[Tumor predisposition in endocrinology - from MEN to FIPA]. / Tumorprädisposition in der Endokrinologie ­ von MEN bis FIPA.

Understanding genetic predisposition has a significant impact on the management of patients with endocrine tumours, including therapy, early detection and prevention. These tumours, which develop as part of a familial predisposition, often manifest early in life and frequently affect several endocrine organs. In the following article, both common syndromes, such as multiple endocrine neoplasia (MEN) syndromes, and rare syndromes, such as familial isolated pituitary adenoma (FIPA), are presented based on their indicator diseases.

Updates on the genetics of multiple endocrine neoplasia.

Multiple endocrine neoplasia (MEN) is a group of syndromes with a genetic predisposition to the appearance of endocrine tumors, and shows autosomal dominant transmission. The advent of molecular genetics has led to improvements in the management of MEN in terms of diagnosis, prognosis and therapy. The genetics of MEN is the subject of regular updates, which will be presented throughout this paper. MEN1, the first to be described, is associated with the MEN1 gene. MEN1 is well known in terms of the observed phenotype, with genetic analysis being conclusive in 90% of patients with a typical phenotype, but is negative in around 10% of families with MEN1. Improvement in analysis techniques and the identification of other genes responsable for phenocopies allows the resolution of some, but not all, cases, notably non-familial forms suspected to be fortuitous assocations with tumors. MEN4 is a rare phenocopy of MEN1 linked to constitutional mutations in the CDKN1B gene. Though it closely resembles the phenotype of MEN1, published data suggests the appearance of tumors is later and less frequent in MEN4. MEN2, which results from mutations in the RET oncogene, shows a strong genotype-phenotype correlation. This correlation is particularly evident in the major manifestation of MEN2, medullary thyroid carcinoma (MTC), in which disease aggressiveness is dependent on the pathogenic variant of RET. However, recent studies cast doubt on this correlation between MTC and pathogenic variant. Lastly, the recent description of families carrying a mutation in MAX, which is known to predispose to the development of pheochromocytoma and paraganglioma, and presents a phenotypic spectrum that evokes MEN, suggests the existence of another syndrome, MEN5.

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

BACKGROUND: While primary tumor desmoplasia is a powerful biomarker of node metastases in sporadic medullary thyroid cancer (MTC), information for hereditary MTC is sparse. METHODS: 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. RESULTS: 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. CONCLUSION: This proof-of-concept study suggests that primary tumor desmoplasia is an equally powerful biomarker of node metastasis in hereditary MTC.

Multiple endocrine neoplasia type 4 (MEN4): a thorough update on the latest and least known men syndrome.

PURPOSE: Multiple endocrine neoplasia type 4 (MEN4) is a rare multiglandular endocrine neoplasia syndrome, associated with a wide tumor spectrum but hallmarked by primary hyperparathyroidism, which represents the most common clinical feature, followed by pituitary (functional and non-functional) adenomas, and neuroendocrine tumors. MEN4 clinically overlaps MEN type 1 (MEN1) but differs from it for milder clinical features and an older patient's age at onset. The underlying mutated gene, CDKN1B, encodes the cell cycle regulator p27, implicated in cellular proliferation, motility and apoptosis. Given the paucity of MEN4 cases described in the literature, possible genotype-phenotype correlations have not been thoroughly assessed, and specific clinical recommendations are lacking. The present review provides an extensive overview of molecular genetics and clinical features of MEN4, with the aim of contributing to delineate peculiar strategies for clinical management, screening and follow-up of the last and least known MEN syndrome. METHODS: A literature search was performed through online databases like MEDLINE and Scopus. CONCLUSIONS: MEN4 is much less common that MEN1, tend to present later in life with a more indolent course, although involving the same primary organs as MEN1. As a consequence, MEN4 patients might need specific diagnostic and therapeutic approaches and a different strategy for screening and follow-up. Further studies are needed to assess the real oncological risk of MEN4 carriers, and to establish a standardized screening protocol. Furthermore, a deeper understanding of molecular genetics of MEN4 is needed in order to explore p27 as a novel therapeutic target.

