Coexistence of MEN 2A and Papillary Thyroid Carcinoma and a Recurrent Pheochromocytoma 23 Years after Surgery: Report of a Case and a Review of the Japanese Literature

A 59-year-old woman who had undergone bilateral partial adrenalectomy23 years previously was referred to our hospital because ofneck masses and a left adrenal tumor. Fine needle aspirationbiopsy of the neck tumor and elevated levels of calcitonin andCEA revealed medullary thyroid carcinoma. Slightly elevatedlevels of urinary normetanephrine and metanephrine, and resultsof a clonidine suppression test, CT, magnetic resonance imaging,and ¹³¹l-metaiodo-benzylguanidine scintigraphy of the abdomenindicated that the left adrenal tumor was a recurrent pheochromocytomain the residual adrenal gland. After total thyroidectomy, bilateralmedullary thyroid carcinomas and papillary thyroid carcinomawere recognized pathologically. Although the coexistence ofbilateral pheochromocytoma and medullary thyroid carcinoma issuggestive of multiple endocrine neoplasia (MEN), associationof MEN type 2A (MEN 2A) with papillary thyroid carcinoma mayhave occurred incidentally. A retrospective analysis of 9 casesof pheochromocytoma associated with papillary thyroid carcinomareported in the Japanese literature demonstrated a male-to-femaleratio of 1:8, and an average patient age of 56.2 years. Thepresent case indicates that association between pheochromocytomaand thyroid carcinoma may not always involve medullary thyroidcarcinoma.     

Ventricular fibrillation resulting from electrolyte imbalance reveals vipoma in MEN1 syndrome

Sporadic VIPoma is an exceedingly rare tumor with an annual incidence of 1:10 million people worldwide, yet it is described in approximately 5 % of MEN1 patients. The majority of VIPomas are malignant and radical surgery is the best therapeutic option. A 58-year-old man presented with cardiocirculatory arrest due to ventricular fibrillation. The patient had a 3-month history of epigastric pain with diarrhea. After reanimation, laboratory data revealed severe hypokalemia and hypercalcemia. Further investigations showed hyperparathyroidism, left adrenal adenoma and pituitary microprolactinoma and genetic diagnosis of MEN1 syndrome was made. Abdominal computed tomography revealed a 45 × 30 mm mass of the pancreatic head and two hepatic lesions, which proved to be neuroendocrine after 68 Ga PET and needle biopsy. Vasoactive intestinal peptide (VIP) serum level had increased. Subsequently the patient underwent pylorus-preserving pancreaticoduodenectomy and hepatic resection. Intraoperative VIP returned to normal values. Histopathology confirmed a pancreatic VIPoma metastatic to the liver. The postoperative course was unremarkable and the patient is well with no evidence of disease at a 48 months follow-up. Even in case of anusual presentation, when two or more main clinical findings of MEN1 related tumors are present, unrespectively to the presence of MEN1 mutation, MEN1 syndrome should be suspected. Surgery in MEN1 pancreatic neuroendocrine tumors is indicated both to treat symptoms and to avoid oncological progression even in advanced cases.     

Low incidence of loss of chromosome 10 in sporadic and hereditary human medullary thyroid carcinoma

