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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
Medicine (Baltimore). Author manuscript; available in PMC 2014 May 1.
Published in final edited form as:
PMCID: PMC3727638
NIHMSID: NIHMS475074

Causes of Death and Prognostic Factors in Multiple Endocrine Neoplasia Type 1: A Prospective Study. Comparison of 106 MEN1/Zollinger-Ellison Syndrome Patients With 1613 Literature MEN1 Patients With or Without Pancreatic Endocrine Tumors

Tetsuhide Ito, M.D., Ph.D.,1,2 Hisato Igarashi, M.D., Ph.D.,1,2 Hirotsugu Uehara, M.D. Ph.D.,2 Marc J. Berna, M.D.,2,3 and Robert T. Jensen, M.D.2

Abstract

Multiple Endocrine Neoplasia-type 1 (MEN1) is classically characterized by the development of functional/nonfunctional hyperplasia/tumors in endocrine tissues (parathyroid, pancreas, pituitary, adrenal). Because of the development of effective treatments of the hormone-excess states, which use to be a major cause of death in these patients, coupled with the recognition of the increasing development of nonendocrine tumors late in the disease course, the natural history of these patients late in their disease course has changing. An understanding of these patient’s current causes of death would be important in tailoring treatment for these patients and identifying prognostic factors, however it is generally lacking. The present study was designed to address this area by reporting the causes of death and a detailed analysis of prognostic factors from a prospective long-term National Institutes of Health (NIH) study of 106 MEN1 patients with pancreatic endocrine tumors with ZES (MEN1/ZES) and comparing our results to those from the pooled literature data of 227 MEN1/PET patients in case reports/small series as well as to 1386 patients in large MEN1 literature series. In the NIH series over a mean followup of 24.5 years, 24(23%) patients died [14 MEN1 and 10 nonMEN1-related]. Causes of death were compared with results from the 227 patients in the pooled literature series to determine prognostic factors. In our two series (NIH/pooled literature), no patients died of acute complications due to acid hypersecretion, 8–14% died of other hormone excess causes, which is similar to the results in 10 large MEN1 literature series published since 1995. In both our series 2/3rd of patients died from an MEN1-related cause and 1/3rd from a nonMEN1-related cause, which agrees with the mean values from 10 large MEN1 series in the literature, however in the literature they varied widely. In our two series the main causes of MEN1-related deaths were due to the malignant nature of the PETs, followed by the malignant nature of thymic carcinoid tumors. These results differ from a number of literature series especially those reporting before 1990s.The causes of nonMEN1 related death in decreasing frequency for our two series were: cardiovascular disease, other nonendocrine tumors>lung diseases, cerebrovascular diseases. The most frequent nonMEN1-related tumor deaths were colorectal, renal>lung>breast, oropharyngeal. Although both overall and disease-related survivals are better than in the past (30 yr, NIH-82, 88%)the mean age of death was 55 years, which is shorter than expected for the general population. Detailed analysis of causes of death correlated with clinical, laboratory and tumor characters of patients in our two series allowed identification of a number of prognostic factors. Poor prognostic features included higher fasting gastrin levels, presence of other functional hormonal syndromes, need for >3 parathyroidectomies, presence of liver metastases or distant metastases, aggressive PET growth, large PETs or the development of new lesions. The results of this study have helped define the cause of death of MEN1 patients at present, and allow identification of a number of prognostic factors that should be helpful in tailoring treatment for these patients for both short- and long-term management as well as directing research efforts at better defining the natural history of the most important factors determine long-term survival at present.

INTRODUCTION

The autosomal dominant disorder, Multiple Endocrine Neoplasia type (MEN1) has an incidence of 0.22–0.25% in postmortem studies 32,239,418. MEN1 is caused by alterations in the 10 exon Menin gene located on chromosome 11q13 which result in abnormalities (mutations, deletions, truncations. primarily) in the 610 amino acid nuclear protein, menin 62,195,419. Although the exact mechanisms by which altered or absent menin causes the clinical/pathological changes characteristic of MEN1 are not known, numerous studies demonstrate that menin is involved in many important cellular processes such as cell cycle regulation, transcriptional control, cell division and genomic stability 16,50,195,419,469.

Patients with MEN1 classically develop adenomas or hyperplasia of multiple endocrine glands with parathyroid hyperplasia resulting in hyperparathyroidism being the most frequent clinical abnormality [90–100%], followed by pancreatic endocrine tumors (PETs)(functional [20–70%] or nonfunctional PETs [80–100%]), pituitary adenomas (functional/nonfunctional) [20–65%], adrenal tumors (occasionally functional)[10–73%] and thyroid adenomas (primarily nonfunctional) (0–10%)48,102,140,195,228,239,262,279,280,374,388,390,418. Recently it is increasingly recognized that MEN1 patients have an increased occurrence of other endocrine and non-endocrine tumors including carcinoid tumors (thymic [0–8%], gastric [7–35%], bronchial [0–8%], rarely intestinal); skin tumors [angiofibromas (88%), collagenomas (72%), lipomas (34%), melanomas]; central nervous system tumors(meningiomas, ependymonas, schwanomas)[0–8%]; and smooth muscle tumors (leiomyomas, leiomyosarcomas) [1–7%] 13,46,48,49,74,131,176,209,228,261,274,354,388,393,413,465. In other reports small numbers of other tumors are also described, although it is unclear if they are increased in frequency or aggressiveness in MEN1 patients [lymphoma, renal cancer, hematological disorders (thrombotic thrombocytopenic purpura, myeloma), ovarian tumors, gastrointestinal stromal tumors, seminomas, chondrosarcoma, mesothelioma, thymomas] 1,77,84,89,150,214,216,256,312,341,410,432.

