Recent Topics Around Multiple Endocrine Neoplasia Type 1

Abstract

Introduction

Multiple endocrine neoplasia type 1 (MEN1) is complex with regard to clinical expressions, management, and molecular pathways. Advances are being made broadly and in focused aspects. Selected topics are presented for their developments since publication of the most recent MEN1 consensus guidelines 6 years ago.

Methods

Topics were selected for clinical impact or broad interest or both. For each topic, information was obtained from original reports and reviews.

Results

The selected topics are as follows: tumor behavior and breast cancer in MEN1; foregut neuroectoderm tumor screening, biomarkers periodically to detect tumor emergence of foregut neuroectoderm tumors, ⁶⁸Ga dotatate positron emission tomography/computed tomography for pancreatic and duodenal neuroectodermal tumor imaging, and glucagon-like peptide-1 receptor scintigraphy for insulinoma; therapy, the size of pancreatic neuroendocrine tumor (NET) as one criterion for surgery, minimally invasive surgery of pancreatic NETs, and 177Lu dotatate therapy; MEN1 gene, the search for the MEN1/menin pathway and MEN1 or GCM2 mutation in familial isolated hyperparathyroidism, and MEN1 mutation-positive vs mutation-negative cases of MEN1 are different.

Conclusions

MEN1 topics are a rich and fast-moving area. Important highlights stand out, and major and rapid advances will continue into the near future.

Topics around MEN1 were selected from the past 6 years with emphasis on general interest and/or clinical impact. The topics pointed to advances in management and understanding.

Multiple endocrine neoplasia type 1 (MEN1) is a case with tumor in two of its three main tissues (parathyroid, foregut neuroendocrine, and anterior pituitary) or, alternately, a case with MEN1 in a first-degree relative and with tumor in one of the three main tissues. MEN1 is complex with regard to clinical expressions, management, and molecular pathways (1). The population frequency is ∼1 in 30,000 persons. This low frequency is the main reason for rarity of controlled clinical trials. Hormone-secreting and hormone-nonsecreting tumors may occur among some 30 tissues in MEN1. The causes of this tissue selectivity of tumors are not known. There is a high penetrance among adults for tumor in the main tissues: parathyroid, 90%; foregut neuroendocrine, 50%; and pituitary, 40%. Although MEN1 is rare, its high penetrance can make for striking and unequivocal presentations in cases and in families. Contributions to high penetrance come from tumor multiplicity in a tissue (rarely in pituitary) and from susceptibility to malignancy in neuroendocrine tissues. These same features can make the tumors of MEN1 more difficult to manage than sporadic tumor of the same tissue. This diagnosis has many implications in managing the case periodically. Cost and efficacy are major considerations. It also has important implications for counseling and managing interested members of the family. Serial advances are being made broadly and in focused aspects. Many of these advances have been reported in consensus guidelines (1, 2). Some of the advances relevant to MEN1 arise from work on the more frequent sporadic tumor of the same tissues (3). However, some tumors have features that are relatively specific for MEN1 rather than sporadic tumor; understanding their pathophysiology may benefit the most from study in MEN1. For example, MEN1 is present in 25% of thymic carcinoids, but ectopic secretion of adrenocorticotropic hormone is frequent only in those thymic carcinoids without MEN1 (4). Also, sporadic primary hyperparathyroidism begins at an average age of 55, whereas MEN1 primary hyperparathyroidism begins at an average age of 20. Because of the rarity of MEN1, collections of cases from multiple institutions have contributed to some recent advances. Overviews are presented in this review for selected topics, developing since publication of the most recent MEN1 consensus guidelines 6 years ago (1).

Methods

Topics were chosen for clinical impact or broad interest or both. For each topic, information was obtained from original reports and reviews.

