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.

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.

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.

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.

[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.

[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.

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.

Familial parathyroid tumors: diagnosis and management.

BACKGROUND: The management of hyperparathyroidism (HPT) in the familial setting is complex. Due to the rarity of familial HPT and its different presentation within and between the familial syndromes and individual kindreds, treatment recommendations based on high levels of evidence cannot be made. However, based on the molecular genetic studies and case series from institutions with significant experience, important management principles (grade C recommendations) have been developed. METHODS: We conducted a systematic review of the literature using evidence-based criteria. RESULTS: Issue 1: initial operation in multiple endocrine neoplasia type 1 (MEN1), a grade C recommendation can be made for subtotal parathyroidectomy. Issue 2: initial surgery in MEN 2A, a grade C recommendation can be made for excision of enlarged glands only. Issue 3: surgery in familial isolated HPT and HPT-jaw tumor (HPT-JT) syndrome may be treated with parathyroidectomy that is subtotal or less, although the risk of parathyroid cancer in HPT-JT requires attention (no grade of recommendation). Issue 4: parathyroid surgery in familial HPT syndromes in the setting of underlying mutations in the calcium receptor (CASR) gene involves subtotal parathyroidectomy (no grade of recommendation). Issue 5: the use of intraoperative PTH measurements in familial HPT may guide the extent of parathyroid resection (no grade of recommendation). CONCLUSIONS: The goals of parathyroidectomy in familial HPT are to achieve and maintain normocalcemia for the longest time possible, avoid both iatrogenic hypocalcemia and operative complications, and facilitate future surgery for recurrent disease.

[Prophylactic thyroidectomy in multiple endocrine neoplasia syndrome]. / Tiroidectomía profiláctica en el síndrome de neoplasia endocrina múltiple.

Multiple endocrine neoplasia (MEN) 2a consists on medullary thyroid carcinoma, pheochromocytoma and hyperparathyroidism. The identification of the RET proto-oncogene in 1993 has changed the prognosis of the disease. We have retrospectively studied the patients diagnosed of MEN 2a in our centre for the last 7 years in order to establish the most adequate age to undergo surgery. We present ten patients diagnosed with MEN 2a, whose ages ranged from 1.5 to 11 years old. Mean age at time of operation: 6,4 years An ultrasound study, calcitonin determinations and cathecholamines and urinary metanephrine levels were obtained before surgery. The surgical treatment is based on total total thyroidectomy, in selected cases lymph node resection in the central zone lf the neck. The most frequent RET mutation is the one affecting codon 634 (exon 10), which was found in children. Both of them had an alteration in codon 611 (exon11). No complications appeared after surgery and hospital discharge took place in the 2nd-4th day after surgery. Pathological findings were medullary thyroid microcarcinoma (MTMC) in 3 out of 10 patients, calcitonin preoperative tests were high in one of them. No tumoral cells were found in the lymph nodes. During the follow up period, 9 out of 10 from the operated patients, maintained normal calcitonin, CEA, PTH, calcium, cathecholamines and urinary metanephrine levels. Since there are 3 cases of MTC in patients between 3 and 6 years old, and diagnostic test data are not conclusive, we thoroughly recommend prophyilactic thyroidectomy at early ages, from 3 to 4 years old.

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.

Primary hyperparathyroidism in neonates and childhood. The French experience (1984-2004).

OBJECTIVES: Primary hyperparathyroidism (HP1) in childhood is thought to be extremely rare. Its exact incidence remains unknown, as do the characteristics of HP1. A retrospective study collection was conducted on cases supplied by members of the Working Group on Calcium Metabolism throughout France over a 20-year period (1984-2004), since the availability of the intact parathormone (iPTH) radioimmunoassay. RESULTS: 55 cases were collected of which 11 were neonates. Among the 44 children and adolescents, there were 18 male and 26 female patients, ranging in age from 6 to 18 (mean 13) years. 83% were symptomatic and 43% had nephrolithiasis. Symptoms were associated with high serum calcium and inappropriate iPTH levels. Ultrasonography and technetium-labelled methoxyisobutylisonitrile scintigraphy are useful tools for the preoperative localization of adenomas, particularly in adolescents. Intraoperative iPTH assays are effective in minimizing invasive parathyroidectomy. All patients, except neonates, underwent surgery: 29 adenomas and 11 hyperplasias were found. Two multiple endocrine neoplasias (MENs) were subsequently discovered. Since the calcium-sensing receptor (CaSR) mutation was reported, the form of management in neonates has become more medical (intravenous diphosphonates) than surgical. On follow-up no recurrence was observed except for MEN. CONCLUSION: These national results reflect HP1 epidemiology. HP1 is a rare entity and appears to be a severe disease in terms of symptoms with regard to management. The use of molecular biology tests could be useful not only in neonatal cases (CaSR mutation) but also prior to surgery in children (MEN mutation).

