Multiple Endocrine Neoplasia Type IIb Research Articles

Sporadic Medullary Thyroid Carcinoma: Towards a Precision Medicine.

Medullary thyroid carcinoma (MTC) is a neuroendocrine malignant tumor originating from parafollicular C-cells producing calcitonin. Most of cases (75%) are sporadic while the remaining (25%) are hereditary. In these latter cases medullary thyroid carcinoma can be associated (multiple endocrine neoplasia type IIA and IIB) or not (familial medullary thyroid carcinoma), with other endocrine diseases such as pheochromocytoma and/or hyperparathyroidism. RET gene point mutation is the main molecular alteration involved in MTC tumorigenesis, both in sporadic and in hereditary cases. Total thyroidectomy with prophylactic/therapeutic central compartment lymph nodes dissection is the initial treatment of choice. Further treatments are needed according to tumor burden and rate of progression. Surgical treatments and local therapies are advocated in the case of single or few local or distant metastasis and slow rate of progression. Conversely, systemic treatments should be initiated in cases with large metastatic and rapidly progressive disease. In this review, we discuss the details of systemic treatments in advanced and metastatic sporadic MTC, focusing on multikinase inhibitors, both those already used in clinical practice and under investigation, and on emerging treatments such as highly selective RET inhibitors and radionuclide therapy.

Una patología muy infrecuente: ganglioneuromatosis intestinal. Reporte de un caso

Intestinal ganglioneuromatosis is an unusual pathology, especially in adults. It is associated with multiple endocrine neoplasia type IIb and Von Recklinghausen´s neurofibromatosis. Histologically, it is characterized by hyperplasia of the intramural plexuses of the gastrointestinal tract and enteric nerve fibres. Clinical manifestations include abdominal pain, distension and changes in bowel habits. We report the case of a 38-year-old patient, with a multiple endocrine neoplasia syndrome type IIb, presenting with repeated partial or complete intestinal obstruction that requires partial colectomy. Pathology of the resected colon revealed intestinal ganglioneuromatosis.

Isolated intestinal ganglioneuromatosis - A rare entity

Intestinal ganglioneuromatosis are rare benign tumour of ganglionic cell origin, most of them associated with neurofi bromatosis type I and multiple endocrine neoplasia type IIB. They are benign tumours with rare malignant transformation, have a varied clinical presentation and long indolent course. Surgical resection is the only modality of treatment and diagnosis is based on histopathological examination and immunohistochemistry. We report a case, 55 year old male who was diagnosed as a case of isolated intestinal ganglioneuromatosis, i.e no association with neurofibromatosis type I and multiple endocrine neoplasia type IIB. He is on regular follow up with normal daily activities and no evidence of recurrence.Journal of Kathmandu Medical College, Vol. 5, No. 4, Issue 18, Oct.-Dec., 2016, Page: 131-135

Perioperative Severe Hypotension in a Patient with Multiple Endocrine Neoplasia Type IIb and Bilateral Adrenalectomies: Time to Review the Evidence for Stress Dose Steroids.

Multiple endocrine neoplasia type IIb (MEN IIb) is an endocrine disorder which can manifest with tumors such as pheochromocytomas and neuromas. We present the case of a patient with MEN IIb, after bilateral adrenalectomies, on maintenance steroid replacement, who underwent a neuroma resection and developed severe hypotension. There is persistent controversy regarding the general administration of perioperative “stress dose” steroids for patients with adrenal insufficiency. While the most recent literature suggests that stress dose steroids are unnecessary for secondary adrenal insufficiency, the rarer form of primary adrenal insufficiency always requires supplemental steroids, specifically hydrocortisone, when undergoing surgical procedures.