Results

Tumor behavior

Breast cancer in MEN1

Most of the main tumors of MEN1 (parathyroid, foregut neuroendocrine, and anterior pituitary) are rare without MEN1 but increased on the order of 100-fold in MEN1. The penetrance of breast cancer in MEN1 vs control was increased by 2.3- to 2.8-fold among four cohorts in Holland, United States, Tasmania, and France (5). Thus, this common tumor was increased only mildly in frequency in MEN1 but with likely importance in total morbidity of MEN1. Age at diagnosis of breast cancer among MEN1 cases was decreased to 48 years vs 58 and 61 years in controls. Due to the younger age at diagnosis, breast cancer surveillance was recommended beginning at age 40 years in women with MEN1 (6). The role of the MEN1 gene in the breast cancers of MEN1 is uncertain (7); thus, indirect causes such as via disturbance in prolactin or estrogen metabolism are still to be explored.

Tumor screening

Biomarkers periodically to detect emergence of foregut neuroectoderm tumor

Foregut neuroectodermal tumors include thymic carcinoid, bronchial carcinoid, gastric carcinoid, duodenal gastrinoma, and pancreatic islet tumor (mainly hormone-nonsecreting or insulinoma). Foregut neuroendocrine tumors (NETs) cause 50% of deaths in MEN1 (8). Early diagnosis of a tumor may lead to interventions that decrease eventual morbidity. Noninvasive screening such as serum markers is particularly desirable. Chromogranin A and pancreatic polypeptide are broad markers that can be oversecreted by any foregut neuroectodermal tumor and other tumors as well (9). The recent MEN1 guideline included annual screening for emergence of pancreatic NETs by serum tests of a gastrointestinal profile, consisting of chromogranin A, pancreatic polypeptide, glucagon, and vasoactive intestinal polypeptide (1). This recommendation seemed promising, but it was based on extrapolations from established tumors and not based on systematic data about early emergence of tumor in MEN1 (9). Two retrospective analyses of chromogranin A, pancreatic polypeptide, and glucagon to screen for emergence of tumor in MEN1 found that singly or in combination, these tests were not effective in early diagnosis of tumors (10, 11). This difficulty presumably reflects the low amounts of these peptides secreted by small tumors. Imaging tests were judged as more appropriate than these biomarkers for periodic screening for emergence of neuroendocrine pancreatic tumors.

⁶⁸Ga dotatate positron emission tomography/computed tomography for pancreatic and duodenal NET imaging

¹¹¹In-pentetreotide single-photon emission computed tomography (CT)/CT (octreoscan) can image many of the foregut NETs of MEN1. However, it fails to image 35% to 50% of pancreatic NETs <1 cm in diameter (12). Endoscopic ultrasound can detect smaller pancreatic tumors (<0.5 cm) but is invasive and has limited availability (12, 13). ⁶⁸Ga dotatate positron emission tomography/CT was threefold more sensitive than octreoscan or CT scan in a study of multiple imaging modalities in 26 cases of MEN1 (14). In 31%, the addition of ⁶⁸Ga dotatate (Netspot; Advanced Accelerator Applications USA, Inc.) scan caused a change in recommended therapy. These changes in approaches were related to metastases and believed to have been beneficial. This reagent is preferable to octreoscan for imaging pancreatic tumor about MEN1, and, when available, it should replace octreoscan for periodic imaging. On 1 June 2016, Netspot was approved by the US Food and Drug Administration for use in scanning. Its use in MEN1 for screening of thymic carcinoid, bronchial carcinoid, stomach carcinoid, or insulinoma remains to be studied in detail.