Whereas there have been many advances in a number of aspects related to MEN1 including its molecular understanding, development of molecular screening methods, and in the treatment of various MEN1-related disorders, one area that remains unclear, even though it has an impact on many aspects of the management of these patients, is a description of the late course of the disease, particularly the causes of death at present. An understanding of the late course of these patients could allow specific treatments to be better tailored to the subsequent importance of the various disorders that occur in MEN1 patients (for example, treatment of PETs). This is important because these patients have a long course in many cases and thus there is often opportunities to institute treatments earlier. Furthermore, the identification of the late course of the disease and causes of death could allow the possible identification of risk factors and prognostic factors that could alter treatment approaches. This lack of information in this area has occurred because of the lack of prospective studies evaluating long-term the course/causes of death of MEN1 patients at present. Furthermore, this lack of information is a particular problem at presence because of numerous treatment changes over the last few years that have altered the late course of patients with MEN1 and likely altered the causes of death. These changes in treatment are widespread and have affected almost all aspects of treatment and therefore are likely having a prominent effect on changing the late course of disease in many patients and the causes of death. These changes include the increased ability to control various hormone-excess states that were a frequent cause of death in early studies of MEN1 patients 15,43,72,73,83,88,158,180,188,224,225,240,254,279,307,353,366,386,399,438,444,458,461,465,466, accounting for up to 73–91% of all deaths in some early series 15,195,224,254,444. These include particularly the ability to treat the gastric acid hypersecretion in Zollinger-Ellison syndrome, earlier diagnosis/better treatment of insulinomas, and the increased use of somatostatin analogues or other treatments of other hypersecretory states (I.e. VIPomas, etc). This also includes an understanding of the diffuse nature of the parathyroid disease in these patients resulting in hyperparathyroidism, which almost all patients develop early in their disease course, and the development of effective treatment with multigland parathyroidectomies, which prevents the development of nephrolithiases, and renal failure54,57,78,129,149,150, which not infrequently occurred in earlier series 15,32,68,88,129,224,285,438,444,465,466. Similarly, the recognition of the pituitary disease and more aggressive treatments have made this a rare cause of morbidity and death at present as opposed to reported in earlier studies 49,129,150,222,378,379,465. Lastly, it is now increasingly recognized that MEN1 patients develop neoplasms besides those classically described (pituitary, pancreas, parathyroid, adrenal) such as various carcinoid tumors, CNS tumors, skin tumors and soft tissue tumors. Of these the carcinoid tumors are of particular concern because they can be aggressive and develop later in the disease’s course 34,40,94,131,150,151,253,326,360,465. The thymic carcinoids, which are rarely reported in series before 1990, are of particular concern, especially in males, because they as a group, they are the most aggressive tumors that MEN1 patients develop and are an increasing cause of death, later in the disease course 111,130,131,151,408,413,413,414,465. With the effective treatment of hormone-excess states they are becoming of increasing important.

This study was designed to attempt to address the issue of the largely unclear course of MEN1 patients late in their disease history at present, as well as the causes of death at present and to attempt to identify prognostic factors for different causes of death. To accomplish this study the long-term courses of 106 MEN1 patients with PETs causing ZES (MEN1/ZES) who were prospectively follow-up over a 24 ± 1.2 [range 3.6–59.3] year period from MEN1 onset was analyzed with particular attention to the exact causes of death. Unfortunately there are no reports in the literature of prospective studies of MEN1 patients containing sufficient deaths to allow a direct comparison to a similar group of patients to ours in the present study. However, to allow comparison to existing data in the literature our results were compared to outcomes reported in two other groups of MEN1 patients. First our results were compared to results of a pooled literature review of small series (<7 patients) or case reports of patients who had MEN1 with a PET who died of non-gastric acid related cause. Only patients with MEN1 and PETs were included in the pooled literature review of case reports/small series, to allow a better comparison with the NIH series in which all of the patients had PETs. These literature cases were largely from 1980 on when effective medical control of gastric acid secretion became widespread. The majority (67%) of these pooled patients had ZES and therefore most resembled those in the NIH series, although 1/3 had a PET without ZES and therefore differed. An additional comparison was performed comparing our series’ results to that of MEN1 patients reported in larger series (>10 cases) of MEN1 with follow-up data. From the literature twelve such series were identified 15,53,54,57,78,88,129,150,217,224,226,254,289,378,379,379,444,448,465,465, involving 1386 MEN1 patients, and their courses were compared to the our two other series. In this groups 60% had a PET and 54% had ZES and this group resembling the general population of MEN1 patients reported in large series with or without ZES. Comparison of our results with this latter group allowed identification of similarities and differences from series more typical of a general population of MEN1 patients with advanced disease. From these comparisons a number of conclusions were drawn as well as identifying a number of prognostic factors, which could effect clinical management.

