterozygous mutation generated a DeltaT(m) of -5.72 +/- 0.11 degrees C. Samples with the targeted RET mutation genotypes were accurately detected and easily distinguishable from five other reported sequence changes using these probes. Thus, MEN2B diagnosis using unlabeled probes and the LightCycler 480 is a rapid, closed-tube method that is less time consuming and less expensive than sequencing. This assay demonstrates 100% specificity and sensitivity for the identification of RET mutations causative of MEN2B.

MEN 2B syndrome should be part of the working diagnosis of constipation of the newborn

MEN 2B syndrome should be part of the working diagnosis of constipation of the newborn

Ocular Findings in a Child With Multiple Endocrine Neoplasia Type 2b

A 16-year-old girl was admitted with severe bilateral conjunctival hyperemia and stinging lasting for more than 1 year. Slit-lamp biomicroscopic examination revealed extremely thickened corneal nerves and multiple small plexiform subconjunctival neuromas. Both eyes had thickened upper and lower eyelids and a neuroma was found on the left upper conjunctival lid margin. On physical examination, a 2 x 3 cm nodule was detected within the thyroid gland. Medullary thyroid carcinoma was diagnosed by fine needle aspiration biopsy and thyroidectomy ensued. Further investigation with abdominal computed tomography revealed a pheochromocytoma (3 x 4.5 x 2 cm) of the right adrenal gland, which was removed surgically. Ophthalmologists must remember multiple endocrine neoplasia 2b in the presence of greatly thickened corneal nerves and subconjunctival neuroma because this may be the first sign of the disease. Early diagnosis and prophylactic thyroidectomy may be life saving.

Poster 079: A Review of 308 Oral Peripheral Nerve Sheath Tumors

Recently we have started the classification of all oral soft tissue tumors that have been accessioned at the Oral Pathology Laboratories, University of Minnesota, School of Dentistry. We reviewed first peripheral nerve sheath tumors (PNST). In general, oral PNSTs are not infrequent and they may be occasionally associated with syndromes such as neurofibromatosis types 1, schwannomatosis, and multiple endocrine neoplasia type 2B. In this study we included neurofibromas, schwannomas, palisading encapsulating neuromas (PEN), and traumatic neuromas. Also we tried to identify unusual types of PNSTs such as myxomas, perineuriomas, neurothekeomas, etc. Granular cell tumors, although they are of apparent neural origin, were not included this time. The archives from 1959 to 2006 included 410 cases of PNSTs. From these cases we have completed the evaluation of 308. Clinicodemographic data were available in all these cases as were histologic preparations. We performed descriptive statistics. Out of 308 cases of PNSTs, 141 (∼45.8%) were neurofibromas, 74 (∼24.0%) were traumatic neuromas, 48 were (∼15.6%) schwannomas, 39 (∼12.6%) were PEN and 2 (∼0.6%) were nerve sheath myxomas. In this first cataloguing we did not include a potential case of perineurioma since the immunohistochemical evaluation is not performed yet. There were no confirmed cases of neurothekeomas. Among the 141 cases of neurofibromas, 85 (∼60.3%) patients were females and 56 (∼39.7%) males. Age ranged from 11-93 years with the mean of 41 years. The location was known for 139 cases. Specifically, 35 (∼25%) occurred in the palate, 28 (∼20%) on the mandibular gingiva, 19 (∼14%) in the tongue, 15 (∼11%) in the buccal mucosa, 12 (∼8.5%) on the maxillary gingiva, 8 (∼5.7%) on the lower lip, 7 (∼5%) in the mandible, 4 (∼3%) in the retromolar mucosa, 3 (2%) in the upper lip, 2 (∼1%) in the floor of the mouth, and 2 (∼1%) in the maxilla. Among traumatic neuromas, 47 (∼63.5%) patients were females and 27 (∼36.5%) males. Age ranged from 5-90 years with a mean of 41 years. The location was known for 72 cases. Specifically, 23 (∼31%) were found in the tongue, 22 (∼30%) in the lower lip, 8 (∼11%) in the buccal mucosa, 6 (∼8%) in the palate, 3 (∼4%) in the mandibular gingiva, 3 (∼4%) in the upper lip, 2 (∼3%) in the maxillary gingiva and 1 (∼1%) on the floor of mouth. Among 48 schwannomas, 19 (∼39.6%) patients were females and 29 (∼60.4%) were males. Age ranged from 9-71 with a mean 31 years. The location was known for all cases. Specifically, 13 (∼27%) found in the tongue, 9 (∼19%) in the mandible, 5 (∼11%) in the mandibular gingiva, 5 (∼11%) in the lower lip, 4 (∼8%) in the upper lip, 4 (∼8%) in the palate, 4 (∼8%) in the buccal mucosa, 3 (∼6%) on the floor of mouth and 1(∼2%) in the maxillary gingiva. Among 39 PEN, 12 (∼30.7%) were females and 27 (∼69.2%) males. Age ranged from 20-71 year with a mean of 47 years. The location was known for 38 cases. Specifically, 22 (∼56%) found in the palate, 5 (∼13%) in the tongue, 4 (∼10%) in the maxillary gingiva, 4 (∼10%) in the upper lip, 2 (∼5%) in the lower lip and 1 (∼3%) in the maxilla. Of the two nerve sheath myxoma cases both patients were female. Also, among these peripheral nerve sheath tumors there were three hyperplastic neuromas that occurred in patients with MEN 2B. Histologically, most neurofibromas were solitary and showed typical histologic characteristics. Seven patients with solitary neurofibromas had neurofibromatosis type 1. Eleven neurofibromas were intraneural and 12 had a plexiform pattern with 3 of the 12 patients having a history of neurofibromatosis. Since plexiform neurofibromas are seen mostly in association with neurofibromatosis we tried to inquire additional patient information. Among schwannomas we identified 6 cases that were classified as plexiform. None of these patients had schwannomatosis. The above study represents the largest series of oral peripheral nerve sheath tumors.

