Multiple Endocrine Neoplasia 2B Research Articles

Innovations in the systemic treatment of medullary thyroid cancer with kinase inhibitors

Introduction: Medullary thyroid carcinoma is a primary thyroid neoplasm originating from thyroid C cells. It can be familial or sporadic. The familial form is associated with multiple endocrine neoplasia (MEN) syndrome types 2A and 2B and is caused by a mutation in the RET gene, which encodes a tyrosine kinase receptor. Treatment of medullary thyroid cancer is mainly based on surgical resection of the thyroid gland, usually a total thyroidectomy. It can be followed-up by a chemotherapy, which has limited efficacy. Hence, there is a growing interest in new molecular therapies, such as tyrosine kinase inhibitors, which include vandetanib, cabozantinib, selpercatinib, pralsetinib, sorafenib and lenvatinib.
 Objective: The review and presentation of the current state of knowledge on the systemic treatment of medullary thyroid cancer with kinase inhibitors.
 Material and methods: Literature review based on available sources from PubMed database and Google Scholar.
 Conclusions: Though systemic treatment options for medullary thyroid cancer continue to improve, patients with advanced neoplasms still have limited therapeutic options. Hence, further development of targeted treatment with kinase inhibitors, particularly those selective for the RET receptor is crucial. Molecular studies of mutations and signaling pathways involved in the oncopathogenesis of medullary thyroid cancer could contribute to the discovery of new therapeutic mechanisms, and drugs that target them, could potentially further improve disease progression-free survival (PFS) and overall survival (OS).

Comparing nodal with primary tumor desmoplasia uncovers metastatic patterns in multiple endocrine neoplasia 2B.

While primary tumor desmoplasia is a powerful biomarker of node metastases in sporadic medullary thyroid cancer (MTC), information for hereditary MTC is sparse. This proof-of-concept study, comprising 3 consecutive children with multiple endocrine neoplasia 2B, evaluated simultaneously the metastatic behavior of multiple primary thyroid tumors of disparate size and extent of desmoplasia within patients. Altogether, MTC typically involved the ipsilateral central neck before spreading to the ipsilateral lateral and the contralateral neck. Medullary thyroid cancer in the upper thyroid lobe leaped the ipsilateral central neck to invade the ipsilateral lateral neck. Unlike the desmoplasia-positive 6-mm high-grade and 7-mm low-grade primary thyroid tumors, the desmoplasia-negative 8-, 11-, and 16-mm low-grade primary thyroid tumors did not spread to ipsilateral neck nodes. With extranodal growth, the extent of nodal desmoplasia was greater than with intranodal growth. This proof-of-concept study suggests that primary tumor desmoplasia is an equally powerful biomarker of node metastasis in hereditary MTC.

A rare case of medullary carcinoma

Medullary thyroid cancer (MTC) accounts for 5–10 % of all thyroid cancers. Most cases (75 %) are sporadic, but the proportion of patients with MTC and a familial predisposition syndrome is the highest among those with any hereditary cancer syndrome (about 25 %), and this possibility should be considered when examining a patient with MTC. Familial syndromes include multiple endocrine neoplasia (MEN) 2A, MEN 2B, and non-MEN familial MTC (familial MTC). Familial MTC syndromes occur in approximately one case per 30,000 of the population. Reduced penetrance and clinical variability are well-established features of many monogenic disorders, particularly phenotypes associated with the RET proto-oncogene. They require an individual assessment of the pathogenic effects and clinical significance of any identified new sequence of the RET va­riant as prerequisites for individual genetic counseling and planning of medical monitoring and treatment. Diagnostic criteria for the disease have been outlined, molecular and genetic aspects have been discussed, and the determination of treatment and further observation has been addressed. The article describes a clinical case of a rare variant of MTC. Treatment of this pathology with radical extrafascial thyroidectomy is under consideration. Given the ineffectiveness of radioiodine and chemotherapy, the main task in the treatment of MTC is early diagnosis, radical surgical intervention, and active monitoring aimed at early detection of disease recurrence. When planning prophylactic thyroidectomy, it is recommended to focus on the stratification of the level of RET gene mutations and the timing of prophylactic thyroidectomy proposed by the American Thyroid Association. The introduction of molecular genetic research into clinical practice for the purpose of diagnosing MTC allows for the objective assessment of the genetic lineage of the disease within a biological family. A timely diagnosis of MTC makes it possible to prescribe an adequate treatment at the stage of preclinical manifestations of the disease, which can significantly increase the quality and duration of life.