Multiple endocrine neoplasia with pulmonary localization: a new protocol of approach.

We present three patients with bronchial carcinoids, in which a more probed study emphasized the presence of three multiple endocrine neoplasia (MEN). Assessment included a total-body computerized tomography, a total-body single-photon emission computerized tomography by 111In-DTPA-D-Phe1 octreotide, and genetic map. Two patients presented an atypical MEN 1 and one patient showed an atypical MEN 1 with a familial medullary thyroid carcinoma. All patients were operated upon: two are still alive and one died 50 months after the first intervention. Precocious diagnosis of MEN permits a good long-term outcome.

Endocrine surgical aspects of multiple endocrine neoplasia syndromes in children.

BACKGROUND: All patients diagnosed with medullary thyroid carcinoma (MTC) should undergo RET mutation analysis to exclude familial disease - multiple endocrine neoplasia (MEN)-2A and -2B and familial medullary thyroid carcinoma (FMTC). In young patients at risk of genetically determined MTC, the key to a good outcome is an appropriate first operation, and this will depend upon the codon mutation, patient age, calcitonin level and disease extent at presentation. When MTC has already developed, a therapeutic intervention is required. CONCLUSIONS: The thyroid, pituitary, adrenal, parathyroid and pancreatic components of MEN-1 and -2 require close collaboration of a specialist and experienced multidisciplinary team.

Current applications of the intraoperative parathyroid hormone assay in parathyroid surgery.

Parathyroid hormone measurement using a two-site immunochemiluminometric assay has allowed for a rapid and accurate technique that has found its way into the operative armamentarium of some parathyroid surgeons. It can be used to assess the completeness of parathyroid gland resection and allow for a minimally invasive parathyroidectomy. This operative approach has become a popular marketing tool, providing patients with confidence in their surgical outcome. The purpose of this review is to provide the surgeon with the practical points and pitfalls of the use of intraoperative parathyroid hormone in the treatment of parathyroid disease.

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.

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.

What is the link between nonlocalizing sestamibi scans, multigland disease, and persistent hypercalcemia? A study of 401 consecutive patients undergoing parathyroidectomy.

BACKGROUND: We hypothesized that nonlocalizing sestamibi scans would correlate with multigland disease and persistent primary hyperparathyroidism. METHODS: We reviewed records for 401 consecutive patients who underwent parathyroidectomy from 1999 to 2004. Gender, age, preoperative imaging, surgical findings, gland weight and volume, and 6-month calcium levels (Ca) were examined. RESULTS: We identified 289 women and 112 men, 297 of whom had a preoperative sestamibi scan localized to a single gland (localized group; LG). Ninety-six percent of the LG were found to have single-gland disease, and 4% had multigland disease (MGD). In the nonlocalized group (NLG), 76% had single-gland disease and 24% MGD. Mean gland weight was greater in the LG than in the NLG (1128 mg vs 699 mg; P < .05). Mean gland volume was larger in the LG (1.34 cc vs 0.89 cc; P < .05). A localizing sestamibi scan had a positive predictive value (PPV) of 96% and a likelihood ratio of 2.29 for predicting "curative" intraoperative parathyroid hormone drop after removal of a single abnormal gland. Patients were stratified into normocalcemic (NCa) and hypercalcemic (HCa) groups based on 6-month postoperative serum calcium data (n = 328). HCa incidence at 6 months did not differ significantly between the LG (5%) and NLG (3%). A localizing scan had a PPV of 95% for normocalcemia at 6 months. A nonlocalizing scan had a PPV of 21% for HCa at 6 months. CONCLUSIONS: Nonlocalizing sestamibi scans were more common in primary hyperparathyroidism with MGD and were associated with smaller-volume abnormal glands found at operation. Preoperative sestamibi scan-results did not predict HCa at 6 months.

[Neuroendocrine tumors. A rare case of duodenal carcinoids]. / Tumori neuroendocrini. Un raro caso di carcinoidi duodenali.

The authors report their experience with a case of double duodenum carcinoid tumors occurring in a 59-year-old female patient. She presented with a one-year history of frequent abdominal painful episodes, associated with dyspepsia, emesis, pyrosis, eructation, skin flushing and easy strain. The laboratory examinations point out high hematic values of serotonin and gastrin, with a raising of urinary 5-HIAA. Preoperative endoscopic examinations showed the presence of 2 little sessile polypoid growths, placed in the duodenal bulb, one of this interested muscular tunic. The patient underwent Billroth I resection and was discharged on postoperative day 8. The authors after a little dissertation on that topic, go on to examine the current diagnostic and therapeutic possibilities. They confirm the elective role of surgical treatment of these rare tumors.