MATERIAL AND METHODS

All patients admitted to the National Institutes of Health (NIH) [Digestive Diseases Branch] with a diagnosis of a PET with ZES with Multiple Endocrine Neoplasia-type 1 (MEN1) over a 32-year period 140 were evaluated for eligibility for this study. Eligibility requirements included the presence of MEN1 with a PET with ZES and an agreement to participate prospectively in the initial and follow-up evaluations. The present study is part of a prospective study of patients withMEN1 with MEN1/ZES at the NIH approved by the Clinical Research Committee of the National Institute of Diabetes and Digestive and Kidney Diseases. Diagnostic criteria for a PET included either functional, pathological or imaging evidence for the presence of a PET. Diagnostic criteria for ZES were as previously described 115,365 and included; 1) the presence of an elevated fasting serum gastrin (i.e., >100 pg/mL until 1994, >200 pg/mL since 1994)36,135; 2) the presence of an elevated BAO (BAO >15 mEq in unoperated patients, >5 mEq if previous acid-reducing surgery had been performed 200,290,364; 3) positive provocative testing with secretin (an increase of >120 pg/mL post injection) or with calcium (an increase >395 pg/mL) 35,85,122; 4) a positive histological confirmation of gastrinoma; or 5) a combination of these criteria 115,200,365. Secretin testing was performed as described previously 35,122. The calcium provocative test was performed as described previously 35,122. An increase >395 pg/mL over the average of the pre-injection values was considered a positive response 35,85,122. The calcium infusion test was not performed if the patient was hypercalcemic prior to starting the test.

Diagnostic criteria for MEN1 with MEN1/ZES included ZES plus either a family history of MEN1 or evidence of hyperparathyroidism or pituitary disease as previously described 31,189,195. Serum gastrin levels were determined by Bioscience Laboratories (New York, NY) until 1994 and subsequently by Mayo Clinic Laboratories (Rochester, MN) 36,64,115,122. BAO and MAO were measured when off all antisecretory medications as described previously 115,282,364. Briefly, patients were not treated with anticholinergic agents for 3 days, oral histamine H2-receptor antagonists for at least 30 hrs, proton pump inhibitors for 1 week, and all intravenous infusions of H2-receptor antagonists stopped for at least 12 hrs 282,364. MAO was assessed whenever possible if either pentagastrin or histalog was available by administering either histolog (1.5 mg/Kg intramuscularly, Eli Lilly, Indianapolis, TN) or pentagastrin (6 µg/Kg subcutaneously, Ayerst Laboratories, New York, NY) as described previously 115,282,364. All results were expressed as mEq/hr.

On the initial evaluation, a family and personal history for endocrinopathies or other illness in their families was obtained as described previously 31,195,365. Using a questionnaire, outside records and correspondence from referring physicians, a detailed review of the MEN1-related disease was performed. A detailed record of diagnosis and treatment of all endocrinopathies was obtained, with particular attention to parathyroid, pituitary, and pancreatic disorders. For parathyroid disorders the time of first determination of hypercalcemia, history of renal colic, parathyroidectomy history (time, number, type of operation, result, and time of last calcium and/or parathormone assessment) were obtained. The time of first onset of renal colic or determination that hypercalcemia or hyperparathyroidism was present was taken as the time of establishment of hyperparathyroidism and used in the study as the time of diagnosis of hyperparathyroidism as described previously 140. Each patient underwent extensive questioning regarding symptoms compatible with gastric acid hypersecretion including abdominal pain, heartburn, nausea, vomiting, weight loss, diarrhea and gastrointestinal bleeding 140,365. A complete review of past medical history for other diseases including other gastrointestinal and hepatic disorders present at the time of the initial admission was also obtained 365. The time of onset of ZES and time of diagnosis were determined as described previously 365,459. The duration of ZES from onset to diagnosis was calculated as the interval from the time of onset to the time of diagnosis of ZES. The time of onset of MEN1 was the time of the first clinical manifestation of MEN1 (renal colic, pituitary disease, symptomatic PET) or the time the disease was first detected by biochemical screening 31,140,175. Most of the time period over which this study occurred preceded the widespread use of genetic testing and no patients were initially identified by genetic testing. The time of diagnosis and onset of MEN1 or pituitary disease was determined as described previously 31,140,175. To establish the presence of lipomas, melanomas, smooth muscle tumors, thyroid disease or other PETs prior to evaluation at the NIH, the hospital pathology and physician’s records from pre-NIH evaluations were obtained and reviewed. Family history of MEN1 was considered positive if any sibling, parent, or grandparent had any of the principal manifestations compatible with MEN1 (parathyroid, pituitary, PET).

Patients were admitted for the initial evaluation and then yearly as described previously, except for patients with advanced disease who were admitted more frequently depending on the antitumor treatment protocol (3–6 monthly)140,351,382,450,476. On the initial admission and subsequent admissions, all patients had laboratory evaluations including complete blood count, urinalysis, at least 3 fasting serum gastrin levels, tumor imaging studies, biochemistry studies including liver function tests and an upper gastrointestinal endoscopy. Cross sectional imaging studies [ultrasound 242,335, computed tomographic scan with contrast 220,335,415,456, magnetic resonance imaging (MRI) 121,335,349,415] were performed to assess tumor location and extent as described previously 335,476. If the tumor localization or extent were unclear, selective abdominal angiography was performed 132,269,335. Since 1994, all patients underwent initially and then yearly somatostatin receptor scintigraphy (SRS) using 6 mCi of [111In-DTPA-dPhe1]octreotide with spot views and single photon emission CT imaging at 4 hours and 24 hours post-injection performed as previously described 134,137,138,415,416. Liver metastases were established by biopsy in all patients as described previously 405,459,476. Bone metastases were assessed using bone scanning, SRS and MRI of the spine as described recently 133,137,138,476. If results remained uncertain from imaging studies, bone biopsy was performed 133. Gastric acid hypersecretion was controlled in all patients using either histamine receptor antagonists (cimetidine, ranitidine, famotidine) alone or with an anticholinergic agent until 1983, then primarily with the use of proton pump inhibitors (omeprazole, lansoprazole) as described previously 123,192,200,266,281284,294,350,417. Sufficient antisecretory drug was given to reduce acid secretion to <10 mEq/hr in the hour before the next dose of medication or to <5 mEq/hr (or to the absence of symptoms) in patients with prior partial gastrectomy 266 or severe gastroesophageal reflux disease 266,281,283,284,295.