Glucagon-like peptide-1 receptor scintigraphy for insulinoma

Insulinoma is difficult to image with somatostatin-2 radioligands (i.e., octreoscan), with positive rates of only 25% (15, 16). There is a need for a noninvasive imaging test that will give a positive signal in insulinoma of MEN1 without a signal in accompanying noninsulinoma islet tumors of MEN1. Such a test would be applicable for tumor localization, not for tumor diagnosis. ⁶⁸Ga dotatate can image 90% of sporadic insulinomas but is expected to give misleading positive signals for accompanying islet tumors in the MEN1 pancreas (17). Benign insulinomas express more glucagon-like peptide-1 (GLP-1) receptors than somatostatin-2 receptors (18). GLP-1 belongs to the incretin mimetic class of peptides, some of which are used to improve glycemic control (19). GLP-1 receptor (GLP-1R) positron emission tomography/CT with ⁶⁸Ga-NOTA–exendin-4 and other GLP-1R ligands have shown high promise, with localization of 42 of 43 sporadic benign insulinomas in one series (20). Various isotopes bound to various GLP-1R agonists or antagonists are under exploration (21). Few cases of MEN1 insulinoma have been tested but with promising selectivity in one report (22). This is important in MEN1, in which a benign insulinoma is often accompanied by one or more other islet tumors. The selectivity of these tracers for insulinoma rather than for islet tumors other than insulinoma in MEN1 will need further exploration; for example, gastrinoma, vasoactive intestinal polypeptide-oma, or pheochromocytoma can give a positive signal (18).

Therapy

Size of pancreatic NET as one criterion for surgery

Several criteria can be used to recommend surgery for pancreatic NET. These include growth rate, metastases, histology, and hormonal secretion. A major criterion is tumor size. There is considerable disagreement even among consensus groups about a cutoff of size between 1 and 3 cm as the criterion to offer surgery in pancreatic NETs (1, 23, 24). There is agreement that omitting surgery for tumors of ≥3 cm has an unfavorable prognosis (25). Setting a low cutoff might result in too many unneeded operations, including complications (24). For lesions of ≤1.0 cm, endoscopic ultrasound serially in MEN1 shows an absent or minimal annual growth rate (26). Recent retrospective studies of MEN1 representing a collaboration from Holland found that, at ≤2 cm (99 cases followed for 3 years), omitting surgery was preferable to doing surgery (24, 25, 27). A recent retrospective study from the French/Belgian collaboration (46 cases followed for 11 years) reached a similar conclusion (28). Although differing opinions about size at cutoff will persist, these two recent studies are a strong voice for the size cutoff to be at 2 cm.

Minimally invasive surgery of pancreatic NETs

Minimally invasive surgical approaches, such as laparoscopic approaches, are under exploration for most of the tumors in MEN1. In general, due mainly to tumor multiplicity as in the parathyroids, the minimally invasive operations are more difficult and less frequently recommended in MEN1 than in sporadic tumors (1, 29). The pancreas gland presents special problems for laparoscopic approaches, mainly exposure and friability (30, 31). Only small series of MEN1 cases have been reported. For example, for nonfunctional pancreatic NETs operated laparoscopically or robotically, a recent series reported 21 and 43 cases of MEN1, respectively (32, 33). The outcomes and complications were similar to those with traditional open surgery but with less operating time and less blood loss. It is too early to make a broad recommendation to change surgical strategy for pancreatic tumors in MEN1.

¹⁷⁷Lu dotatate therapy

Somatostatin analogs bind to receptors on most neuroendocrine cells. These analogs have been explored as carriers to deliver various isotopes for radiation to tumors. Peptide receptor radionuclide therapy has been under study for >15 years in Europe (34). A controlled trial of ¹⁷⁷Lu dotatate was completed in 229 patients among 8 countries, including the United States, with advanced midgut NET (35). Mainly in the ileum, this is not the location of a typical MEN1 tumor, and few if any MEN1 cases were included in the trial. Both groups received high doses of somatostatin, and the trial group additionally received ¹⁷⁷Lu dotatate (Lutathera; Advanced Accelerator Applications USA, Inc.) as peptide receptor radionuclide therapy. At 20 weeks, progression-free survival was lower in the Lutathera group (11% vs 65%). As of 25 January 2018, Lutathera has received approval of its new drug application by the US Food and Drug Administration. Some patients may qualify to receive it in the United States through Expanded Access (“compassionate use”).