Genetic linkage has been recently documented between a centromeric region of chromosome 10 and familial multiple endocrine neoplasia type II (MEN II). This syndrome consists of initial thyroid C-cell and adrenal chromaffin cell hyperplasia which result in multifocal medullary thyroid carcinomas and bilateral adrenal pheochromocytomas. Other hereditary cancers, such as retinoblastoma, appear to result from a series of genetic events involving, first the inheritance of a germ line abnormality, and subsequent loss of chromosome loci opposite this initial defect. In these cancers, this loss of the normal alleles in both familial and sporadic cases, is frequently manifest as a reduction to homozygosity for polymorphic DNA markers near the involved locus. It might then be expected that chromosome 10 regions would be lost with high frequency in tumor DNA from patients with MEN II and sporadic medullary thyroid carcinoma (MTC). We now demonstrate that only two of 16 MTC tumors studied by analysis of restriction fragment length polymorphisms for multiple regions of the short and long arms of chromosome 10 showed loci reduced to homozygosity. One of these tumors was from a patient with MEN II and the other from a patient with nonfamilial MTC. Importantly, no such chromosome 10 changes were noted in pheochromocytomas from the patient with MEN II or his sister. These findings strongly suggest that the sequence of genetic events for familial MTC is either different from that for retinoblastoma or that loss of normal alleles opposite the germ line genetic defect occurs by mechanisms other than gross loss of chromosomal material in MTC. A model is proposed suggesting that the mechanism involving loss of alleles opposite one another is operative in hereditary tumors, such as retinoblastoma, which do not arise within a setting of initial polyclonal cellular hyperplasia. In contrast, in tumors such as familial MTC and polyposis coli which arise as individual clones of neoplastic cells from a setting of preexistent polyclonal hyperplasia, the first genetic event may underlie hyperplasia, and additional events, frequently at other chromosomal loci, may cause individual clonal neoplasms.     

Identification of MEN1 gene mutations in families with MEN 1 and related disorders

Following identification of the MEN1 gene, we analysed patients from 12 MEN 1 families, 8 sporadic cases of MEN 1, and 13 patients with MEN 1-like symptoms (e.g. cases of familial isolated hyperparathyroidism (FIHPT), familial acromegaly, or atypical MEN 1 cases) for the presence of germline MEN1 mutations. The entire coding region of the MEN1 gene was sequenced, and mutations were detected in 11 MEN 1 families; one sporadic MEN 1 patient, one case of FIHPT and one MEN 1-like case. Constitutional DNA samples from individuals without MEN1 mutations were digested with several restriction enzymes, Southern blotted and probed with MEN1 cDNA to analyse for the presence of larger deletions of the MEN1 gene unable to be detected by PCR. One MEN 1 patient was found to carry such a deletion. This patient was heterozygous for the D418D polymorphism, however sequence analysis of RT-PCR products showed that only the variant allele was transcribed, thus confirming the result obtained by Southern analysis, which indicated loss of a region containing the initiation codon of one allele.     

Malignant melanoma in multiple endocrine neoplasia

Because of its neurocrest APUD origin, malignant melanoma has been postulated to be a component of the multiple endocrine neoplasia (MEN) syndromes; however, such a case has not been previously described. Prior associations of melanocytes with the MEN syndromes have been confined to hyperplasia. This report describes the first case of malignant melanoma occurring in a patient with the MEN IIA syndrome (bilateral pheochromocytomas and medullary thyroid carcinoma). The role of melanocytic hyperplasia and neoplasia within the MEN syndromes is discussed.     

Late onset asymptomatic pancreatic neuroendocrine tumor – A case report on the phenotypic expansion for MEN1

Background

Multiple endocrine neoplasia type 1 (MEN1) is a hereditary cancer syndrome associated with several endocrine as well as non-endocrine tumors and is caused by mutations in the MEN1 gene. Primary hyperparathyroidism affects the majority of MEN1 individuals by age 50 years. Additionally, MEN1 mutations trigger familial isolated hyperparathyroidism. We describe a seemingly unaffected 76-year-old female who presented to our Genetics Clinic with a family history of primary hyperparathyroidism and the identification of a pathogenic MEN1 variant.