At the initial NIH evaluation and on subsequent NIH admission all patients underwent detailed clinical, biochemical, and imaging studies to assess the possible presence of MEN1 and, if present, additional studies to assess the extent of MEN1 involvement 13,31,131,139,141,175,315. To assess parathyroid function all patients had total serum calcium, albumin, plasma, PTH determination using an assay that identified the mid portion of PTH [performed at the NIH (1974–1983) or by Bioscience Laboratories (1983–1991)]. Since 1988 an assay measuring the intact PTH molecule (Nichols Institute, San Juan Capistrano, CA) was performed 140,328. Plasma ionized calcium levels were performed in the last 10 years. To assess pituitary disease, serum prolactin, ACTH, TSH, growth hormone, luteinizing hormone, LH, FSH, thyroid function studies (T4, T3) and urinary cortisol excretion were performed as well as an assessment of sella turcica size and pituitary imaging abnormalities using a CT and/or MRI of the sella turcica 13,133,140. To assess for the presence of a functional PET in addition to fasting gastrin levels, plasma insulin, proinsulin, glucose, ACTH, glucagon, pancreatic polypeptide, serotonin, calcitonin and urinary 5-hydroxyindolacetic acid, N-methyl histamine excretion and cortisol excretion were determined 24,139,141,267. Prior to surgery in patients with insulinomas and selected patients with gastrinomas, functional localization studies were performed assessing hormonal gradients either using selective venous sampling or hepatic vein sampling after intra-arterial injections of either calcium or secretin as described previously 64,91,92,293,422. The presence of a PET was also assessed by tumor imaging studies using cross sectional imaging (ultrasound, CT scan, MRI and, if results unclear, angiography) and SRS as described above. Thymic carcinoids were assessed by chest CT scanning, SRS and, since 2000, MRI of the chest as described recently 131. Lung/bronchial carcinoids were assessed by chest CT and chest X-ray and since 2000, by MRI of the chest. Lung/bronchial carcinoids were confirmed by thoracotomy. The presence of gastric carcinoids was assessed by performing upper gastrointestinal endoscopy using a videoscope GIF 100 endoscope (Olympus America, Inc., Melville, NY) with a 3.7 mm biopsy channel 34,139,268,344. Skin lesions associated with MEN1 (collagenoma, angiofibromas, lipomas, melanomas)74,195 were investigated in all patients since 2000 as described previously14. Other tumors that are found in MEN1 patients [smooth muscle tumor (leiomyomas, leiomyosarcomas, etc), CNS tumors (meningiomas, ependymomas, schwanomas)]13,42,195,261,418 were sought for using cross-sectional imaging studies as well as upper and lower gastrointestinal endoscopy as described previously 13,131.

Exploratory laparotomy was performed in patients with MEN1 with PET/ZES with an imageable lesion >2.5 cm, who did not have diffuse liver metastases or an intercurrent illness limiting life-expectancy189,195,314,315,318,324,380. At exploration all patients had a standard operation consisting of an extensive search for a PET/gastrinoma as described previously 7,250,314316. Because of the frequent occurrence of gastrinomas in the duodenum 9,195,347,421, which are frequently small and multiple in MEN1 9,195,250,347, particular attention was paid preoperatively and intraoperative to the duodenum by performing an extended Kocher maneuver, intraoperative endoscopic transillumination of the duodenum 124, intra-operative ultrasound with a 10 MHz real time transducer 318 and a 3 cm longitudinal duodenotomy 124,195,324,403,421. Parathyroidectomy was performed in all patients with renal colic, nephrolithiases, reduced bone density or with symptoms due to the hyperparathyroidism 317,328. Initially, either a 3.5 gland resection or 4 glands with an implant was performed 317,328. All lung carcinoids and thymic carcinoids were treated with surgical resection as described previously 131. Gastric carcinoids were treated by endoscopic resection, except in 3 cases which underwent total gastrectomy because of the extensiveness of the disease and their growth as described previously 326.

In patients with liver metastases, after histological confirmation no anticancer treatment was given initially and the growth of the liver metastases were evaluated by repeated imaging studies in 3–6 months as described previously 133,351,450. If on recent imaging, no growth was seen, growth was reassessed at 3- to 6-monthly intervals. If growth were seen, patients were treated with either interferon (5 × 106 units/day) 351, with chemotherapy (streptozotocin, fluorouracil and doxorubicin) 450, or octreotide -LAR 382. Patients who initially had metastases limited to one lobe of liver or that were considered potentially resectable were considered for exploratory laparotomy and partial hepatic resection as described previously 58,315,325,327,329. For each patient the number and size of each measurable tumor were determined in transverse sections of an imaging modality and the rate of growth on serial imaging studies calculated as described previously 141,476. The rate of change of the most rapidly growing hepatic or extrahepatic tumor was used to determine the growth category. Patients were stratified in two groups based on their tumor growth rate. Patients were classified as having an aggressive form of MEN1 if there was tumor growth >25% increase in volume per month or appearance of new lesion(s) at any follow-up evaluation . Patients were classified as developing liver metastases or any new lesion(s) if during follow-up evaluations a new lesion(s) appeared either in the liver or in other sites.