Characterising the natural history of Multiple Endocrine Neoplasia 2B caused by M918T RET pathogenic variants in children and young people

Characterising the natural history of Multiple Endocrine Neoplasia 2B caused by M918T RET pathogenic variants in children and young people

FRI213 Multiple Endocrine Neoplasia Syndromes: A Rare Case With Variable Presentation

Abstract Disclosure: D.J. Gomez D' Aza: None. M. Kasap: None. T. Zahedi: None. F. Zhang: None. Introduction: Multiple endocrine neoplasia (MEN) syndromes are rare autosomal dominant inherited groups of disorders characterized by the presence of two or more primary endocrine glands tumors. MEN type 1 is usually associated with neoplastic lesions of the pituitary gland, the parathyroid gland, and the pancreas. MEN type 2 typically presents with overgrowth of parathyroid, adrenal glands (pheochromocytoma), and parathyroid hyperplasia (MEN 2A), Marfanoid body habitus, or mucosal neuromas (MEN 2B). It can also manifest with non-endocrine tumors including carcinoid tumors, adrenocortical tumors, meningiomas, facial angiofibromas, collagenomas, lipomas, and germline mutations (MEN type 4). It is extremely rare for MEN type 1 syndrome to have concomitant pheochromocytoma. Case Report: We present a case of a 69 yo female with multiple comorbidities who was hospitalized for heart failure exacerbation. CT scan showed incidental findings of a 4.1 cm right adrenal nodule, a 2.1 cm left anterior mediastinum nodule, and a 1.1 cm oval pituitary mass. She had multiple episodes of hypertension urgency during the last two years. After patient recovered to her base line, workup labs revealed elevated serum Catecholamine with Metanephrine 431.1 pg/mL, Normetanephrine 466.5 pg/mL, Norepinephrine 137 pg/mL, and high PTH 258 pg/mL. Further study was normal for pituitary function tests, aldosterone, renin, cortisol, thyroid, and renal function. PET scan showed mild hypermetabolic activity in bilateral adrenal glands without any abnormal hypermetabolic activity in the chest. Thyroid Ultrasound identified a 1 cm thyroid nodule. Phenoxybenzamine was started due to concern for pheochromocytoma. Patient was monitored closely since she declined surgical intervention. Discussion: MEN syndromes have variable clinical presentation with multiple hormone excess. This patient has imaging and laboratory findings highly suggestive of MEN syndrome with pituitary adenoma, pheochromocytoma, and hyperparathyroidism. Further work up and genetic testing would be helpful to identify the mutation of MEN type 1 or type 2. Clinicians should be aware of the variable presentation of MEN syndrome, and prompt treatment is warranted to prevent life-threatening conditions. Presentation: Friday, June 16, 2023

SAT561 Pathogenic RET V804M Germline Variant Without Clinical Manifestations Of Multiple Endocrine Neoplasia Type 2 In An Elderly Male