Pediatric head and neck manifestations associated with multiple endocrine neoplasia syndromes.

INTRODUCTION: Multiple endocrine neoplasia (MEN) syndromes are a group of hereditary cancer syndromes that can predispose children to endocrine neoplasms developing within the head and neck. OBJECTIVE: To examine the neoplastic manifestations of MEN type 1 (MEN1) and MEN type 2 (MEN2) in the pediatric head and neck. METHODS: Single-institution, retrospective review of pediatric MEN between 2005 and 2022. RESULTS: Fifty-three children were genetically confirmed with MEN (15 MEN1, 34 MEN2A, and 4 MEN2B), while three patients received clinical diagnoses of MEN1. The male to female ratio was essentially equal (1.15:1), and a documented family history of cancer was present in 89% (50/56). After multidisciplinary evaluation, a familial MEN diagnosis was confirmed in 91% (51/56). The mean ages of initial presentation and surgical intervention were 8.9 years (SD 5) and 9.8 years (SD 4.8), respectively. Although patients with MEN2 received surgery earlier than patients with MEN1 (8.7 vs 12.7 years), surgical patients with MEN2 in this cohort were older relative to current American Thyroid Association (ATA) guidelines primarily due to late presentation. Thyroid malignancies were identified in 36% (9/25) of thyroidectomy specimens (21 MEN2A, 4 MEN2B), with medullary thyroid carcinoma (MTC) present in five MEN2A patients and three MEN2B patients (89%), and papillary thyroid carcinoma (PTC) present in one MEN2A patient (11%). Nearly 90% (8/9) of thyroid malignancies were occult, with some occurring earlier than predicted by current guidelines (ATA-MOD and ATA-H). Central neck dissections were performed in 24% (2 MEN1, 2 MEN2A, and 4 MEN2B), with two MEN2B (50%) demonstrating cervical lymph node (LN) metastases. Additional histopathologic findings included C-cell hyperplasia in 57% (12/21) of MEN2A thyroidectomy patients. Of the eight MEN1 parathyroidectomy patients, four demonstrated parathyroid hyperplasia and four presented with parathyroid adenoma. CONCLUSION: Nearly 60% required head and neck procedures. While MEN1 guidelines were appropriate for our cohort, we identified patients with MEN2 that developed MTC earlier than expected based on current ATA guidelines, including children in categories considered lower risk. In conjunction with a multidisciplinary approach, pediatric head and neck surgeons should be aware of the potential need for earlier surgical intervention in the pediatric MEN2 population.

Clinical profile and treatment outcomes among patients with sporadic and multiple endocrine neoplasia syndrome-related primary hyperparathyroidism.

OBJECTIVE: Accurate demarcation between multiple endocrine neoplasia, type 1 (MEN1)- related primary hyperparathyroidism (MPHPT) and sporadic PHPT (SPHPT) is important to plan the management of primary parathyroid disease and surveillance for other endocrine and nonendocrine tumours. The objective of this study is to compare the clinical, biochemical and radiological features and surgical outcomes in patients with MPHPT versus SPHPT and to identify the predictors of MEN1 syndrome in PHPT. DESIGN, PATIENTS AND MEASUREMENTS: This was an ambispective observationalstudy involving 251 patients with SPHPT and 23 patients with MPHPT evaluated at the endocrine clinic of All India Institute of Medical Sciences, New Delhi, India between January 2015 and December 2021. RESULTS: The prevalence of MEN1 syndrome among patients with PHPT was 8.2% and a genetic mutation was identified by Sanger sequencing in 26.1% of patients with MPHPT. Patients with MPHPT were younger (p < .001), had lower mean serum calcium (p = .01) and alkaline phosphatase (ALP; p = .03) levels and lower bone mineral density (BMD) Z score at lumbar spine (p < .001) and femoral neck (p = .007). The prevalence of renal stones (p = .03) and their complications (p = .006) was significantly higher in MPHPT group. On multivariable analysis, factors predictive of MPHPT were hyperplasia on histopathology [OR 40.1, p < .001], ALP levels within reference range [OR 5.6, p = .02] and lumbar spine BMD [OR 0.39 per unit increase in Z score, p < .001]. CONCLUSIONS: Patients with MPHPT have more severe, frequent and early onset of bone and renal involvement despite milder biochemical features. A normal serum ALP, low BMD for age and gender at lumbar spine and histopathology evidence of hyperplasia are predictive factors for MEN1 syndrome in PHPT.