A Colonic Polypoid Ganglioneuroma: An Unexpected Finding on a Screening Colonoscopy

Introduction: Ganglioneuromas are benign peripheral neuroblastic tumors of the neuroectodermal family composed of mature ganglion cells, schwann cells, and supporting cells. They can occur anywhere along the sympathetic chain, most commonly in the mediastinum, retroperitoneum, and adrenal glands. They most often occur in the pediatric population in association with genetic syndromes with 60% being diagnosed before age 20, and occur most often in females. Case Description: A 56 year old African-American male with Diabetes Mellitus and chronic HCV infection underwent first average-risk screening colonoscopy. The colonoscopy was completed to the cecum with good bowel preparation. A 7 mm sessile polyp, which was not characteristically adenomatous under white light, was seen at the distal sigmoid colon. This polyp was completely excised by hot snare polypectomy. The polyp was retrieved and sent for histologic examination. Immunohistochemical stain S100 highlighted the ganglion and spindle cells, supporting the diagnosis of ganglioneuroma. This unique finding highlights an unexpected case of an asymptomatic, solitary polypoid colonic ganglioneuroma. Ganglioneuromas are most often found in constellation syndromes such as multiple endocrine neoplasia type IIB (MEN-IIB), Von Recklinghausen's disease, and Cowden Syndrome. However, for a solitary colonic ganglioneuroma to be found in an asymptomatic individual, especially in an adult male; this is an exceedingly rare presentation for a rare tumor.Figure 1Figure 2Figure 3

Multiple Ganglioneuromatous Polyps of the Colon: What Lies Beneath the Surface of Colon?

Purpose: Ganglioneuromatous polyps of the colon are rare. They are seen in neurofibromatosis, multiple endocrine neoplasia (MEN) type IIb, phosphatase and tensin homolog (PTEN) gene mutations and tuberous sclerosis. Case: A 25-year-old healthy Caucasian female had been suffering from recurrent rectal bleeding. Her family history included early onset uterine cancer, and total abdominal hysterectomy and thyroidectomy in her sister; her mom had bilateral breast cancer at 46. Physical exam showed body mass index (BMI) of 34, macrocephaly, papules over the left nostril, right and left hand. The rest of the examination was unremarkable. Initial lab work-up including CBC, metabolic panel and infectious diarrhea was unremarkable. She underwent a colonoscopy with biopsy that revealed ganglioneuromatous polyps. EGD showed multiple papules and Brunner gland hamartomas. DNA revealed heterozygous mutation in one copy of the PTEN gene mutation, which corroborated the clinical diagnosis of Cowden syndrome. Cowden syndrome is a rare genetic disorder occurring in one in 1,000,000 people. Since this is quite a rare disorder, patients may not be diagnosed until their 20s or 30s. Lesions in this syndrome could arise from any of the three germ cell layers. Reports of ganglioneuromas of the colon seen in this patient are quite rare. Colon polyps stained with hematoxylin and eosin stain showed spindle cell proliferations, which were positive for S-100 and neuron-specific enolase, indicating neural crest origin of these tumors. This case demonstrates that this disorder could be more frequent than is currently estimated. A combination of macrocephaly and recurrent gastrointestinal bleeding with skin manifestations should raise suspicions for this disorder. Due to its autosomal inheritance pattern, all family members who have macrocephaly should be evaluated. Screening is important, as there is increased risk for breast (85%), thyroid (35%) and endometrial (28%) cancer. Usual GI manifestations include colorectal hamartomas with esophageal glycogenic acantholysis (seen in this patient), which could be as high as 85%.Table. ICCC: criteria for Cowden syndromeFigure: Colonic mucosa with spindle cell proliferation essentially replacing the lamina propria between crypts (200x).

Everolimus (E) and octreotid (O) in metastatic high-risk MEN IIb disease: A case report.