Abstract Disclosure: R. Ghosh: None. G. Al-Naqeeb: None. P. Veeraraghavan: None. C. Craig: None. J. Klubo-Gwiezdzinska: None. S. Gubbi: None. Background: Germline pathogenic variants in the RET protooncogene give rise to multiple endocrine neoplasia (MEN) types 2A and 2B. MEN2A is mainly characterized by MTC (∼100%), pheochromocytoma (PHEO; 4% - 88%), and primary hyperparathyroidism (HPTH; 2% - 30%), while MEN2B predominantly manifests with MTC (100%), PHEO (50%), mucocutaneous neuromas, and marfanoid habitus. Both MEN2A and 2B follow an autosomal dominant mode of inheritance. While certain pathogenic RET variants (M918T, A883F, and C634X) have high penetrance and present with aggressive disease, other variants such as V804M are of low penetrance and manifest with clinically mild disease.Clinical case: A 75-year-old male was referred to our center for further evaluation of the finding of an abnormal RET gene that was identified on a peripheral blood whole-exome gene sequencing research panel performed at an outside center. The patient was noted to have a germline RET c.2410 G>A, p.V804M heterozygous pathogenic variant. The patient denied any history of lump in the neck, symptoms of hyper- or hypothyroidism, tremors, headaches, fatigue, facial flushing, palpitations, constipation, diarrhea, anxiety, depression, or history of fragility fractures. Medical history consisted of hypertension, nephrolithiasis, type 2 diabetes mellitus, obstructive sleep apnea, interstitial pulmonary fibrosis, and colonic diverticula and polyps. Family history was significant for leukemia, colon, and breast cancers, but none of the relatives had a history of MTC, PHEO, or MEN2, and his children, while healthy, had not undergone RET germline testing. Physical examination showed no evidence of hypothyroidism or hyperthyroidism. Neck examination showed no evidence of thyromegaly or cervical lymphadenopathy. Laboratory investigations were unremarkable [serum calcitonin: 7.9 pg/ml (NL: </=14.3), CEA 2.8 mcg/L (NL: 0.8-3.4), thyrotropin (TSH): 1.92 microIU/ml (NL: 0.35-4.94), free thyroxine: 0.9 ng/dl (NL: 0.7-1.5), plasma free normetanephrine: 0.31 nmol/L (NL: <0.9), plasma free metanephrines 0.24 nmol/L (NL: <0.5), parathyroid hormone: 28.2 pg/ml (NL: 15-65), and ionized calcium 1.23 mmol/l (NL: 1.09-1.30)]. Thyroid sonogram was normal. We recommended active annual surveillance with biochemical markers and imaging along with genetic testing of the RET gene in his children. Conclusion: The V804M RET variant has been often associated with MTC or MEN2A phenotypes [1]. However, the variable expression of this variant may lead to a mild clinical phenotype or even absence of MTC/MEN2A manifestations. Hence, active surveillance as opposed to radical surgery like prophylactic thyroidectomy would be more beneficial in patients with no clinical or biochemical evidence of disease. Reference: Pinna et al., 2007, V804M is the most frequent mutation and may be associated with FMTC/MEN-2A phenotype. Thyroid, 17(2), 101-104. Presentation Date: Saturday, June 17, 2023

Hereditary medullary thyroid cancer

ParafollicularC cells progress via C cell hyperplasia to medullary thyroid cancer (MTC), which can be present even in the first years of life in multiple endocrine neoplasia (MEN) type2A and 2B patients. Basal calcitonin and carcinoembryonic antigen (CEA) are useful tumor markers for the diagnosis and monitoring. The prognosis depends on the stage when the disease is diagnosed and there is a good genotype-phenotype correlation with the RET proto-oncogene, which can be used for estimation of the risk. The risk-stratified prophylactic thyroidectomy plays a decisive role in the prognosis of known gene mutation carriers.

Multiple Sclerosis and MEN2 Neoplasia in a Female Patient: A Unique Co-Existence with Expanded Immunological Interest and Therapeutical Challenges, before and after Patient’s COVID-19 Infection

Multiple sclerosis (MS) and its various comorbidities that may be observed are of great interest due to the complexity of MS pathophysiology and all of the immunological changes that follow. The incidence of cancer in MS has been investigated for several years, as not only does it affect ongoing therapeutical decisions, but also, certain disease-modifying treatments (DMTs) may increase the risk of tumorigenesis. For the first time, we present a case of a female patient with pediatric-onset MS (POMS) and multiple endocrine neoplasia 2B (MEN2B) and analyze the immunological impact of these diseases on the therapeutical choice, under the umbrella of her COVID-19 infection and the SARS-CoV-2 pandemic as a whole. We also review the existing literature regarding the immunogenetic and immunological correlations between these two extremely rare diseases and discuss the most suitable treatment for our case, which seems to be an anti-CD20 agent due to a better outcome in putative MS worsening and tumor progression, when killer immunoglobulin-like receptors' (KIR) expression is reduced in natural killer (NK) cells. We also broaden our concerns on this comorbidity issue, at the same time focusing on the future research needed in this unexplored field of the comorbidity of MS and cancers.