Any deaths during follow-up were classified as either MEN1-related or not. MEN1- related deaths were any death due to an MEN1 associated feature including endocrinopathy, metastatic neuroendocrine tumor, MEN1 treatment or other MEN1 feature. MEN1-related deaths were also classified into whether they were ZES-related or not. ZES-related deaths were defined as due to the tumor because of metastatic spread of the gastrinoma , tumor-related complications or due to the acute effects of gastric acid hypersecretion (N=0) as described previously 141,476. The causes of MEN1-related deaths (including all ZES-related deaths) were further subcategorized into five subgroups groups including: death due to ZES/PET with progressive liver metastases causing progressive inanition or sepsis; death due to the development of a progressive thymic carcinoid tumor; death due to the development of a non-ZES functional PET; death due the development of another (nongastrinoma, nonthymic carcinoid tumor) MEN1 associated malignant tumor or death due to tumor-related embolism. The causes of non-MEN1-related deaths were further subcategorized into 5 categories including: death due to cardiac causes including myocardial infarction, arrhythmia or cardiac arrest; death due to the development of an additional nonMEN1-associated malignancy; death due to a cerebrovascular accident; death due to a drug-related causes which were not related to treatment of advanced metastatic disease, and death due to progressive aplastic anemia. Sequence analysis of the MEN1 gene was performed since 1998 through our laboratory 146, the Molecular Diagnosis program of the Children’s Research Institute (Children’s National Medical Center, Washington, DC), or through GeneDx Inc. (Gaithersburg, MD). The PCR conditions and primers were as previously described 146,384.

Literature review of causes of death in MEN1 patients with or without PETs

For a direct comparison, unfortunately there are no series in the literature comparable to ours in which a large number of MEN1/ZES patients have been prospectively followed. Furthermore, there are insufficient literature patients with MEN1/ZES described with causes of death defined not due to acid hypersecretion. Therefore attempt to allow comparisons of our data to the existing literature we made two detailed comparisons, realizing these groups of literature patients were not completely comparable in all aspects to our population. First, we compared our results with any larger MEN1 series in the literature that reported the cause of death of ≥10 patients who died from any cause other than a peptic ulcer related cause. These patients were similar to ours in that all had MEN1, however they could differ in that not all had PETs or ZES. Second, we compared our results to a summary of a literature search for any case report or small series of MEN1 patients (i.e < 7 deaths) where the patients had a PET of any kind, the cause of death was reported, and the cause of death was non-peptic ulcer related. This second group was similar to our population in that all had MEN1, all had PETs, 67% had ZES however, all did not have ZES. The search for these patients included primarily reports since 1980 when widespread availability of effective medical/surgical treatments for the gastric acid hypersecretion of MEN1 patients with ZES became available and was generally used. Specifically, patients in series or any report where the long-term survival was limited due to death from the complications of uncontrolled acid-peptic disease were excluded, because especially in many early series including patients treated prior to 198043,60,158,225,260,265,275,307,332,366,399,404,438,445,458, this was the major cause of death and thus few patients had long term follow-up, which is not the case at present. Since the mid 1970’s adequate medical antisecretory treatments with either H2-histamine receptor antagonists or proton pump inhibitors (PPIs) became generally available 15,69,73,108,135,192,224,254,278,282,287,444,483 and this in addition to the use of total gastrectomy in selected patients, has led to the result that at present few patients die of acid-peptic related disease and the current natural history and causes of death are though to differ markedly from these early reports 54,57,78,88,150,217,367,378,379,448,465. To accomplish these comparisons, MEDLINE (National Library of Medicine, Bethesda, MD) was used to search using the key words: MEN1 or Multiple Endocrine Neoplasia combined with gastrinoma, pancreatic endocrine tumor, glucagonoma, Zollinger-Ellison syndrome, thymic carcinoid,. hyperparathyroidism, death, survival, and pituitary tumor either alone or in combination. The bibliographies of all papers were reviewed to identify papers as well as book chapters and other reports not referenced in MEDLINE. All papers were reviewed and relevant data entered into an EXCEL spreadsheet which was used for all analyses, and for comparison of our data with data in the literature. The Japanese literature was also carefully reviewed both using Medline as well as reviewing symposium proceedings, books and abstract of scientific meetings. Ten reports were found in which they appeared only in Japanese, and in these the titles and data were translated into English to use in the present study. For the first comparison, 18 series were found that reported the non-peptic cause of death in ≥7 MEN1 patients with or without a PET 15,54,57,78,88,129,150,217,224,226,254,289,367,378,379,444,448,465. For the second comparison with small series/case reports of MEN1 with PETs with at least 1 reported no-peptic ulcer disease related death, 108 separate reports containing 227 patients were identified of which 62 reports contained a single case 46,25,28,32,68,70,82,86,97,109,111,112,119,125,142,156,162,165,202,206,207,213,216,229,236,249,264,296,297,300,301,304306,311,313,333,334,358,359,361,369,381,386,387,391,393,396,398,409,411,414,426,430,438,449,460,462,464,467,468 and 40 contain more than one case (mean-4.3 cases/report) 21,22,30,40,40,41,46,94,113,120,153,166,180,203,223,226,230,238,244,246,247,303,346,353,362,372,375,389,398,406,407,413,425,427,431,440,443,458,461,466,475.

All data were entered into EXCEL spreadsheets and analyzed using Statistica MAC (Statsoft, Tulsa, OK) and Statview (SAS Institute, Inc., Casy, NC). Statistical analysis was performed using the Student t test for paired and unpaired values, the Mann-Whitney U test, the Fisher exact test, Chi-squared, and ANOVA. For a post hoc test the Bonferroni/Dunn test was used. P values <0.05 were considered significant. All continuous variables are reported as mean ± SEM. Survival curves were plotted in the form of Kaplan-Meier and 95% confidence interval were calculated plots using Statview (SAS Institute, Inc., Casy, NC).