Neuroendocrine tumors in a patient with multiple endocrine neoplasia type 1 syndrome: A case report and review of the literature.

RATIONALE: Hyperparathyroidism is caused by parathyroid tumors combined with gastroenteropancreatic tumors and pituitary tumors, which is common in patients with multiple endocrine neoplasia 1 syndrome (MEN-1). As its main pathogenic factor involves genetic mutations, it can cause a variety of different clinical symptoms. However, cases with negative genetic testing results and multiple nonfunctional malignant neuroendocrine tumors (NETs) with metastasis are relatively rare. PATIENT CONCERNS: A 33-year-old man was admitted to the hospital for hyperparathyroidism. Imaging examination revealed multiple nodules in the parathyroid gland, pancreas, thymus, and adrenal gland, and multiple metastases to the lung, liver, thoracolumbar, as well as mediastinal lymph nodes. DIAGNOSES: After multidisciplinary consultation, this patient was diagnosed with MEN-1 syndrome with various original tumors and multiple systemic metastases. INTERVENTIONS: The patient underwent parathyroid tumor resection and metastasis biopsy. OUTCOMES: The patient received denosumab and sorafenib treatment. LESSONS: As an autosomal dominant hereditary disease, MEN-1 patients present with parathyroid hyperplasia, pancreatic and intestinal tumors, pituitary tumors, and so on, which are caused by genetic mutations. These patients would have hyperparathyroidism, hypoglycemia, gastric ulcer, and gastrointestinal diseases. However, some patients with MEN-1 syndrome cannot be diagnosed by genetic testing and simultaneously present with multiple nonfunctional NETs with systemic metastasis. This increases the difficulty of diagnosis and the subsequent treatment.

Multiple endocrine neoplasia in a sheep: insulinoma, adrenocortical carcinoma with myxoid differentiation, and thyroid C-cell carcinoma.

An ~10-y-old male sheep had anorexia and progressive weight loss for ~1 mo. The sheep was emaciated, and 20 d later, became recumbent and lethargic, and was hypoglycemic (0.33 mmol/L; RI: 2.6-4.4 mmol/L). The sheep was euthanized because of poor prognosis, and submitted for autopsy. We found no gross lesions in the pancreas; however, histologically, focal proliferations of round-to-polygonal cells were separated by connective tissue into small nests. These proliferating cells, which had abundant eosinophilic-to-amphophilic cytoplasm and hyperchromatic nuclei, were immunopositive for insulin and negative for glucagon and somatostatin; the lesion was diagnosed as an insulinoma. Insulinoma has not been reported previously in sheep, to our knowledge. In addition, autopsy and histologic examination revealed the presence of an adrenocortical carcinoma with myxoid differentiation and a thyroid C-cell carcinoma. Our case indicates that multiple endocrine neoplasms can occur in sheep, as in other animal species.

Ectopic parathyroid adenoma in a patient with multiple endocrine tumours.

Not required for Clinical Vignette.

Thymic atypical carcinoid tumors with elevated mitotic counts in a patient with multiple endocrine neoplasia: A case report.

Thymic neuroendocrine tumors associated with multiple endocrine neoplasia are only defined as carcinoid and are not associated with large-cell neuroendocrine carcinoma (LCNEC). We report the case of a multiple endocrine neoplasia type 1 patient with atypical carcinoid tumors with elevated mitotic counts (AC-h), an intermediate condition between carcinoid and LCNEC. A 27-year-old man underwent surgery for an anterior mediastinal mass and was diagnosed with thymic LCNEC. Fifteen years later, a mass appeared at the same site, which was determined to be a postoperative recurrence based on the pathological results of a needle biopsy and the clinical course. The patient's disease remained stable for 10 months on anti-programmed death-ligand 1 antibody and platinum-containing chemotherapy. The needle biopsy specimen was submitted for next-generation sequencing, which revealed a MEN1 gene mutation, and after further examination, a diagnosis of multiple endocrine neoplasia type 1 was made. A re-examination of the surgical specimen from 15 years prior showed that it corresponded to AC-h. Although thymic AC-h is classified as thymic LCNEC according to the current definition, our data suggests that a search for multiple endocrine neoplasia is warranted in such patients.