Signet-ring cell carcinoma of the appendix with ganglioneuromatosis: a case report

BackgroundPrimary cancer of the appendix, especially signet-ring cell carcinoma, is an uncommon disease, and it is rarely suspected before surgery. Diffuse intestinal ganglioneuromatosis that is not associated with neurofibromatosis-1 or multiple endocrine neoplasia 2b is also rare. The most frequent symptoms caused by it are changes in bowel habits, abdominal pain, and occlusive episodes.Case presentationThe patient was a 48-year-old woman who had a month-long history of chronic abdominal pain, fullness, constipation, and diarrhoea. Enhanced computed tomography showed a 100-mm irregular swelling in the appendix and thickening of the appendiceal wall with cystic dilatation. Based on a preoperative diagnosis of appendiceal cancer, the patient underwent laparoscopic ileocecal resection with D3 lymph node dissection. Pathological diagnosis revealed a signet-ring cell carcinoma of the appendix with ganglioneuromatosis. The patient completed four courses of capecitabine plus oxaliplatin (CAPEOX) as postoperative adjuvant chemotherapy, and 23-month postoperative outcome was noneventful without recurrence.ConclusionWe report a signet-ring cell carcinoma of the appendix that was detected early because of its presence with ganglioneuromatosis.

Young woman with Multiple Endocrine Neoplasia 2B (MEN 2B) Diagnosed by PET-CT-A Case Report

Multiple endocrine neoplasia, type 2B (MEN2B) is an autosomal dominant syndrome characterized by medullary thyroid carcinoma, pheochromocytoma, multiple mucosal neuromas & intestinal ganglioneuromas. A young woman of 20 years presented with irregularity of both lips since childhood and a midline neck swelling which gradually increased in size within last 1 year. She had hypertension and history of three episodes of paroxysmal spells characterized by headache, palpitations and excessive sweating during past 5 months. On physical examination, patient was having tachycardia, high blood pressure level (140/100 mmHg), sweaty with no tremor or exophthalmos. She had bumpy lips, multiple mucosal neuromas in lip & buccal mucosae, a hard nodular goiter and no marfanoid habitus. Core biopsy from right thyroid lobe revealed medullary thyroid carcinoma. Calcitonin level were markedly elevated. 18F-FDG PET-CT scan showed heterogeneous mixed density soft tissue mass involving both lobes and isthmus of thyroid gland with intense FDG uptake and FDG avid enlarged right cervical lymph nodes. A well circumscribed complex mass was found in the left upper abdomen adjacent to pancreas. Left adrenal gland showed a heterogeneous mass with mild FDG uptake and according to PET-CT findings, patient was diagnosed as a case of MEN 2B. Bangladesh J. Nuclear Med. 24(1&2): 60-63, 2021

Case Report: Bilateral Pheochromocytoma: Clinical Characteristics and Surgical Management