e13565 Background: Multiple endocrine neoplasia (MEN) type IIB is characterized by missense mutation in exon 16 of the RET-proto-onkogen. Malignant c-cell-(medullar)-carcinoma of the thyroid gland (MTC) is part of the disease. Prognostic factors for metastatic MTC (m-MTC) are tumor grading, vessel- and peri-neural infiltration, age and performance status (PS). Irradiation and chemotherapy have limited activity in m-MTC. Thyrosine-kinase inhibitors like vandetanib, sorafenib or sunitinib were not admitted in Germany in 2011, August. As mTor-pathway seems to play a role in m-MTC E was suggested to be a treatment alternative. In somatostatin receptor (SR) positive tumors O might be beneficial. Methods: In 2011, August, a 23 years old man presented with metastatic MEN IIB disease after palliative irradiation therapy. ECOG-PS was 2 to 3, Calcitonin was 3.615 pg/ml, CEA was 467 ng/ml. The patient (pt) had a non-resectable m-MTC, SR positive, with esophageal, pleural, tracheal and lymph node infiltration still with metabolic activity in PET-CT. Grading was G3 with strong vessel and peri-neural infiltration. Right adrenal tumor and tongue tumor were present. After written informed consent the pt started treatment with E 10 mg/day orally in 2011, November. A loperamide resistant diarrhea was treated with O 20 mg/4 weeks i. m. additionally since 2012, July. Results: During treatment with E Calcitonin and CEA levels continuously decreased and CT scans every 3 months demonstrated a continuous shrinkage of all tumor sites, especially after additional treatment with O, which also was associated with an improved PS. Since 2012, October, ECOG PS was 0 enabling the patient to go to work again. Since 2012, October no relevant treatment related side effects were present. Conclusions: E showed efficacy as single agent treatment in a young man with metastatic high risk MEN IIB disease, the addition of O seems to reduce side effects and to improve efficacy of single agent E in this case. Further investigation is needed to verify these results

Dystrophia Helsinglandica: a new type of hereditary corneal recurrent erosions with late subepithelial fibrosis

To describe the phenotype of an autosomal-dominant corneal dystrophy with an early onset of recurrent corneal erosions and development of subepithelial fibrosis in the cornea, and also to exclude genetic linkage to known corneal dystrophies with autosomal-dominant inheritance and clinical resemblance. We describe the medical history and clinical findings in individuals from a seven-generation family with recurrent corneal erosions. A total of 43 individuals were evaluated by ophthalmological examination. Genomic DNA was prepared from peripheral blood and polymorphic microsatellite markers were analysed to study haplotypes surrounding genes causing corneal dystrophies with similar phenotypes. Erosive symptoms usually lasted for between 1 and 10 days. By the age of 7 almost all of the affected individuals suffered from recurrent corneal erosions. The attacks generally declined in frequency and intensity from the late 20s, but all examined individuals had developed subepithelial fibrosis by the age of 37. The fibrosis generally started in the mid periphery and was followed in some family members by central fibrosis and the development of gelatinous superficial elevations. Only a marginal reduction of visual acuity was seen in a few individuals. The affected individuals did not share haplotypes for genetic microsatellite markers surrounding genes that are known to cause autosomal-dominant corneal dystrophies. We describe a new type of autosomal-dominant corneal disorder with recurrent corneal erosions and subepithelial fibrosis not significantly affecting visual acuity.

Hybrid neurofibroma-perineurioma: an additional example of an extradigital tumor

Peripheral nerves are complex tissues composed of a variety of cellular elements, specifically Schwann cells, perineurial cells, and neuronal processes (axons), enveloped by connective tissue elements. Neoplasms originating from peripheral nerve often recapitulate the phenotype of underlying cell elements and range from benign, circumscribed tumors easily cured by surgery (e.g., schwannoma), locally aggressive neoplasms with potential for malignant degeneration (e.g., plexiform neurofibromas), to overtly malignant, highly aggressive neoplasms (malignant peripheral nerve sheath tumors, MPNST). The proper diagnosis of these tumors not only has therapeutic implications but is also increasingly relevant to genetic counseling given their association with multisystemic genetic syndromes, including neurofibromatosis types 1 and 2, schwannomatosis, Carney Complex, and multiple endocrine neoplasia type IIB. Recent concepts in peripheral nerve tumor classification are covered in this review, including the increasing recognition of tumors with hybrid features. Although there have been no major recent changes in the overall diagnostic categories of nerve sheath tumors, our basic understanding of these tumors has been accelerated by comprehensive genomic studies. Malignant peripheral nerve sheath tumors have recently been found to have frequent mutations in components of the polycomb repressive complex 2 (SUZ12, EED), resulting in consistent epigenetic alterations, particularly loss of histone H3K27 trimethylation. All these findings have translated into diagnostic biomarkers useful in surgical pathology diagnosis, including immunohistochemical antibodies recognizing loss of neurofibromin and H3K27 trimethylation. In summary, peripheral nerve sheath tumors represent a heterogeneous group, with important diagnostic challenges that are important to recognize.