RESULTS (Tables 113)

TABLE 1
MEN1 disease characteristics of all 106 NIH MEN1/ZES patients with PETs, 24 who died during the 24 year course of study compared with 227 MEN1/PET patients from the literature who died during followup(8).
Table 13
Comparison of non-MEN1-related causes of death in present series, various series from literature and pooled literature review cases.

General characteristics of the NIH and literature patients with PET/MEN1 studied

In the present study 106 NIH patients with PETs with MEN1 were studied prospectively and their causes of death was compared to 227 MEN1/PET patients from the literature, who died of non-acid related causes that were reported in 108 small series (<7 cases) or case reports of which 62 reports contained a single case 46,25,28,32,68,70,82,86,97,109,111,112,119,125,142,156,162,165,202,206,207,213,216,229,236,249,264,296,297,300,301,304306,311,313,333,334,358,359,361,369,381,386,387,391,393,396,398,409,411,414,426,430,438,449,460,462,464,467,468 and 40 contain more than one case (mean-4.3 cases/report) 21,22,30,40,40,41,46,94,113,120,153,166,180,203,223,226,230,238,244,246,247,303,346,353,362,372,375,389,398,406,407,413,425,427,431,440,443,458,461,466,475.

The general characteristics of the NIH MEN1/ ZES patients are shown in Table 1 and the characteristics of those that died during followup (n=24) are compared the to the pooled literature MEN1/PET patients. For the 106 NIH patients the main features of MEN1 during the course of their 32 year follow-up were that 106/106 (100 %) of the patients had MEN1 with a PET, 100% had ZES, 94% hyperparathyroidism and 58% had pituitary disease, primarily prolactinomas. There was a slight preponderance of males (59%) and 30% had no family history of MEN1. During the course of their disease, with repeated evaluations, almost one half of the patients were found to have adrenal abnormalities which were primarily nonfunctioning adenomas (46%) and 51% had skin tumors, which are increasing described in MEN1 patients (especially angiofibromas, collagenomas)14,59,74,89,313,336,370. One third developed a carcinoid tumor with the most common site a gastric carcinoid followed by bronchial carcinoids (10%) primarily in females and thymic carcinoids in males (6%), similar to reported in other series 98,131,190,195,465. Smooth muscle tumors (5%), thyroid disease (11%), other functional PETs ( primarily insulinomas )were also not uncommon (10%), as were CNS tumors (meningiomas, ependymonas, schwanomas)(7%), as recently described 13,73,95,102,111,131,140,142,195,209,261,414,418,451 (Table 1).

Most of The NIH patients had the onset of MEN1 in the 3rd decade (mean-29.3 yrs) with the development of signs/symptoms of hyperparathyroidism, although a proportion (i.e. 40%) presented with symptoms of ZES as reported in other studies 31,140,378,387,444. However, there was a delay of almost 9 years on the average in establishing the diagnosis of MEN1 (mean-38.2 yrs)(Table 1). Patients on the average were follow-up to their last evaluation or death for almost 25 years (average-24.4 yrs) and 15.5 years from their diagnosis with an average age of 53.9 years at the last follow-up, however this varied widely from age 27 to 80.6 years at the last visit.

For the NIH patients, during the follow-up, which averaged 15.5 ± 0.9 years [range 1–44 yrs] yrs from diagnosis of the MEN1, 24/106 (23%) of the MEN1/ ZES patients died (Fig. 1). The general characteristics of the 24 deceased patients were similar to those of all of the NIH MEN1/ ZES s (compared columns 1 and 2, Table 1). These 24 NIH MEN1/ ZES patients had both similarities and differences from the 227 pooled literature MEN1/PET patients from the small series or case reports (Table 1, compare columns 2 and 3). The were similar in all possessing a PET, in having a high frequency of HPT (95–96%), the rates of occurrence of thymic carcinoids (12.5–13.3%), the frequency of non ZES functional PETs (21–23%), of CNS tumors (0.5–4.2%) or smooth muscle tumors (0–0.9%) and some skin tumors (melanomas, lipomas)(0.5–4.6%). They were also similar in the high frequency of a family history of MEN1 in both groups of patients, in both having a slight male predominance (58–61%) and in their mean ages at last follow-up (51.6–55.1 yrs) (Table 1).

Figure 1
Schematic diagram of causes of death in the two study groups

In contrast the 24 NIH MEN1/ ZES patients who died during follow-up differed from the 227 deceased MEN1/PET literature patients in the 3-fold higher frequency of pituitary disease in the NIH patients, a 5-fold higher frequency of adrenal abnormalities, a higher incidence of ZES (100 vs 67%), a 2-fold higher frequency of any carcinoids found with an 8-fold higher for gastric and 6-fold for bronchial carcinoids, a higher frequency of the common skin tumors found in MEN1 (collagenomas, angiofibromas), and a 12-fold higher frequency of thyroid disease (Table 1). The NIH deceased NIH patients also had a younger age of onset of MEN1 than the literature patients (27.3 vs 36.4 yrs) and were younger at the diagnosis of MEN1 (37.1 vs 45.8 yrs) (Table 1). Many of these differences were likely do to the regular systematic follow-up visits the NIH patients underwent with a mean number of 15 visits and also the more recent appreciation of the presence of various features of MEN1 (such as smooth muscle tumors, adrenal disease, skin tumors, carcinoid tumors) 14,42,74,131,140,195,261,280,414,418, that were thus not routinely sought for in older studies.

