Evaluation and Surgical Management of Multiple Endocrine Neoplasias.

Multiple endocrine neoplasia (MEN) syndromes are rare autosomal dominant diseases that are associated with a mixture of both endocrine and non-endocrine tumors. Traditionally, there are 2 types of MEN that have unique clinical associations: MEN 1 (parathyroid hyperplasia, pancreatic neuroendocrine tumors, and pituitary tumors) and MEN 2 (medullary thyroid carcinoma and pheochromocytoma), which is further classified into MEN 2A (adds parathyroid adenomas) and 2B (adds ganglioneuromas and marfanoid habitus). Many of the endocrine tumors are resected surgically, and the pre, intra, and postoperative management strategies used must take into account the high recurrence rates asscioated with MEN tumors.

HEREDITARY ENDOCRINE TUMOURS: CURRENT STATE-OF-THE-ART AND RESEARCH OPPORTUNITIES: Early thyroidectomy in multiple endocrine neoplasia: a four decade experience.

Forty years ago, physicians caring for the J-kindred, a 100+ member family with multiple endocrine neoplasia type 2A (MEN2A), hypothesized that early thyroidectomy based on measurement of the biomarker calcitonin could cure patients at risk for development of medullary thyroid carcinoma (MTC). We re-evaluated 22 family members with proven RET proto-oncogene mutations (C634G) who underwent thyroidectomy and central lymphadenectomy between 1972 and 1994 based on stimulated calcitonin abnormalities. Current disease status was evaluated by serum calcitonin measurement and neck ultrasound in 18 of the 22 prospectively screened patients. The median age of the cohort at thyroidectomy was 16.5 years (range 9-24). The median duration of follow-up at the time of examination was 40 years (range 21-43) with a median current age of 52 years (range 34-65). Fifteen of the 18 patients had no detectable serum calcitonin (<2 pg/mL). Three had detectable serum calcitonin measurements, inappropriately elevated following total thyroidectomy. None of the 16 patients imaged had an abnormal ultrasound. Survival analysis shows no MTC-related deaths in the prospectively screened patients, whereas there were many in prior generations. Early thyroidectomy based on biomarker testing has rendered 15 of 18 MEN2A patients (83%) calcitonin-free with a median follow-up period of 40 years. There have been no deaths in the prospectively screened and thyroidectomized group. We conclude that early thyroidectomy and central lymph node dissection is an effective prophylactic treatment for hereditary MTC.

Risk factors of post-surgery complications in children with thyroid cancer.

INTRODUCTION: Thyroid cancer in children is a hot topic because of the large clinical heterogeneity and the risk of severe complications. We aimed to study 1. The frequency, 2. Etiology, and 3. Risk factors of post-surgery complications of thyroid cancer. MATERIAL AND METHODS: A retrospective analysis including risk factors for post-surgery complications of patients treated for thyroid malignancies in years 2006-2018 was performed. RESULTS: Over a period of 12 years 22 patients with thyroid malignancy (68% female; 12.6 ±â€¯4.0 years of age, median follow-up 6 years) were identified. Histologically, 12 (55%) patients had papillary carcinoma. Six patients (27.3%) had multiple endocrine neoplasia type 2 (MEN2) syndrome, 3 (13.7%) patients had medullary carcinoma and 1 patient had follicular carcinoma. Neck lymph node metastases were diagnosed in 8 (36.4%), distant metastases in 6 (27.3%), and both locations were involved in 4 (18.2%) patients. Six (27.3%) children had surgical complications: 1 child had unilateral vocal cord paralysis and transient hypoparathyroidism and 5 had transient hypoparathyroidism. The higher risk of surgery complications in forward stepwise logistic regression was associated in with distant metastases (R2 = 0.584, OR 52.63, p = 0.010). CONCLUSIONS: Postoperative complications were significantly associated with presence of distant metastases. Favorable results were observed in with children with MEN2 syndrome.

Insulinoma: A retrospective study analyzing the differences between benign and malignant tumors.