Case Presentation

The patient was a 76 year-old woman who appeared to be unaffected. She had a family history of a known MEN1 pathogenic variant. Molecular testing for the known MEN1 mutation c.1A > G, as well as, biochemical testing, MRI of the brain and abdomen were all performed using standard methods. Molecular testing revealed our patient possessed the MEN1 pathogenic variant previously identified in her two offspring. Physical exam revealed red facial papules with onset in her seventies, involving her cheeks, nose and upper lip. Formerly, she was diagnosed with rosacea by a dermatologist and noted no improvement with treatment. Clinically, these lesions appeared to be facial angiofibromas. Brain MRI was normal. However, an MRI of her abdomen revealed a 1.5 cm lesion at the tail of the pancreas with normal adrenal glands. Glucagon was mildly elevated and pancreatic polypeptide was nearly seven times the upper limit of the normal range. The patient underwent spleen sparing distal pancreatectomy and subsequent pathology was consistent with a well-differentiated pancreatic neuroendocrine tumor (pNET).

Conclusions

Age-related penetrance and variable expressivity are well documented in families with MEN1. It is thought that nearly all individuals with MEN1 manifest disease by age 40. We present a case of late-onset MEN1 in the absence of the most common feature, primary hyperparathyroidism, but with the presence of a pNET and cutaneous findings. This family expands the phenotype associated with the c.1A > G pathogenic variant and highlights the importance of providing comprehensive assessment of MEN1 mutation carriers in families that at first blush may appear to have isolated hyperparathyroidism.

     

Ganglioneuromas and renal anomalies are induced by activated RET(MEN2B) in transgenic mice

Multiple endocrine neoplasia type 2B (MEN2B) is an autosomal dominant syndrome characterized by the development of medullary thyroid carcinoma, pheochromocytomas, musculoskeletal anomalies and mucosal ganglioneuromas. MEN2B is caused by a specific mutation (Met918-->Thr) in the RET receptor tyrosine kinase. Different mutations of RET lead to other conditions including MEN2A, familial medullary thyroid carcinoma and intestinal aganglionosis (Hirschsprung disease). Transgenic mice were created using the dopamine beta-hydroxylase promoter to direct expression of RET(MEN2B) in the developing sympathetic and enteric nervous systems and the adrenal medulla. DbetaH-RET(MEN2B) transgenic mice developed benign neuroglial tumors, histologically identical to human ganglioneuromas, in their sympathetic nervous systems and adrenal glands. The enteric nervous system was not affected. The neoplasms in DbetaH-RET(MEN2B) mice were similar to benign neuroglial tumors induced in transgenic mice by activated Ras expression under control of the same promoter. Levels of phosphorylated MAP kinase were not increased in the RET(MEN2B)-induced neurolglial proliferations, suggesting that alternative pathways may play a role in the pathogenesis of these lesions. Transgenic mice with the highest levels of DbetaH-RET(MEN2B) expression, unexpectedly developed renal malformations analogous to those reported with loss of function mutations in the Ret gene.     

Acromegaly Caused by Growth Hormone-relating Hormone in a Patient with Multiple Endocrine Neoplasia Type I

A 51-year-old Caucasian man with multiple endocrine neoplasia(MEN) type I syndrome presented with clinical features of acromegaly.Exploration of the pituitary gland only revealed somatotrophichyperplasia and his plasma growth hormone (GH) levels remainedelevated. Production of growth hormone-releasing hormone (CHRH)by an ectopic tumor was suspected and, after additional investigations,a large pancreatic tumor was detected and removed. As the pancreatictail contained multiple (occult) adenomas, lifelong follow-upwas considered necessary. The patient has been recurrence-freefor 10 years. All 19 living relatives of this patient were analysedfor endocrine disorders related to MEN I syndrome. A brotherwas found to suffer from peptic ulcer disease caused by hyperparathyroidismand, during screening for other organ involvement associatedwith the MEN I syndrome, two tumors were found, one (4 cm) inthe pancreatic tail region and one in the right adrenal gland.To date, six other family members have been found to sufferor have suffered from hyperparathyroidism and in a male subject,a prolactinoma and hyperparathyroidism were detected.     