Objective: We would like to report the clinical presentation, surgical treatment and outcomes of this patient with bilateral pheochromocytoma. Introduction: Pheochromocytomas (PHEOs) are rare catecholamine-secreting neuroendocrine tumors of neural crest origin arising from chromaffin cells in the adrenal medulla with estimated incidence of 0.46 to 0.8 cases per 100,000 person-years [1]. Germline pathogenic variants associated with PHEO are now identified in 30-50% of these tumors [2]. Genetic syndromes can predispose to bilateral PHEO, such as multiple endocrine neoplasia (MEN) 2A, MEN 2B, von Hippel-Lindau (VHL), neurofibromatosis type 1 (NF1), as well as mutations in the genes of myc-associated factor X (MAX), transmembrane protein 127 (TMEM127), and mutations in the subunits of the succinate dehydrogenase complex (SDHx) [3]. When we suspect the pheochromocytoma clinically, we should look for biochemical confirmation, by dosing the plasma and urinary catecholamine (adrenaline, noradrenaline) and their metabolites (metanephrine and normetanephrine) [4]. This should be followed by tumor localisation using computed tomography (CT) imaging or magnetic resonance imaging (MRI) of the abdomen and pelvis that are the most commonly used methods and have similar sensitivities (90%-100%) and specificities (70%-80%) for tumor localisation [5]. Surgical resection followed by postoperative monitoring is the safest and the most effective therapeutic intervention for pheochromocytoma [6].

Abstract 142: Endocrine neoplasia type 2B with a rare mutation: A case report

Introduction: Multiple Endocrine Neoplasia (MEN) type 2 is a rare familial endocrine syndrome. MEN 2B syndrome, the least common subtype of MEN 2 syndrome, is characterized by medullary carcinoma of thyroid (MTC), pheochromocytoma and absence of hyperparathyroidism. Identifying the responsible mutation have prognostic consequences. Majority of MEN2B cases occur due to de-novo mutation with 95% cases involving codon 918, and codon 883, 2-3% cases.Objective: Identification of the genetic mutation in patient presented with MTC, and bilateral adrenal pheochromocytoma.Methods: Whole Exome Analysis was performed to identify the genetic defect. The variants were prioritized using standard open-source computational pipelines.Results: Whole exome sequencing and computational analysis identified a non-synonymous single nucleotide polymorphism T1991C in the exon 13 of RET gene on chromosome 10, resulting in a missense mutation (p.M664T) in the protein responsible for phenotypic expression known as MEN 2B syndrome.Conclusion: MTC and bilateral pheochromocytoma are indications for detailed clinical and genetic examination of the proband. Bilateral adrenalectomy, followed by total thyroidectomy and prophylactic central neck dissection was done along with lifetime hormone supplementation. This is a rare mutation reported in MEN2B (A Rare Syndrome) which usually involve codon 918 and 883.

Incidental Colonic Ganglioneuroma on Surveillance Colonoscopy.

CASE REPORT A 73-year-old man with a history of diverticulitis after left hemicolectomy and an end-to-end colo-colonic anastomosis underwent a screening colonoscopy with resection of 4, 2-10-mm tubular adenomas. A 10-mm semipedunculated polyp with a normal mucosal pit pattern under narrow-band imaging was found in the splenic flexure (Figure 1). The polyp was resected using a hot snare and submitted for histopathological diagnosis, which demonstrated colonic mucosa with distorted crypt architecture. The lamina propria was expanded by collection of spindle cells within fibrillary matrix, and irregular nests and groups of ganglion cells indicated a ganglioneuroma (GN) (Figure 2). No clinical symptoms were associated with this finding, and a prior colonoscopy revealed no evidence of GN. Surveillance colonoscopy was recommended in 3 years, given the presence of an adenoma of ≥10 mm in size.Figure 1.: (A) A semipedunculated polyp under white-light imaging in the splenic flexure. (B) A semipedunculated polyp with a normal mucosal pit pattern under narrow-band imaging in the splenic flexure.Figure 2.: (A) An (H&E original magnification 20×) image of the colonic polyp consisting of abnormal appearing ganglion cells (single arrow) and spindled Schwann cells (double arrows). (B) An (H&E original magnification 10×) image of the colonic polyp consisting of abnormal appearing ganglion cells and spindled Schwann cells. H&E, hematoxylin & eosin.Ganglioneuromas of the gastrointestinal tract are rare tumors composed of ganglion cells, nerve fibers, and supporting cells. Gastrointestinal GNs are usually confined to the large intestine and are morphologically classified into 3 categories, namely, polypoid GNs, ganglioneuromatous polyposis, and diffuse ganglioneuromatosis.1 Polypoid GNs are mostly solitary and small (measuring <20 mm), with a sessile or pedunculated appearance. Colonic GNs are characterized by a normal colonic pit pattern under narrow-band imaging. These lesions produce no characteristic symptoms and are usually found incidentally during endoscopy. Rarely, they present with abdominal pain, obstruction, ileus, appendicitis, or weight loss depending on their size and anatomical location.2 Ganglioneuromatous polyposis and diffuse ganglioneuromatosis are associated with genetic syndromes, such as neurofibromatosis 1, multiple endocrine neoplasia 2B syndrome, and juvenile polyposis. Solitary GNs are generally not associated with familial syndromes, although they have been reported in cases of Cowden disease, tuberous sclerosis, polyposis coli, and juvenile polyposis.1 Gastrointestinal GNs are usually treated with endoscopic resection. Currently, no guidelines exist on the management of solitary GNs or recommendations for interval surveillance colonoscopy. Repeat colonoscopy is not necessary because of the benign nature of these lesions, which tend not to recur.3 DISCLOSURES Author contributions: S. Agarwal and Y. Wang designed and drafted the article and acquired data. PG Iyer drafted and revised the article for intellectual content. CL Leggett designed and drafted the article , acquired data, revised the article for important intellectual content, and is the article guarantor. Financial disclosure: None to report. Informed patient consent was obtained for this case report.