BACKGROUND/OBJECTIVES: Insulinoma is a rare pancreatic tumor and, usually, a benign disease but can be a malignant one and, sometimes, a highly aggressive disease. The aim of this study was to determine differences between benign and malignant tumors. METHODS: Retrospective study of 103 patients with insulinoma treated in a tertiary center. It was analyzed demographic, clinical, laboratory, localization and histologic analysis of tumor and follow up data of subjects in order to identify differences between individuals benign and malignant disease. RESULTS: Almost all patients (87%) had a benign tumor and survival rates of 100% following pancreatic tumor surgery. Those with malignant tumors (13%) have a poor prognosis, 77% insulinoma-related deaths over a period of 1-300 months after the diagnosis with a survival rate of 24% in five years. The following factors are associated with an increased risk of malignant disease: duration of symptoms < 24 months, fasting time for the occurrence of hypoglycemia < 8 h, blood plasma insulin concentration ≥ 28 µU/mL and C-peptide ≥ 4.0 ng/mL at the glycemic nadir and tumor size ≥ 2.5 cm. CONCLUSIONS: Our data help to base the literature about these tumors, reinforcing that although insulinoma is usually a single benign and surgically treated neoplasia, the malignant one is difficult to treat. We highlight the data that help predict a malignancy behavior of tumor and suggest a long follow up after diagnosis in these cases.

Laparoscopic adrenalectomy as an effective approach to massive bilateral pheochromocytomas.

Pheochromocytomas are catecholamine-secreting neoplasms, arising from adrenomedullary chromaffin cells. In type 2 multiple endocrine neoplasia (MEN2) syndrome, pheochromocytomas are usually benign but with predisposition to be bilateral (50%-80% of cases).The authors present the case of a young patient diagnosed with uncommonly large bilateral cystic pheochromocytomas and simultaneous detection of medullary thyroid carcinoma. Molecular testing confirmed germline RET codon C634 mutation, consistent with MEN2A syndrome. The patient underwent bilateral laparoscopic adrenalectomy plus total thyroidectomy with central lymph node dissection without associated complications. The histopathological study of the surgical specimens revealed bilateral benign pheochromocytomas (Ki67 of 2%) and a medullary carcinoma of the thyroid T1bN0M0; R0, respectively. One year after surgery, the patient was considered free of disease.This case demonstrates that bilateral laparoscopic adrenalectomy can be a safe and feasible approach for phechromocytomas in MEN2 syndrome, even in lesions with large diameter. However, due to elevated possibility of recurrence, patients should maintain lifelong follow-up.

Cytomorphological Features Useful to Prevent Errors in the Diagnosis of Pancreatic Adenocarcinoma by Fine Needle Aspiration Cytology.

OBJECTIVES: Endoscopic ultrasound-guided fine-needle aspiration (FNA) is now widely used as a primary tool to diagnose pancreatic neoplasms. However, criteria that can reduce the risk of overdiagnosing pancreatic adenocarcinoma by FNA have not been adequately defined in the literature. This study aims to identify characteristic cytomorphological features that are helpful in distinguishing pancreatic adenocarcinoma from its mimics. STUDY DESIGN: Five false-positive FNA cases (group A) diagnosed as adenocarcinoma (4 cases) and suspicious for adenocarcinoma (1 case) by FNA, were identified by searching our laboratory information system. Cytomorphological features of group A cases were compared to 12 true-positive, histologically confirmed FNA cases (group B). RESULTS: Subsequent histological follow-ups of 5 misdiagnosed FNA cases showed 2 cases of intraductal papillary mucinous neoplasm with focal high-grade dysplasia, 1 case attributed to tumor contamination from a gastroesophageal junction adenocarcinoma, and 2 cases of pancreatic intraepithelial neoplasia (PanIN1/reactive change and PanIN2, respectively). Cytomorphological features present in both groups A and B included nuclear enlargement/overlapping, mild to moderate anisonucleosis, granular chromatin and prominent nucleoli. However, 1 or more of these 4 characteristic morphological features such as 3-dimensional cluster with cell disorientation, isolated malignant cells, irregular nuclear contour/nuclear grooves/notches (>5% atypical cell population), and marked nuclear size variation 1:4 or higher was mainly present in adenocarcinoma. CONCLUSIONS: A combination of at least 2 of these 4 characteristic cytomorphological features needs to be present before rendering an unequivocal diagnosis of adenocarcinoma. Using these strict cytological criteria would have eliminated these false-positive diagnoses.