Hamartomatous Polyps of the Colon: Ganglioneuromatous, Stromal, and Lipomatous

Intestinal ganglioneuromas comprise benign, hamartomatous polyps characterized by an overgrowth of nerve ganglion cells, nerve fibers, and supporting cells in the gastrointestinal tract. This polyposis has been divided into 3 subgroups, each with a different degree of ganglioneuroma formation: polypoid ganglioneuroma, ganglioneuromatous polyposis, and diffuse ganglioneuromatosis. The ganglioneuromatous polyposis subgroup is not known to coexist with systemic disorders that often have an associated intestinal polyposis, such as multiple endocrine neoplasia type IIb, neurofibromatosis type I, and Cowden syndrome. We report a case of ganglioneuromatous polyposis plus cutaneous lipomatosis in a 41-year-old man with no established systemic disease. However, he possessed unique anatomic findings in addition to his ganglioneuromatosis, suggesting that the ganglioneuromatosis-lipomatosis in our patient may represent an unrecognized syndrome. This case report and brief review of the literature provide an overview of intestinal ganglioneuromatosis in relation to the hereditary polyposis syndromes and describe the individual ganglioneuromatosis subgroups.

Sporadic ganglioneuromatosis of esophagogastric junction in a patient with gastro-esophageal reflux disorder and intestinal metaplasia

A 58-year-old female with a recurrent history of upper abdominal pain and intermittent dysphagia underwent endoscopic evaluation that demonstrated an irregular and nodular esophago-gastric (EG) junction and grade I erosive esophagitis. Biopsies showed prominent intestinal metaplasia of Barrett's type without dysplasia, chronic inflammation and multiple aggregates of large cells within the mucosal lamina propria, some with spindle shaped nuclei. Immunohistochemistry stains for keratins AE-1/AE-3 were negative, while S-100 and NSE were positive. This, together with routine stains, was diagnostic for mucosal ganglioneuromatosis. The background of chronic inflammation with intestinal type metaplasia was consistent with long-term reflux esophagitis. No evidence of achalasia was seen. Biopsies of gastric antrum and fundus were unremarkable, without ganglioneural proliferation. Colonoscopy was unremarkable. No genetic syndromes were identified in the patient including familial adenomatous polyposis and multiple endocrine neoplasia type IIb (MEN IIb). Iansoprazole (Prevacid) was started by oral administration each day with partial relief of symptoms. Subsequent esophagogastroscopy repeated at 4 mo showed normal appearing EG junction. Esophageal manometry revealed a mild non-specific lower esophageal motility disorder. Mild motor dysfunction is seen with gastro-esophageal reflux disease (GERD) and we feel that the demonstration of localized ganglioneuromatosis was not likely related etiologically. In the absence of findings that might suggest neural hypertrophy, such as achalasia, the nodular mucosal irregularity seen with this instance of ganglioneuromatosis may, however, have exacerbated the patient's reflux.

Familial medullary thyroid carcinoma without associated endocrinopathies: a distinct clinical entity.

In an evaluation of 213 patients from 15 kindreds with familial medullary thyroid carcinoma (MTC), we detected 41 subjects from two kindreds (L and O) who had MTC but no extra-thyroidal manifestations (hyperparathyroidism, phaeochromocytomas or mucosal neuromas) of multiple endocrine neoplasia (MEN) type IIa or IIb. In screening 178 members of the L and O kindreds, we found no evidence that any of them had died from MTC. To assess whether the malignancy was relatively indolent in these families, 20 selected subjects from the two kindreds were compared with 33 MEN IIa subjects. Both groups had clinically occult disease which was diagnosed biochemically by documenting elevated plasma calcitonin (CT) levels following stimulation with intravenous calcium and pentagastrin. There were no differences in the peak stimulated plasma CT levels at the time of diagnosis (1055 +/- 236 pg/ml versus 1096 +/- 191 pg/ml) or the incidence of regional lymph node metastases (0/20 versus 1/33) in the two groups. The mean age at diagnosis, however, was significantly higher in patients of the L and O kindreds than in patients with MEN IIa (43.1 +/- 3.4 years versus 21.1 +/- 2.2 years; P less than 0.001) indicating that in the two kindreds the MTC either developed at a later age or grew more slowly. This study demonstrates that MTC may occur in a familial pattern distinct from its presentation as MEN IIa or MEN IIb. In this setting it appears to be the least aggressive form of MTC yet described.