The characteristics of the 106 NIH MEN/ ZES patients and the 227 pooled MEN1/PET patients from the literature from case reports and small series who died from a reported cause, had both similarities and differences from the 15 larger literature series of all MEN1 patients whose survival data was also compared (Tables 11 and and12).12). Results were similar in all three groups in the high percentage of patients with hyperparathyroidism, as was the high frequent of PETs which averaged 74 ± 5 [range 36–100%] in the 14 series (Table 12). The occurrence of ZES varied widely in the 15 large MEN1 literature series [range 23–100%, mean 47 ± 4 %) (Table 12), which was lower in a number of these series that the percentage seen in the pooled literature series and NIH MEN1/PET patients (Table 12).

Table 11
Survival in MEN1/PET patients from NIH and the literature.
Table 12
Comparison of MEN1 characteristics and MEN1-related causes of death in present series, various series from literature and pooled literature review cases.

Causes of Death in the 24 NIH and 227 literature patients with PET/MEN1 studied (Fig. 5)

During the mean 15.5-year of follow-up from MEN1 diagnosis (24.1 years from onset), 24 (23%) of the 106 NIH patients died (Fig. 1). In 14 patients (13% total, 58% of total deaths) the deaths were determined to be due to MEN1-related disease, and in 9 patients (9% of total patients, 38% of deaths) the deaths were due to a malignant PET (Fig. 1). In no patient was death due to the acute complications of peptic ulcer disease due to uncontrolled gastric acid hypersecretion as was commonly reported in the past 15,43,72,73,83,88,158,174,180,224,225,240,254,307,353,366,386,399,438,444,458,461,465,466, demonstrating the effectiveness of long-term medical management of the acid hypersecretion as reported in a number of studies 69,123,136,172,192,201,268,278,279,284,287,350, because no patient underwent a total gastrectomy during follow-up at NIH for control of the gastric acid hypersecretion. In the NIH patients all the MEN1-related deaths were due to a neuroendocrine tumor (NET) in some manner (carcinoid, PET, other endocrine tumor) and in 79% it was due to the malignant nature of the NET. In five patients the MEN1-related death was due to a malignant NonPET which included one case of meningioma, three of thymic carcinoid and one due to the gastrinoma causing long-standing GERD which was inadequately controlled, leading to the development of Barretts esophagus with high grade dysplasia and esophageal cancer. A hormone excess state caused death in 2/14 patients (14%) due to an uncontrolled malignant insulinoma in one patient and in the one patient with the long-term GERD which likely lead to the development of Barretts esophagus leading to the development of terminal esophageal cancer. In the NIH patients a PET-related death occurred in 71% of patients, which in 64% was due to the malignant nature of the gastrinoma and in one case to a malignant insulinoma. In the NIH patients 3/14 (21%) deaths were due to carcinoid tumors and none to gastric or lung carcinoids, demonstrating the particularly aggressive behavior of thymic carcinoids which has recently been pointed out in a number of studies 111,131,151,414,465. In the NIH patients there were no deaths related to pituitary disease and in contrast to number of older studies 88,224,438,444,465, there were no deaths due to HPT-related disease, because the HPT was effective treated by parathyroidectomy in all patients 104,195,317,328.

When the cause of death results from the 24 NIH MEN1/ZES deceased patients are compared to the 227 pooled literature PET/MEN1 patients who died during follow-up, the proportion dying from a MEN1-related cause was not different (68 vs 66%, p=0.38) (Fig. 1, Table 2). The 227 pooled literature results were similar to the NIH causes of MEN1-related death in that there were no significant differences in the percentage of deaths in all of the categories analyzed including death due to any NET, to the presence of a malignant NET, to a NET hormone excess state, to a PET, a malignant PET, functional PET syndrome, to pituitary disease, HPT-related disease or to the presence of a thymic carcinoid or other carcinoid tumor (Table 2).

Table 2
Causes of death of MEN1/PET patients [NIH and from literature review]

For the NIH MEN1/ZES patients 10/24 (42% of deaths) were due to non-MEN1 related causes (Fig. 1). The most common cause of nonMEN1 death was cardiac 4/10=40% of nonMEN1 deaths) due to myocardial infarction, arrhythmia or cardiac arrest (Table 2) followed by death due to a non-MEN1 related malignancy (3/10=30% non-MEN1 deaths) which include one case of death due to squamous cell cancer of the oro-naso-pharynx, breast cancer and one due to urinary bladder cancer (Table 2). Three additional non-MEN1 related deaths included one death because of a hematological cause (aplastic anemia), one due to a cerebrovascular accident and one due to a drug overdose (cocaine)(Table 2). The proportion of non-MEN1- related deaths in the 227 pooled literature patients did not differ from that seen in the NIH MEN1/ZES patients (32% vs 42%, p= o.38)(Fig. 1). Similarly, there were no difference in the proportion of the pooled literature patients dying of various non-MEN1 related causes including an additional non-MEN1 malignancy, cerebrovascular disease, hematological disorders, suicide or dying from accidents (Table 2). There was a significant difference in that one patient in the NIH series died of a drug overdose (cocaine use), whereas none were reported in the 227 literature patients (10% vs 0% of non-MEN1 deaths, p=0.007)(Table 2).