Four cases of medullary thyroid carcinomas associated with multiple endocrine neoplasia 2B with rearranged during transfection codon M918T mutation in the same family.

Multiple endocrine neoplasia (MEN) with medullary thyroid carcinoma (MTC) is associated with rearranged during transfection (RET) mutations. The authors encountered four cases of MTC-related MEN type 2B (MEN2B) with RET codon M918T mutation in one family. Case 1 included a 19 year-old male diagnosed with MTC with lung metastases. Genetic testing revealed an RET codon M918T mutation, which indicated MEN2B. The patient responded partially to vandetanib and the disease has shown no progression in 25 months. Case 2 involved the mother of the patient in Case 1. She underwent total thyroidectomy (TT) when diagnosed with MTC-related MEN2B at 12 years of age, but was not counseled adequately. Cases 3 and 4 involved the sisters of the Case 1 patient and were assessed after Case 1 was diagnosed. Genetic testing revealed the same mutation. Case 3 was diagnosed with MTC and underwent TT. Case 4 was asymptomatic but underwent prophylactic TT; histopathologic examination revealed MTC tissue. Prophylactic TT prevented MTC from being detected at an advanced state. Genetic counseling is essential in treating MEN2B. The mother was uninformed about the genetic characteristics of MEN2B, delaying the detection of MTC in her children. The present study reaffirms the importance of family history and screening.

Clinical and laboratory features of hereditary pheochromocytoma and paraganglioma

The widespread introduction of genetic testing in recent years has made it possible to determine that more than a third of cases of pheochromocytomas and paragangliomas (PPPGs) are caused by germline mutations. Despite the variety of catecholamine-producing tumors manifestations, there is a sufficient number of clinical and laboratory landmarks that suggest a hereditary genesis of the disease and even a specific syndrome. These include a family history, age of patient, presence of concomitant conditions, and symptoms of the disease. Considering that each of the mutations is associated with certain diseases that often determine tactics of treatment and examination of a patient, e.g. high risk of various malignancies. Awareness of the practitioner on the peculiarities of the course of family forms of PPPGs will allow improving the tactics of managing these patients.The article provides up-to-date information on the prevalence of hereditary PPPGs. The modern views on the pathogenesis of the disease induced by different mutations are presented. The main hereditary syndromes associated with PPPGs are described, including multiple endocrine neoplasia syndrome type 2A and 2B, type 1 neurofibromatosis, von Hippel-Lindau syndrome, hereditary paraganglioma syndrome, as well as clinical and laboratory features of the tumor in these conditions. The main positions on the necessity of genetic screening in patients with PPPGs are given.