A novel germline mutation of the MEN1 gene, L259del, in a patient with sporadic multiple endocrine neoplasia type 1 (MEN1)

A Japanese woman was treated for insulinoma when she was 29 years old. Ten years later, heperparathyroidism and non-functioning adrenal tumor were found and she was diagnosed as having multiple endocrine neoplasia type 1 (MEN1). No other family members have developed MEN-related lesion(s). Genomic DNA of the patient was analyzed by sequencing for the MEN1 gene and a novel, three-base in-frame deletion resulting in deletion of an amino acid Leu259 was identified. Her two children showed a wild-type sequence at this codon.     

A whole MEN1 gene deletion flanked by Alu repeats in a family with multiple endocrine neoplasia type 1

Multiple endocrine neoplasia type 1 is an autosomal dominant cancer syndrome characterized by pituitary, parathyroid and enteropancreatic endocrine tumors, which is caused by germline mutations of the tumor suppressor gene MEN1. In the case reported here, the patient had family with this disease whose germline MEN1 mutation was undetectable by conventional sequencing analysis. Further investigations involving polymorphism analyses, gene dose assay and nucleotide sequencing identified a large germline deletion of approximately 29 kilobase pairs spanning the whole MEN1 gene. The deletion was flanked by Alu repetitive sequences, suggesting unequal homologous recombination as the deletion mechanism. The polymorphism linkage data suggested that an asymptomatic son of the proband did not carry the family mutation. More direct evidence was obtained by gene dose assay and deletion-specific polymerase chain reaction, which demonstrated the normal MEN1 gene dosage and the absence of the deletion breakpoints in this asymptomatic subject and thus definitely excluded the possibility of disease predisposition.     

Multiple endocrine neoplasia type 1 presented with manic-depressive disorder: a case report with an identified MEN1 gene mutation

We report a case of multiple endocrine neoplasia type 1 who had repeated hypoglycemic episodes and had previously been diagnosed with bipolar manic-depressive disorder. The patient had a positive family history of multiple endocrine neoplasia type 1 and had multiple pancreatic endocrine tumors, hyperparathyroidism and possibly a pituitary tumor. The pancreatic tumors were resected by subtotal pancreatectomy and examined by histochemical staining and gene analysis. The tumor cells were positive for immunoreactive insulin and glucagon. A microsatellite polymorphism analysis revealed loss of heterozygosity on 11q13 in the tumors. By polymerase chain reaction-based nucleotide sequencing, we identified a germline mutation 483del2 of the MEN1 gene in the normal pancreatic tissue of the patient. This mutation causes a shift of the reading frame of menin mRNA at codon 125. It seems that the wild type allele of the MEN1 gene had been lost in the tumor cells whereas the mutant allele remained intact. This is the first identified MEN1 gene mutation in Japanese families and is different from all MEN1 gene mutations reported previously.      

Broad tumor spectrum in a mouse model of multiple endocrine neoplasia type 1

Multiple endocrine neoplasia type 1 (MEN1) is an inherited cancer predisposition syndrome typified by development of tumors in parathyroid, pituitary and endocrine pancreas, as well as less common sites including both endocrine and nonendocrine organs. Deletion or mutation of the tumor suppressor gene MEN1 on chromosome 11 has been identified in many cases of MEN1 as well as in sporadic tumors. The molecular biology of menin, the protein encoded by MEN1, remains poorly understood. Here we describe a mouse model of MEN1 in which tumors were seen in pancreatic islets, pituitary, thyroid and parathyroid, adrenal glands, testes and ovaries. The observed tumor spectrum therefore includes types commonly seen in MEN1 patients and additional types. Pancreatic pathology was most common, evident in over 80% of animals, while other tumor types developed with lower frequency and generally later onset. Tumors of multiple endocrine organs were observed frequently, but progression to carcinoma and metastasis were not evident. Tumors in all sites showed loss of heterozygosity at the Men1 locus, though the frequency in testicular tumors was only 36%, indicating that a different molecular mechanism of tumorigenesis occurs in those Leydig tumors that do not show loss of the normal Men1 allele. Menin expression was below the level of detection in ovary, thyroid and testis, but loss of nuclear menin immunoreactivity was observed uniformly in all pancreatic islet adenomas and in some hyperplastic islet cells, suggesting that complete loss of Men1 is a critical point in islet tumor progression in this model.     