Germline CDKN1B variant type and site are associated with phenotype in MEN4.

Multiple endocrine neoplasia 4 (MEN4) is a rare multiglandular endocrine neoplasia syndrome clinically hallmarked by primary hyperparathyroidism (PHPT), pituitary adenoma (PitAd), and neuroendocrine tumors (NET), clinically overlapping MEN1. The underlying mutated gene - CDKN1B, encodes for the cell-cycle regulator p27. Possible genotype-phenotype correlations in MEN4 have not been thoroughly assessed. Prompted by the findings in three Israeli MEN4 kindreds, we performed a literature review on published and unpublished data from previously reported MEN4/CDKN1B cases. Univariate analysis analyzed time-dependent risks for developing PHPT, PitAd, or NET by variant type and position along the gene. Overall, 74 MEN4 cases were analyzed. PHPT risk was 53.4% by age 60 years (mean age at diagnosis age 50.6 ± 13.9 years), risk for PitAd was 23.2% and risk for NET was 16.2% (34.4 ± 21.4 and 52.9 ± 13.9 years, respectively). The frameshift variant p.Q107fs was the most common variant identified (4/41 (9.7%) kindreds). Patients with indels had higher risk for PHPT vs point mutations (log-rank, P = 0.029). Variants in codons 94-96 were associated with higher risk for PHPT (P < 0.001) and PitAd (P = 0.031). To conclude, MEN4 is clinically distinct from MEN1, with lower risk and older age for PHPT diagnosis. We report recurrent CDKN1B frameshift variants and possible genotype-phenotype correlations.

[MEN for multiple endocrin neoplasms: When evokate MEN? Update 2022]. / Mise au point sur les néoplasies endocriniennes multiples.

Multiple endocrine neoplasia (MEN) are genetic predisposition syndromes to endocrine tumors including MEN1, MEN2 and exceptionally MEN4. MEN are transmitted in an autosomal dominant fashion with a high penetrance. Classically, there is no genotype/phenotype correlation for NEM1 whereas this is the case for NEM2. Patients with NEM1, linked to an inactivating mutation of the menin gene, may present with: primary hyperparathyroidism, pituitary adenoma, duodeno-pancreatic neuroendocrine tumors (NETs), bronchial tumors with an increased risk of thymoma, adrenal cortical tumors, an increased risk of breast cancer and characteristic skin involvement such as collagenomas, lentiginomas and an increased risk of skin cancer. These patients require at least annual follow-up. Screening of children is proposed from the age of 5 years. Patients with NEM2, linked to an activating mutation of the RET proto-oncogene, all present with medullary thyroid carcinoma (MTC) at a variable age depending on the genotype. Some patients present a pheochromocytoma (50 %) and hyperparathyroidism (20 %). Pediatric forms with aggressive CMT, ganglioneuromatosis and marfanoid syndrome exist (rare NEM2B). Some mutations are associated with a risk of aggressive CMT, justifying prophylactic thyroidectomy before 6 months of age. The age of genetic testing depends on the mutation subtype in the NEM2 parent. NEM4, related to a mutation in the CDKN1B gene, are rare, with a less well-known pathogenesis and their follow-up is not well codified.

The Classic, the Trendy, and the Refashioned: A Primer for Pathologists on What Is New in Familial Endocrine Tumor Syndromes.