Growth Patterns in Children With Multiple Endocrine Neoplasia Type 2B: Small Stature in Childhood

Background: Multiple Endocrine Neoplasia 2B (MEN2B) is characterized by medullary thyroid carcinoma (MTC) before the age of one, pheochromocytoma and several non-endocrine manifestations. Marfanoid habitus is considered to be an important related feature, leading to the assumption that children with MEN2B have a tall stature. However, very little is known about actual growth patterns in children with MEN2B and its implication for final height. Aim: To describe the growth patterns during childhood and adolescence and relate final height to target height (TH) in MEN2B patients. Methods: Growth during childhood was investigated in eight patients with MEN2B under care in a Dutch MEN expertise center. Growth charts were assessed in relation to parental height, age at diagnosis and at thyroidectomy, body mass index (BMI), pubertal development and extensiveness of disease manifestations. Results: Four out of eight patients showed longitudinal growth below their TH range. Three others showed prepubertal growth in the lowest margin of their TH range. Small stature was accompanied by delayed bone maturation. Arm span to height ratio was not increased in any of the (six) patients studied. All four patients who reached adulthood attained final height within their TH range, despite small stature during childhood. Small stature in childhood was not associated with age at diagnosis, age at thyroidectomy, extensiveness of MTC, BMI or endocrine deficiencies. Conclusions: Children with MEN2B did not present with marfanoid features regarding height or arm span. In contrary, short stature may be prevalent, with longitudinal growth beneath the individual TH range. Nevertheless, a normal final height within the TH range may well be reached. Growth patterns seem to be independent of both age at diagnosis and thyroidectomy as well as disease severity.

Timely diagnosis of multiple endocrine neoplasia 2B by identification of intestinal ganglioneuromatosis: a case series

BackgroundMedullary thyroid carcinoma (MTC) in childhood is rare and has an unfavorable prognosis. To improve outcome, early diagnosis is essential. In patients with multiple endocrine neoplasia type 2B (MEN2B), MTC can occur already before the age of 1 year. Recognition of non-endocrine features of MEN2B may lead to timely diagnosis.PurposeTo describe how early recognition of non-endocrine features can lead to a timely diagnosis of MEN2B as well as the effect of recognition of premonitory symptoms on prognosis.MethodsA retrospective case series from the University Medical Center Utrecht/Wilhelmina Children’s Hospital, a Dutch national expertise center for MEN patients. All eight MEN2B patients in follow-up between 1976 and 2020 were included and medical records reviewed.ResultsIntestinal ganglioneuromatosis (IGN) as the cause of gastrointestinal (GI) symptoms was detected in seven patients. In three of them within months after birth. This led to early diagnosis of MEN2B, which allowed subsequent curative thyroid surgery. On the contrary, a MEN2B diagnosis later in childhood—in three patients (also) triggered by oral neuromas/neurofibromas—led to recurrent, persistent, and/or progressive MTC in five patients.ConclusionsNeonatal GI manifestations offer the most important window of opportunity for early detection of MEN2B. By accurate evaluation of rectal biopsies in patients with early onset severe constipation, IGN can be timely detected, while ruling out Hirschsprung’s disease. MEN2B gene analysis should follow detection of IGN and—when confirmed—should prompt possibly still curative thyroid surgery.