Medullary thyroid carcinoma in multiple endocrine neoplasm type II syndromes

A case of multiple endocrine neoplasm (MEN) type IIa and 2 cases of MEN type IIb are reported. The biological behavior of medullary thyroid carcinoma was more aggressive in the MEN type IIb. C-cell hyperplasia was present in the thyroid gland of the patient with a positive family history.     

Adrenal Medullary Hyperplasia Is a Precursor Lesion for Pheochromocytoma in MEN2 Syndrome

Adrenal medullary hyperplasias (AMHs) are adrenal medullary proliferations with a size < 1 cm, while larger lesions are considered as pheochromocytoma (PCC). This arbitrary distinction has been proposed decades ago, although the biological relationship between AMH and PCC has never been investigated. Both lesions are frequently diagnosed in multiple endocrine neoplasia type 2 (MEN2) patients in whom they are considered as two unrelated clinical entities. In this study, we investigated the molecular relationship between AMH and PCC in MEN2 patients. Molecular aberrations of 19 AMHs and 13 PCCs from 18 MEN2 patients were determined by rearranged during transfection (RET) proto-oncogene mutation analysis and loss of heterozygosity (LOH) analysis for chromosomal regions 1p13, 1p36, 3p, and 3q, genomic areas covering commonly altered regions in RET-related PCC. Identical molecular aberrations were found in all AMHs and PCCs, at similar frequencies. LOH was seen for chromosomes 1p13 in 8 of 18 (44%), 1p36 in 9 of 15 (60%), 3p12-13 in 12 of 18 (67%), and 3q23-24 in 10 of 16 (63%) of AMHs, and for chromosome 1p13 in 13 of 13 (100%), 1p36 in 7 of 11 (64%), 3p12-13 in 4 of 11 (36%), and 3q23-24 in 11 of 12 (92%) of PCCs. Our results indicate that AMHs are not hyperplasias and, in clinical practice, should be regarded as PCCs, which has an impact on diagnosis and treatment of MEN2 patients. We therefore propose to replace the term AMH by micro-PCC to indicate adrenal medullary proliferations of less than 1 cm.Abbreviations: AMH, adrenal medullary hyperplasia; LOH, loss of heterozygosity; MEN2, multiple endocrine neoplasia type 2; PCC, pheochromocytoma; RET, rearranged during transfection proto-oncogene     

A complex endocrine conundrum

We describe a case of recurrent primary hyperparathyroidism, manifested as 3 metachronous parathyroid adenomata, in a 50 year-old woman who also had Hashimoto hypothyroidism, gastric gastrointestinal stromal tumour (GIST), cysts in liver and kidneys, 5 intestinal polyps (one of these a villous adenoma), diverticulitis and telangiectasia of lips. She did not have medullary thyroid carcinoma (MTC). Genetic analysis of the CDC73 gene [for Hyperparathyroidism—jaw tumor (HPT-JT)], MEN1 for Multiple Endocrine Neoplasia Type1, CDKN1B for MEN4, SDHB and SDHD for Paraganglioma/Pheochromocytoma susceptibility, VHL for von Hippel-Lindau Syndrome, BMPR1A and SMAD4 for Juvenile Polyposis Syndrome (JPS) (sequencing and MLPA), karyotype and array CGH (44 K) were all normal. She was found to be homozygous for a synonomous germline variant in exon 14 (p. Ser836Ser) of the RET oncogene. This RET variant is of unclear clinical significance, and has been previously reported both in normal individuals and in individuals with MTC. It is unlikely that homozygosity for the RET variant has been casual in the multiple pathologies that our patient has developed.     