Familial endocrine tumor syndromes are continuously expanding owing to the growing role of genetic testing in routine clinical practice. Pathologists are usually the first on the clinical team to encounter these syndromes at their initial presentation; thus, recognizing them is becoming more pivotal in routine pathology practice to help in properly planning management and further family testing. Our increasing knowledge about them is reflected in the newer syndromes included in the new World Health Organization classification and in the evolving discovery of new endocrine tumors and new familial associations. In many of these syndromes, the clinical features and co-occurrence of multiple neoplasia are the only clues (multiple endocrine neoplasia syndromes). In other syndromes, specific morphologic findings (pituitary blastoma and DICER1 syndrome, cribriform morular thyroid carcinoma, and AFP syndrome) and available ancillary studies (SDHB in SDH-deficient tumor syndromes) can aid pathologists. The aim of this review is to provide a primer on recent updates on familial endocrine tumor syndromes and related tumors, focusing on recent classification changes or tumor syndromes where a clearer role for pathologists is at play.

How to treat gastrinomas in patients with multiple endocrine neoplasia type1: surgery or long-term proton pump inhibitors?

In patients with multiple endocrine neoplasia type 1 syndrome (MEN 1) and Zollinger-Ellison syndrome (ZES), gastrinomas arise from the duodenum, about 60% are multiple, and about 15% of patients have coexisting pancreatic gastrinomas, which can be localized by the selective arterial secretagogue injection test (SASI test). The guidelines (GLs) by the Japanese Neuroendocrine Tumor Society (JNETS) recommend surgical resection for functioning duodenopancreatic neuroendocrine tumors (NETs), including gastrinomas, in patients with MEN1 (Grade A, 100% agreement among members). Conversely, the GLs of the National Comprehensive Cancer Network (NCCN) in the USA recommend observation and treatment with proton pump inhibitors (PPIs) or exploratory surgery for occult gastrinomas. An international Consensus Statement (ICS) from the European Union (EU) also does not recommend resection of gastrinomas in patients with MEN1, despite some surgeons having reported surgery being curative for gastrinomas in MEN1 patients. In this review, we discuss the serious side effects and tumorigenic effects of the prolonged use of PPIs and the safety and curability of surgery, supported by our results of curative surgery for gastrinomas in 20 patients with MEN1 over 30 years. We conclude that surgery should be the first-line treatment for gastrinomas in MEN1 patients.

[Primary lymph node gastrinoma]. / Gastrinoma primario de ganglio linfático.

Gastrinomas are neuroendocrine tumors usually located in the duodenum and pancreas, in the context of a Multiple Endocrine Neoplasm and forming a Zollinger-Ellison syndrome. The location of this type of lymph node tumor is extremely unusual and its early diagnosis constitutes a real challenge to be able to establish an adequate treatment and manage the complications that these entail. We present the case of a 64-year-old male patient with a lymph node gastrinoma and whose surgical removal resulted in the immediate remission of the patient's symptoms.

Multiple endocrine neoplasia type 2 and autoimmune polyendocrine syndromes (type 1 diabetes mellitus and Graves' disease) in a 16-year-old male with Kabuki syndrome.

Multiple endocrine neoplasia type 2A (MEN2A) is caused by germline pathogenic variants in the RET proto-oncogene and is characterized by medullary thyroid cancer (MTC), pheochromocytoma, and hyperparathyroidism. Autoimmune polyendocrine syndromes (APS) are defined as multiple endocrine gland insufficiency associated with loss of immune tolerance. APS type 2 (APS-2) consists of at least two of the following diseases: type 1 diabetes mellitus (T1DM), autoimmune thyroid disease, and Addison's disease. We describe the clinical, molecular, and biochemical findings of MEN2A, APS-2, and Kabuki syndrome (KS) in a 16-year-old male. Whole exome sequencing was performed to identify the genetic cause of the pheochromocytoma and syndromic features including facial dysmorphism, developmental delay, and epilepsy. RET pathogenic variant and KMT2D pathogenic variant were identified, and he was diagnosed with MEN2A and KS. This is the first case of association between MEN2 and APS in adolescence and the second proven case in humans. In addition, this is the first report of MEN2 and APS in KS.

Long delay in diagnosis of a case with MEN1 due to concomitant presence of AIMAH with insulinoma: a case report and literature review.