CARCINOMA MEDULAR DA TIREOIDE EXPRESSADO POR RARA MUTAÇÃO DO PROTO-ONCOGENE RET: RELATO DE CASO

INTRODUÇÃO: O carcinoma medular de tireoide (CMT) é uma neoplasia das células C parafoliculares. A forma esporádica está presente na maioria dos pacientes, os quais manifestam mutações somáticas no proto-oncogene RET. Os demais pacientes podem apresentar mutação germinativa neste mesmo gene, resultando em 3 tipos: carcinoma medular de tireoide familiar (CMTF), neoplasia endócrina múltipla (NEM), subdividindo-se em subtipos 2A e 2B. O diagnóstico se dá por Punção Aspirativa por Agulha Fina (PAAF) e histopatológico. OBJETIVOS: Relatar o caso de CMT com rara mutação no gene RET e atípica evolução clínica. RELATO DE CASO: mulher, 71 anos, procura atendimento em 2001 queixando-se de mal estar ao deglutir, dor à compressão do pescoço e constipação intestinal. Apresenta ao exame físico nódulo tireoidiano palpável, doloroso, em lobo esquerdo. Mãe falecida por tumor tireoidiano sem investigação. Foi realizada ultrassonografia, evidenciado imagem sólida de 2,1cm. Submetida à PAAF, negativa para malignidade. Indicada cervicotomia exploradora para elucidar diagnóstico, realizada tireoidectomia total e esvaziamento linfático da cadeia central e anatomopatológico constatou CMT. Rastreamento negativo para patologias associadas a NEM 2A e 2B. Realizado teste genético positivo para mutação no gene RET. Em 2010, apresenta altos níveis de calcitonina, sendo indicada reexploração cervical, constatando sítios linfonodais de CMT após exérese dos mesmos. Atualmente segue em acompanhamento, clinicamente bem. CONCLUSÃO: Por se tratar de uma patologia rara, com prognóstico reservado, faz-se necessário a investigação minunciosa de mutação no protoncogene RET na suspeita de CMT, mesmo que não existam outras manifestações que possam incluir o paciente no diagnóstico de NEM.

Dermal hyperneury

Dermal hyperneury (DN) is a rarely reported form of small nerve hypertrophy characterized by an exaggerated size and prominence of dermal nerve fibers. Clinically, it can present with or without visible lesions, within a syndrome or sporadically, and in solitary or multiple fashion. The syndromes most commonly associated with DN include multiple endocrine neoplasia 2B and 2A, neurofibromatosis type II, and Cowden syndrome. Patients with syndrome-associated DN have an increased risk for various malignancies. Sporadic DN has been reported either in association with cutaneous tumors/reactive lesions, such as nodular prurigo, or in idiopathic form, where it can present with multiple DN lesions. There is a morphologic overlap between mucocutaneous neuromas and DN, as the former can have the appearance of either bulkier circumscribed lesions or tortuous and hyperplastic nerves more akin to DN. Epithelial sheath neuroma also shares a similar appearance to DN, from which it can be distinguished by a squamoid-appearing and thickened perineurium.

Management of medullary thyroid carcinoma

: Medullary thyroid carcinoma (MTC) is a rare malignancy arising from parafollicular C-cells and accounts for 3–10% of all thyroid malignancies. MTC occurs mostly as a sporadic disease, but in at least 30% of cases is hereditary, caused by RET germline mutations. In this setting, different germline RET mutations lead to distinct clinical phenotypes of hereditary MTC such as familial MTC and multiple endocrine neoplasia 2A and 2B. RET genetic screening should be performed in all new discovered cases of MTC since about 4–10% of patients with apparently sporadic MTC have RET germline mutations and therefore an inheritable disease. Calcitonin (CT) is the most reliable marker of MTC for both diagnosis and follow-up after thyroidectomy. In sporadic MTC, a routine determination of CT in patients with nodular goiter has been correlated to a lower rate of advanced tumor stages. Surgery is the only curative treatment. Since the relatively high risk of multifocal and bilateral disease and the early spread to cervical lymph nodes, total thyroidectomy and central neck lymph node dissection is the standard initial treatment. Lateral neck lymph node dissection might be considered according to imaging results and CT levels. The potential benefit of neck reiterative surgery for persistent or recurrent MTC should be balanced against the increased surgical morbidity in a scarred operative field. The treatment of locally advanced MTC that is not amenable to surgery or metastatic MTC benefits of tyrosine kinase inhibitors that have shown some effects on disease progression. External radiotherapy and cytotoxic chemotherapy have demonstrated little benefit. Prognosis strictly depends on stage of disease at diagnosis, with lower survival and cure rate for stage IV disease. The purpose of this review is to describe the management and treatment of patients with MTC, focusing on biochemical and imaging diagnostic tools, preoperative work-up, treatment and prophylactic surgery for hereditary variants.