Parathyroid adenoma arising within the sternocleidomastoid muscle: a rare complication of autotransplantation.

A 19-year-old patient presented with slowly enlarging, painless, left-sided cervical mass. She had a background of multiple endocrine neoplasia 2B and had undergone a total thyroidectomy for medullary thyroid carcinoma during childhood. A cervical recurrence was therefore suspected. Ultrasonographic and MRI examination revealed a well-defined lesion within the left sternocleidomastoid muscle. Further evaluation with sestamibi and single-photon emission CT revealed elevated tracer uptake within the lesion. Cytological analysis, following ultrasound-guided sampling, revealed absent staining for calcitonin and blood samples confirmed a normal serum calcitonin level; however, the serum parathyroid hormone level was elevated. Overall, summative findings were consistent with a diagnosis of a parathyroid adenoma arising within the left sternocleidomastoid muscle. Given that this is not a location for a physiological parathyroid tissue, the adenoma might have arisen within the autotransplanted parathyroid tissue, injected into the muscular sheath during thyroidectomy. The clinical, radiological and pathological features are considered in this article.

Multiple endocrine neoplasia, the old and the new: a mini review.

Multiple endocrine neoplasia syndromes have since been classified as types 1 and 2, each with specific phenotypic patterns. MEN1 is usually associated with pituitary, parathyroid and paraneoplastic neuroendocrine tumours. The hallmark of MEN2 is a very high lifetime risk of developing medullary thyroid carcinoma (MTC) more than 95% in untreated patients. Three clinical subtypesdMEN2A, MEN2B, and familial MTC (FMTC) have been defined based on the risk of pheochromocytoma, hyperparathyroidism, and the presence or absence of characteristic physical features). MEN2 occurs as a result of germline activating missense mutations of the RET (REarranged during Transfection) proto-oncogene. MEN2-associated mutations are almost always located in exons 10, 11, or 13 through 16. Strong genotype-phenotype correlations exist with respect to clinical subtype, age at onset, and aggressiveness of MTC in MEN2. These are used to determine the age at which prophylactic thyroidectomy should occur and whether screening for pheochromocytoma or hyperparathyroidism is necessary. Specific RET mutations can also impact management in patients presenting with apparently sporadic MTC. Therefore, genetic testing should be performed before surgical intervention in all patients diagnosed with MTC. Recently, Pellegata et al. have reported that germline mutations in CDKN1B can predispose to the development of multiple endocrine tumours in both rats and humans and this new MEN syndrome is named MENX and MEN4, respectively. CDKN1B. A recent report showed that in sporadic MTC, CDKN1B V109G polymorphism correlates with a more favorable disease progression than the wild-type allele and might be considered a new promising prognostic marker. New insights on MEN syndrome pathogenesis and related inherited endocrine disorders are of particular interest for an adequate surgical and therapeutic approach.

Multiple endocrine neoplasia in an orthodontic patient: Interprofessional diagnostic and treatment implications.

BACKGROUND: Multiple endocrine neoplasia, type 2B (MEN 2B), is an autosomal-dominant condition characterized by the development of multiple endocrine tumors. All affected people develop an aggressive form of medullary thyroid cancer (MTC). Without early prophylactic thyroidectomy, the prognosis for patients with MEN 2B is poor; the average age at death is 21 years. CASE DESCRIPTION: The authors present a case of a 16-year-old girl who had a diagnosis of MEN 2B and was treated successfully for metastatic MTC. CLINICAL IMPLICATIONS: Given the striking orofacial manifestations of MEN 2B (marfanoid habitus; dolichocephaly; everted and thickened lips; mucosal neuromas on lips, tongue, buccal mucosa and eyelids), dental professionals are well positioned to recognize the disorder. Early identification of patients with the condition permits screening for preclinical thyroid disease, molecular genetic testing, counseling and lifesaving thyroid surgery.

Duodenal adenocarcinoma with neuroendocrine features in a patient with acromegaly and thyroid papillary adenocarcinoma: a unique combination of endocrine neoplasia.