Chronic macrocheilia: a clinico-pathological study of 28 patients.

Chronic macrocheilia has a multifactorial aetiology and is often a diagnostic and therapeutic challenge. Epidemiological information on this condition is scarce, most of the data reported relating only to granulomatous cheilitis. We have performed a detailed clinico-pathological analysis of all patients with chronic macrocheilia presenting to us during the last 6.5 years. Of the 28 patients identified, 13 (46.4%) had granulomatous cheilitis (GC), six (21.4%) had tuberculosis of the lip, three (10.7%) had leprous macrocheilia, two (7.1%) had multiple endocrine neoplasia type IIb, and one each had Ascher's syndrome and non-Hodgkin's lymphoma. Two patients were diagnosed as 'nonspecific cheilitis'. Histopathological differentiation between tuberculosis and GC was often not possible; but PCR for Mycobacterium tuberculosis was positive in all patients with tuberculosis and negative in four patients with GC in whom M. tuberculosis was sought. In spite of detailed clinical examination and investigations, a therapeutic trial was required to confirm the diagnosis in five (17.9%) patients. We have reviewed the available literature on this subject, and to our knowledge this study is the first of its kind. More such studies from other centres will help physicians to make an accurate aetiological diagnosis and treat this uncommon but disfiguring condition with confidence.

Pheochromocytoma multisystem crisis in a patient with multiple endocrine neoplasia type IIB and pyelonephritis

A patient with pyelonephritis developed multiorgan failure resulting in death. Clinical findings were consistent with multiple endocrine neoplasia type II, with bilateral pheochromocytomas identified by computed tomography scan. We hypothesize that either the infection or the administration of radiocontrast media led to a massive release of catecholamines from the pheochromocytomas. As a result, tissue perfusion was severely compromised, and multiorgan failure developed. This exceedingly rare complication of pheochromocytoma has been termed pheochromocytoma multisystem crisis. © 2002 by the National Kidney Foundation, Inc.

Three-Dimensional Cytomorphology in Fine Needle Aspiration Biopsy of Medullary Thyroid Carcinoma

To elucidate three-dimensional (3-D) cytomorphology in fine needle aspiration biopsy (FNAB) of medullary thyroid carcinoma (MTC). ENAB was performed on tumors from five patients with MTC. The aspirate was stained and observed under a light microscope (LM). The aspirate was also fixed, dehydrated, critical point dried, spattered with gold ions and observed with a scanning electron microscope (SEM). For transmission electron microscopy (TEM), the specimen was fixed, dehydrated, embedded in an Epon mixture, cut with an ultramicrotome, mounted on copper grids, electron doubly stained with uranium acetate and lead citrate, and observed with TEM. Findings under SEM were correlated with those under LM and TEM. Under SEM, 3-D cytomorphology of MTC displayed a disorganized cellular arrangement with indistinct cell borders in three cases. The cell surface was uneven and had granular protrusions that corresponded to secretory granules observed under TEM. In one case with multiple endocrine neoplasia type IIB, there were abundant granules on the cell surface. In one case of sporadic MTC with multinucleated tumor giant cells and small cells, granular protrusions also were noted on the cell surface. Granular protrusion was a characteristic finding in FNAB of MTC tinder SEM and might be helpful in the differential diagnosis.

Familial thyroid cancer.