MEN1 gene

Search for the MEN1/menin pathway

The MEN1 gene functions in MEN1 tumorigenesis as a growth suppressor, showing biallelic inactivation of MEN1 by several criteria, mainly loss of heterozygosity at the menin locus of chromosome 11q13. Some 30 menin molecular partners have been reported in efforts to uncover menin’s molecular pathway (36). None of these partners or pathways has yet been proven to be a central mediator of MEN1 tumorigenesis. The most extensive work has been with mixed lineage leukemia (MLL). MLL [also termed lysine (K)-specific methyl transferase 2A or KMT2A] fusion genes account for 10% of leukemias. More than 80 partner genes have rearrangement/fusions with the C terminus of the MLL gene. These MLL fusions are oncogenes, and many or all are activated further by binding to menin (37). Small-molecule inhibitors of this menin interaction with MLL are under development, with promise of therapeutic efficacy against leukemias in animal and cell models (38). This oncogenic role of menin in leukemia has no clear relevance to menin’s tumor suppressor molecular pathway in MEN1, nor do the small-molecule inhibitors of menin interaction with MLL (39, 40).

MEN1 or GCM2 mutation in familial isolated hyperparathyroidism

Until recently, MEN1 had been the only frequently mutated known gene (20%) in kindreds with familial isolated hyperparathyroidism (FIHP) (41, 42). Activating mutation in a small domain of GCM2 was newly identified in FIHP (43). GCM2 encodes a transcription factor with no known molecular relation to the menin pathway. Inactivating mutations of GCM2 had previously been identified as a cause of hereditary hypoparathyroidism (43). Among 40 kindreds with FIHP and lacking mutation of MEN1, CDC73, or CASR, 8 or 20% had a GCM2 mutation, indicating a similar frequency of mutation in MEN1 and GCM2 genes in FIHP.

MEN1 mutation-positive vs mutation-negative cases of MEN1 are different

In 293 cases of the Dutch MEN1 series, 90% were MEN1 mutation positive, and 10% were MEN1 mutation negative (44). The mutation-negative cases were diagnosed later (46 vs 33 years) and survived longer (87 vs 73 years). A small minority of these will have mutation of CDKN1B (45) (Online Mendelian Inheritance in Man 600778). The authors suggest that the MEN1 mutation-negative cases have a different syndrome than classical MEN1 or that they have a coincidence of two sporadic tumors. This extends prior observations from Japan and the United States (45, 46). Cases in this category should be managed as the more standard MEN1, with the exception that MEN1 gene testing (and CDKN1B gene testing) is not useful among relatives.

Discussion

The topics discussed in this review summarize some of the important and recent advances in management and understanding of MEN1. Management and understanding of MEN1 has benefitted from studies about sporadic tumor; this is clear in progress about radioisotope imaging. Conversely, knowledge about sporadic tumors has benefitted from studies of MEN1. For example, MEN1 is the gene most frequently mutated in sporadic parathyroid tumor (47).

Management of MEN1 should be coordinated with a team having multiple specializations (1). Although advances are clear, there has not been consequent demonstration of improvement of survival or even of quality of life. Such improvements may have occurred without being identified. Such improvements were evident with the more dramatic serial steps in management of Zollinger-Ellison syndrome over 30 to 50 years (total gastrectomy, H2 histamine receptor blockers, and proton pump inhibitors) (8). It is clear that incremental advances will continue along the lines in this review and other topics. The topic for greatest advancement in the future will probably be the identification of the metabolic pathway of menin in MEN1 tumorigenesis, with the possibility of novel interventions in MEN1 and its sporadic tumors from consequent new drugs. Lastly, gene therapy is a rapidly moving field including in neoplasms arising in somatic and germline tissues (48). Future advances in gene therapy are beyond the scope of this review.

Glossary

Abbreviations:

CT

computed tomography

FIHP

familial isolated hyperparathyroidism

GLP-1

glucagon-like peptide-1

GLP-1R

glucagon-like peptide-1 receptor

MEN1

multiple endocrine neoplasia type 1

MLL

mixed lineage leukemia

NET

neuroendocrine tumor