A 67-year-old woman with familial clustering of thyroid papillary adenocarcinoma was diagnosed with acromegaly due to pituitary macroadenoma. She had multiple skin vegetations, but had no parathyroid and pancreas diseases. Before transsphenoidal surgery, she was further diagnosed as having a duodenal tumor and multiple hypervascular liver nodules. Biopsy specimens from the duodenal tumor and liver nodules were diagnosed histologically as moderately differentiated adenocarcinoma. Immunohistochemically, the tumor cells were positive for chromogranin, synaptophysin and somatostatin receptor 2a, suggestive for neuroendocrine features. After surgery, the patient was not in biochemical remission, and octreotide treatment was initiated. The duodenal cancer was treated with chemotherapy (neoadjuvant cisplatin and S-1). After 24 months, the patient's insulin-like growth factor I level had been normalized, and her liver tumors had not progressed macroscopically. This is a rare case of acromegaly associated with multiple endocrine tumors, not being categorized as conventional multiple endocrine neoplasia. Octreotide treatment might have had beneficial effects on our patient's duodenal adenocarcinoma and liver metastases, both directly via SSTR2a and indirectly via GH suppression, thereby contributing to their slow progression.

Acromegaly caused by growth hormone releasing hormone (GHRH) secreting tumor in multiple endocrine neoplasia (MEN-1).

We are presenting the clinical features, diagnostic work up and treatment of acromegaly caused by Growth hormone releasing hormone (GHRH) secreting neuroendocrine tumor (NECT) in a case of multiple endocrine neoplasia type 1 (MEN-1). A 36 year old man, known case of MEN-1 presented with acromegalic features. He has high IGF-1, GH and very high GHRH levels with a pancreatic head tumor and pituitary mass. He had high GHRH arteriovenous gradient across pancreatic tumor and underwent tumor resection, Post operative GHRH level fell dramatically. Tumor had high GHRH m-RNA level. Acromegalic patients with MEN-1 should be screened for ectopic GHRH secretion. Measurement of GHRH arteriovenous gradient across NECT or mRNA for GHRH in resected tumor can confirm the ectopic source. Treatment of choice is surgical resection of the tumor. Somatostatin analogue is an alternative because of its dual action in the pituitary gland and the NECT. Life long surveillance is needed as recurrence chance is high.

Three endocrine neoplasms: an unusual combination of pheochromocytoma, pituitary adenoma, and papillary thyroid carcinoma.

BACKGROUND: Three endocrine neoplasms-bilateral pheochromocytomas, somatotrophic pituitary adenoma inducing acromegaly, and papillary carcinoma of the thyroid-occurred concurrently in a patient. A genetic mutation was hypothesized. Possible previously described genetic mutations were explored. METHODS: Clinical assessments, laboratory data, images of tumors, histopathology, and immunohistochemistry of excised tissues documented the three neoplasms. Clinical assessment of the patient, family history, and a review of the literature sought a familial basis for the disorders. RESULTS: The methods confirmed the presence of three endocrine neoplasms. Each neoplasm was surgically excised and histologically verified. Surgical and (131)I treatments reduced the papillary carcinoma, but eventually this tumor progressed to a lethal degree. History, including that of nine siblings, uncovered no familial neoplasms. No similar case was found in the literature, but possible associations with germline mutations were considered. CONCLUSIONS: The concurrent development of pheochromocytomas, pituitary somatotrophic adenoma, and papillary thyroid carcinoma appears to be unique. Nevertheless, such tumors, particularly bilateral pheochromocytomas, strongly suggest a de novo germline mutation in a gene not previously associated with multiple endocrine neoplasia syndromes.

[Clinical characteristics of multiple endocrine neoplasia]. / Séance dédiée aux tumeurs endocrines. Néoplasies endocriniennes multiples, aspects cliniques.

Multiple endocrine neoplasia type 1 (MEN1) and type 2 (MEN2) are autosomal dominant inherited multiglandular diseases with familial and individual age-related penetrance and variable expression. The most frequent endocrine features of MEN1 are parathyroid involvement (> 95%), duodeno-pancreatic endocrine tissue involvement (80%), pituitary adenoma (30%), and adrenal cortex tumors (25%), with no clear syndromic variants. Identification of the germline MEN1 mutation confirms the diagnosis, but there is no phenotype-genotype correlation. All patients with MEN2 have medullary thyroid carcinoma (MTC). The most distinctive MEN2 variants are MEN2A (MTC+pheochromocytoma+hyperparathyroidism), MEN2B (MTC+pheo), and isolated familial MTC (FMTC). The prognosis of MEN2 is linked to the progression of MTC, which depends mainly on the stage at diagnosis and the quality of initial surgical treatment. This emphasizes the need for early diagnosis and management. The specific RET codon mutation correlates with the MEN2 syndromic variant and with the age of onset and aggressiveness of MTC. Consequently, RET mutational status should guide major management decisions, such as whether and when to perform thyroidectomy.