Care for patients with multiple endocrine neoplasia type 1: the current evidence base

Multiple endocrine neoplasia type 1 (MEN1) is a rare disease caused by mutations in the MEN1 gene on chromosome 11. It is characterized by the occurrence of primary hyperparathyroidism (pHPT), duodenopancreatic neuroendocrine tumours (pNET), pituitary tumours (PIT), adrenal adenomas (ADR) and neuroendocrine tumours (NET) of the stomach, bronchus and thymus. MEN1 is a syndrome with high penetrance and high morbidity. Malignant NETs are the most important cause of MEN1-related death. Since 1997 the diagnosis can be made by genetic screening. MEN1 is a complex syndrome and the endocrine manifestations cannot be viewed upon as coinciding sporadic tumours. Differences in epidemiology and pathology between MEN1-related tumours and their sporadic counterparts show that a unique approach is needed. Therefore the care for MEN1 patients should be provided by a centre of expertise. Early genetic diagnosis and periodic screening are important pillars of care. For primary hyperparathyroidism surgery is the most important treatment modality, with a subtotal parathyroid gland resection as the procedure of choice. In neuroendocrine tumours surgery also is the most important treatment modality. Selective tumour enucleation has no place in the surgical treatment of MEN1-related pNETs; the exact procedure depends on the functionality of the tumour. In MEN1-associated pituitary and adrenal adenomas, watchful waiting and medical therapy play more important roles. In the twenty-first century new developments will impact the care for MEN1 patients. These developments should be critically evaluated in clinical research with the ultimate goal of optimizing the care for MEN1 patients on an evidence base.     

Radioiodinated meta-iodobenzylguanidine uptake in medullary thyroid cancer. A French cooperative study

Fifty meta-iodobenzylguanidine (MIBG) scintiscans were performed in three groups of medullary thyroid cancer (MTC) patients. Group 1 (n = 11) included treated patients with normal calcitonin levels; Group 2 (n = 24) included patients with elevated calcitonin levels due to sporadic and isolated MTC; Group 3 (n = 15) included patients with elevated calcitonin levels due to familial MTC or multiple endocrine neoplasia Type IIA syndrome (MEN). In Group 1 three pheochromocytoma were depicted by MIBG scintiscan. In Group 2 MTC was seen in a small number of patients (3 of 24). In Group 3, besides adrenal hyperplasia and pheochromocytoma four patients, MIBG scintigraphy showed where MTC had localized and spread in almost half of patients (7 of 15). MIBG uptake occurred in patients with relatively high calcitonin level (greater than 0.6 nmol/l). These data indicate that in patients with familial MTC or MEN syndrome, MIBG scintiscan can be useful not only in detecting associated pheochromocytoma, but also in showing MTC.     

Primary bilateral adrenal lymphoma associated with idiopathic thrombocytopenic purpura

Autoimmune disorders are occasionally associated with malignant lymphoma. To date only one case of primary adrenal lymphoma associated with idiopathic thrombocytopenic purpura (ITP) has ever been reported. This paper reports the case of a 63-year-old man with bilateral adrenal masses whose laboratory data showed decreased platelet count. Despite normal blood pressure, the adrenal tumors endocrinologically appeared to be pheochromocytoma. Core needle biopsy was not done due to thrombocytopenia attributed to concurrent ITP. After intravenous immunoglobulin treatment, splenectomy and bilateral adrenalectomy were performed since the first pathological findings of the frozen specimen suggested the possibility of a poorly-differentiated carcinoma. Immunohistochemical study finally showed the tumors to be diffuse large B-cell lymphoma. The patient underwent a subsequent course of combination chemotherapy and survived 6 years recurrence-free without any need for further treatment other than steroid replacement. The coincidence of adrenal lymphoma and ITP should be considered even if another kind of tumor is suspected, and core needle biopsy should be performed prior to operation, since the specific kind of tumor found alters the therapeutical strategy adopted.