Familial thyroid cancer can arise from parafollicular cells (familial medullary thyroid cancer) or from follicular cells (familial nonmedullary thyroid cancer). Familial medullary thyroid cancer may occur in isolation or as part of multiple endocrine neoplasia (MEN) type II syndromes. Genetic testing for a RET mutation on chromosome 10 is used to identify new family members who are gene carriers. Total thyroidectomy should be used in gene carriers without clinical disease before age 6 in medullary thyroid cancer and MEN type IIA, and as soon as the diagnosis is made in MEN type IIB after the first year of life. Those with clinical disease should have at least a bilateral central neck dissection. Modified radical neck dissection is recommended for patients when the primary tumor is 1.5 cm. A normal postoperative serum calcitonin level suggests that the operation has been curative. Physicians need to be aware of ethical and lifestyle issues related to patients with familial disease and their family members. Familial nonmedullary thyroid cancer occurs as a discrete entity or as part of other family cancer syndromes such as Gardner syndrome, Cowden disease, and other rare syndromes. Familial nonmedullary thyroid cancer almost exclusively includes patients with papillary or Hurthle cell cancers. These families appear to have more benign thyroid conditions. The gene (or genes) for familial papillary thyroid cancer is yet to be identified, whereas that for some Hurthle cells (TCO) has been mapped to chromosome 19p13.2. Familial nonmedullary thyroid cancer is somewhat more aggressive than its sporadic counterpart, but is less aggressive than medullary thyroid cancer. Total thyroidectomy and central neck dissection followed by radioactive iodine ablation and thyroid hormone suppression appear to be the most effective therapy.

Le cancer médullaire de la thyroïde

Medullary thyroid carcinoma is a rare disease which originates from the secretion of calcitonin by thyroid parafollicular cells. Sporadic (75%) and inherited (25%) forms of the disease are encountered. Familial forms (termed multiple endocrine neoplasia type IIa, IIb, or familial medullary thyroid carcinoma) may or may not be associated with other endocrinopathies such as pheochromocytoma and/or hyperparathyroidism. Circulating forms of calcitonin, a marker of the disease, are heterogeneous in blood, thus explaining why assays lead to different results according to the method used. Family screening is much easier, as germ line mutations of the proto-oncogene RET have recently been identified in inherited forms of the disease. Treatment includes extensive surgery. This, and prophylactic thyroidectomy in gene carriers, is discussed. Prognosis is much better nowadays, but precise follow-up has to be instituted.

Constipation and Encopresis in Childhood

Constipation and Encopresis in Childhood

Thickened corneal nerves in multiple endocrine neoplasia type IIb

Thickened corneal nerves are a hallmark of multiple endocrine neoplasia type IIb, a genetic syndrome characterized by medullary carcinoma of the thyroid, pheochromocytomas, and a distinctive phenotype. Both types of neoplasm may be lethal, but recognition of the ocular and non-ocular stigmata can lead to early diagnosis and successful treatment. Here, a presumptive case of multiple endocrine neoplasia type IIb is presented with background information concerning the phenotype, ocular manifestations, inheritance, diagnosis and management of the syndrome.

Ganglioneuromas of the Gastrointestinal Tract

We studied 43 patients with ganglioneuromas of the gastrointestinal tract accessioned at the Armed Forces Institute of Pathology (AFIP) from 1940 to 1990 in order to determine their relation to von Recklinghausen's disease and other multiple tumor syndromes. They fell into three groups: polypoid ganglioneuroma (28 patients); ganglioneuromatous polyposis (7 patients); and diffuse ganglioneuromatosis (8 patients). Follow-up (1-24 years, average 8 years) for 16 of 28 patients with polypoid ganglioneuroma showed that none of these patients developed von Recklinghausen's disease or evidence or multiple tumor syndromes. Three of seven patients with ganglioneuromatous polyposis were alive and well but were reported to have multiple cutaneous lipomas and one reported a family history of multiple intestinal polyps. For seven of eight patients, diffuse ganglioneuromatosis was associated with other tumors, namely multiple endocrine neoplasia type IIb, multiple ganglioneuromas and neurofibromas limited to the gastrointestinal tract, von Recklinghausen's disease and neurogenic sarcoma. We conclude that the solitary polypoid ganglioneuroma of the gastrointestinal tract is not associated with the subsequent development of von Recklinghausen's disease or multiple endocrine neoplasia. All three forms of gastrointestinal ganglioneuromatous disease appear to be largely centered in the colon and rectum, unlike neurofibromas and neurofibromatosis, which, in our experience, occur more commonly in the small intestine and stomach.