The surgical management of medullary thyroid cancer.

Medullary thyroid cancer (MTC), accounts for approximately 5% to 10% of all thyroid cancers. Significant advances in the understanding of the biology and clinical outcomes of MTC have been made over the last decade, culminating most recently in the publication of treatment guidelines by the American Thyroid Association that follow an evidence-based approach that is summarized in this presentation. Prognosis, genetic testing, surgical technique, and re-operation are also discussed.

Primary hyperparathyroidism.

Primary hyperparathyroidism is the most common cause of hypercalcemia in the outpatient setting. Phenotypically, it has evolved from a disease of overt symptomatology to one of vague complaints and biochemical diagnosis. Preoperative localization and intraoperative parathyroid hormone have revolutionized the surgical management of these patients. Minimally invasive operations are now common worldwide with low morbidity and high patient satisfaction.

[Diagnosis of and surgical therapy for pheochromocytoma and paraganglioma]. / Diagnostik und operative Therapie von Phäochromozytomen und Paragangliomen.

Pheochromocytomas and paragangliomas are rare chromaffin tumours that represent an exceptional challenge for the surgeon because of the concomitant secretion of catecholamines. Recent findings on the genetic background of hereditary tumours have challenged the rule of the 10 % -tumour and significantly changed the requirements for preoperative work-up and surgical strategy. Early detection of malignant growth or multiple hereditary tumours is the goal of imaging techniques such as CT/MRI, (123)I-MIBG-(SPECT) or (18)F-DOPA-PET. However, in the absence of metastasis, reliable differentiation between -benign and malignant growth is preoperatively and even histopathologically rarely possible. An essential precondition for successful surgical therapy with low operative risks is an adequate pretreatment with alpha-adrenergic antagonists which should slowly be increased to 3-5 mg/kg BW/day prior to resection. Dopamine-secreting paragangliomas represent the sole exception. Minimally invasive techniques using a transabdominal or retroperitoneal approach have become the gold standard for the resection of unifocal benign pheochromocytomas. In addition, most paragangliomas located below the diaphragm can be resected with a minimally invasive approach which, however, demands exceptional expertise. Open transabdominal resections are an approved therapy for large or potentially -malignant tumours and for settings with multi-focal tumour sites. Even for advanced malignant tumours, surgical debulking may be reasonable to improve the patient's quality of life and prognosis.

Childhood phaeochromocytoma and paraganglioma: 100% incidence of genetic mutations and 100% survival.

INTRODUCTION: The aim is to identify the incidence of genetic mutations and outcome of children presenting with phaeochromocytoma/paraganglioma (PGL) to a single paediatric surgical service to determine the need for genetic counselling in associated kindreds. METHODS: A retrospective case note review was undertaken of all cases treated between 1998 and 2008 with particular reference to presentation, management, and predisposing genetic conditions. RESULTS: Seven cases (4 male, 3 female) were identified (median age, 13 years; interquartile range, 9-16). Three cases had a family history of phaeochromocytoma/PGL. All presented with neurologic symptoms related to hypertension, including headaches (n = 5), hemiparesis (n = 2), facial palsy, and hemianopia. All underwent surgical resection. Five patients had meta-iodobenzylguanidine (MIBG) therapy for apparently malignant features. All cases were found to have a predisposing genetic mutation: von Hippel-Lindau (n = 3), succinate dehydrogenase mutations (n = 3), and multiple endocrine neoplasia (n = 1). All patients are alive after a median follow-up of 5 (interquartile range, 2-7) years. CONCLUSIONS: All 7 cases had a familial genetic mutation identified, and none arose de novo. We advocate genetic counselling for all families of children diagnosed with phaeochromocytoma/PGL with lifelong surveillance tailored to the underlying syndrome because of the increased risk of synchronous and metachronous tumours associated with these genetic syndromes.