Medullary thyroid carcinoma metastatic to the pituitary gland: an unusual site of metastasis

We present a case of metastatic medullary thyroid carcinoma involving the pituitary gland of a 23-year-old woman with multiple endocrine neoplasia type 2b who presented with diabetes insipidus and visual loss. The diagnostic features, including cytomorphology and immunohistochemistry, used to differentiate pituitary adenoma from metastatic medullary carcinoma are discussed. Pituitary metastases and tumor-to-tumor metastases in this region are also highlighted.

RET(MEN 2B) is active in the endoplasmic reticulum before reaching the cell surface

MEN 2B (multiple endocrine neoplasia type 2B) is an autosomal dominant cancer syndrome caused by an oncogenic form of the receptor tyrosine kinase REarranged during transfection (RET). The MEN 2B syndrome is associated with an abnormal autophosphorylation of the mutated receptor even without ligand-stimulation. Here, we characterize the activation of a RET(MEN 2B) variant carrying the point mutation Met918Thr, and show that the 150 kDa precursor of RET(MEN 2B) becomes phosphorylated already during synthesis in the endoplasmic reticulum (ER). At least three different tyrosine residues (Tyr905, Tyr1062, Tyr1096) of the RET(MEN 2B) precursor are phosphorylated before the oncogenic receptor reaches the cell surface. We also demonstrate that the precursor of RET(MEN 2B) interacts with both growth factor receptor-bound protein and Src homology 2 domain-containing already in the ER, and that this interaction is dependent on the kinase activity of RET. With the aid of two RET mutants (RET(MEN 2B/S32L) and RET(MEN 2B/F393L)), which accumulate in the ER, we show that the oncogenic precursor of the receptor has the capacity to activate AKT, extracellular signal-regulated kinase and signal transducer and activator of transcription 3 from the ER. Taken together, our data demonstrate that the oncogenic precursor of RET(MEN 2B) is phosphorylated, interacts with adapter proteins and induces downstream signalling from the ER.