BACKGROUND: ACTH-independent macronodular hyperplasia (AIMAH) is an uncommon disorder characterized by massive enlargement of both adrenal glands and hypersecretion of cortisol. Concomitant AIMAH and multiple endocrine neoplasia type1 (MEN1) is rare to our knowledge. CASE PRESENTATION: Herein, we describe a 32 year old woman with long history of prolactinoma and secondary ammonhrea presented with not-severe manifestation of hypoglycemia due to concomitant presence of insulinoma with AIMAH leading to 12 years delay of MEN1 diagnosis. Laboratory tests showed severe hypoglycemia associated with hyper insulinemia (non-fasting blood sugar = 43 mg/dl, insulin = 80.6 µIU /ml, C-peptide = 9.3 ng/ml) hyperparathyroidism (calcium = 10.3 mg/dl, phosphor = 3.1 mg/dl, PTH = 280 pg/ml) and chemical evidence of an ACTH-independent hypercortisolism (serum cortisol value of 3.5, after 1 mg dexamethasone suppression test serum ACTH value of 17 pg/ml, and high urinary cortisol level). Abdominal CT scan demonstrated two enhancing well-defined masses 27*20 mm and 37*30 mm in the tail and body of the pancreas, respectively, and a 36*15 mm mass in left adrenal gland (seven Hounsfield units). Dynamic pituitary MRI revealed a partial empty sella. The physical examination of the patient was unremarkable. Distal pancreatectomy and a left adrenalectomy were performed. After the surgery, we observed clinical and biochemical remission of hyper insulinemia and gradual decrease in urinary cortisol. The histological features of the removed left adrenal gland were consistent with AIMAH. Histological examination of the pancreatic lesions revealed well differentiated neuroendocrine tumors. Genetic abnormalities in the MEN1, heterozygote for pathogenic variant chr11; 645,773,330-64577333AGAC, c.249-252delGTCT, p. (11e85Serfs Ter33) in exon 2 were found. It was recommended the patient undergoes parathyroidectomy as soon as possible. CONCLUSION: Given the history and presentation of our case, we recommend that the clinicians consider the possibility of autonomous cortisol production in MEN1 patients who do not show severe symptoms of hypoglycemia in the presence of insulinoma.

MEN4, the MEN1 Mimicker: A Case Series of three Phenotypically Heterogenous Patients With Unique CDKN1B Mutations.

CONTEXT: Germline CDKN1B pathogenic variants result in multiple endocrine neoplasia type 4 (MEN4), an autosomal dominant hereditary tumor syndrome variably associated with primary hyperparathyroidism, pituitary adenoma, and duodenopancreatic neuroendocrine tumors. OBJECTIVE: To report the phenotype of 3 unrelated cases each with a unique germline CDKN1B variant (of which 2 are novel) and compare these cases with those described in the current literature. DESIGN/METHODS: Three case studies, including clinical presentation, germline, and tumor genetic analysis and family history. SETTING: Two tertiary University Hospitals in Sydney, New South Wales, and 1 tertiary University Hospital in Canberra, Australian Capital Territory, Australia. OUTCOME: Phenotype of the 3 cases and their kindred; molecular analysis and tumor p27kip1 immunohistochemistry. RESULTS: Family A: The proband developed multiglandular primary hyperparathyroidism, a microprolactinoma and a multifocal nonfunctioning duodenopancreatic neuroendocrine tumor. Family B: The proband was diagnosed with primary hyperparathyroidism from a single parathyroid adenoma. Family C: The proband was diagnosed with a nonfunctioning pituitary microadenoma and ectopic Cushing's syndrome from an atypical thymic carcinoid tumor. Germline sequencing in each patient identified a unique variant in CDKN1B, 2 of which are novel (c.179G > A, p.Trp60*; c.475G > A, p.Asp159Asn) and 1 previously reported (c.374_375delCT, p.Ser125*). CONCLUSIONS: Germline CDKN1B pathogenic variants cause the syndrome MEN4. The phenotype resulting from the 3 pathogenic variants described in this series highlights the heterogenous nature of this syndrome, ranging from isolated primary hyperparathyroidism to the full spectrum of endocrine manifestations. We report the first described cases of a prolactinoma and an atypical thymic carcinoid tumor in MEN4.