The cause of death in all of the 24 deaths in the NIH MEN1/ZES patients could be determined, but in 22/227 (9.7%) of the pooled literature deaths in MEN1/ZES patients the exact cause of death was not reported, however in 19 cases it was specified in the paper whether it was a MEN1 or non-MEN1 related death, therefore in only 4/227(1.7%) of the literature cases was it unknown whether the death was due to a MEN1 or non-MEN1-related causes (Table 2, Fig. 1).

Comparison of general disease features (Table 3), clinical and laboratory ZES (Table 4) and MEN1 (Table 5) features and tumoral features (Table 6) between NIH PET/MEN1 patients alive and dead at end of study follow-up

Because it is unknown at present whether the presence of MEN1 could be possibly contributing even to the deaths that we have characterized as nonMEN1-related, to analyze for possible prognostic factors for survival we first consider a comparison of various characteristics of all NIH MEN1/ZES patients alive to all patients deceased (Tables 36). For general disease features of NIH MEN1/ZES patients there was no significant differences between patients who died and were alive at the last follow-up in terms of gender, race, age at first visit to NIH, age at the last follow-up, or the durations of follow-up from either onset of the MEN1 or from the last visit (Table 3).

In various studies of patients with ZES a number of specific disease related features were reported to have prognostic significance including disease duration 476, extent of hypergastrinemia 191,292,397,405,459,476,484, basal acid output 191,476, the presence of peptic ulcer disease or its complications 108,117,191,199,200,483, previous gastric acid reducing surgery 476 and antisecretory drug used 476. Each of these was compared in MEN1/ZES patients that were alive or that died during follow-up (Table 4). There was no significant difference in the duration of the ZES to last follow-up, the increment in gastrin during the secretin test (delta secretin), the duration or type of antisecretory treatment, peptic ulcer disease history or occurrence of bleeding or other peptic ulcer disease complications between the two groups of patients (Table 4). In contrast deceased patients were more likely to have a very high fasting gastrin level (i.e. >20 fold elevated)(p=0.022), a longer delay in diagnosis (8.1 vs 4.9 yrs, p=0.039), were more likely to have had a prior gastric acid-reducing surgical procedure (33% vs 12%, p=0.026), tended to have taken histamine H2 receptor antagonists for a longer prior of time (p=0.064), to have a history of heartburn/GERD (p=0.065) and have a higher MAO (p=0.059) (Table 4).

A number of features of MEN1 patients are reported to have prognostic significance in various studies including: age at MEN1 onset/diagnosis 46,150,383; disease duration 78,141; presence of a family history 46,150; presence of any PET including gastrinoma, glucagonoma, insulinoma, VIPoma, somatostatinoma, nonfunctional 71,88,150,217,233,234,389,465; presence of adrenal disease 150,228,388,390,465; presence of lung 368,465, gastric 141,326 or thymic carcinoid tumors 111,131,150,151,413,414,465; severity of HPT and adequacy of control of HPT 46,88,224,226,328,444,465. Each of these variables was compared in deceased and NIH MEN1/ZES patients alive at last follow-up (Table 5). Deceased patients more frequently had >3 parathyroidectomies (p=0.008) to control the hyperparathyroidism suggesting they may have had more severe HPT, more frequently had a gastrinoma with another functional syndrome such as carcinoid syndrome or Cushing’s syndrome/disease (p=0.0033) and more frequently had gastrinomas with another functional PET, particularly insulinomas (p=0.031)(Table 5). They tended to have more frequently a positive family history of MEN1 (88% vs 67%, p=0.052) and to be less likely to have a cutaneous manifestation of MEN1 detected (p=0.051). There was no significant difference between the two patient groups in their age at MEN1 onset/diagnosis, onset of hyperparathyroidism or first parathyroidectomy; the duration of follow-up either from time of MEN1 diagnosis, onset of HPT to last follow-up or from time onset of HPT to 1st parathyroidectomy; number of parathyroid glands remove, presence of renal colic or any other feature of MEN1 including frequent of pituitary disease, HPT, adrenal disease, any carcinoid tumor, any MEN1-related skin disorders or the initial MEN1 feature present (Table 5).

Numerous studies, but not all, report that various PET tumoral features and their treatment such as PET size, extent, location, growth rate, distant metastases, PET resection and duration of the PET may all have prognostic significance for either survival or the development of liver metastases, which is the most important determinant of survival 54,141,191,288,338,340,434,459,476, in both patients with sporadic PETs 90,118,133,141,252,288,320,398,405,459,476 and in a few studies of patients with MEN154,88,141,150,195,217,233,234,433,434. Each of these tumoral variables was compared in patients alive or deceased at follow-up (Table 6). Large primary tumor size (> 3 cm) (p=0.022), presence of liver metastases initially (p=0.011), development of bone metastases (p=0.0002), development of liver metastases (p=0.0010), presence of a PET on initial imaging (p=0.0322), or aggressive growth of tumor (p<0.00001) were all more frequent in the deceased patients (Table 6). In contrast, the location of the primary gastrinoma (i.e. duodenal vs pancreatic), the presence of lymph node metastases, age liver metastases were found, whether a PET resection was performed or not, the age a PET resection was performed or the duration from ZES onset to the tumor of a PET resection did not differ between the two groups of patients (Table 6).

Table 3
Comparison of general disease features of NIH MEN1/ZES patients with survival status.
Table 4
Comparison of clinical and laboratory ZES features in the NIH MEN1/ZES patients with survival status.
Table 5
Comparison of clinical and laboratory MEN1 features in NIH MEN1/ZES patients with survival status.
Table 6
Comparison of tumoral features in NIH MEN1/ZES patients with survival status.

Comparison of clinical features (Table 7) and tumoral features (Table 8) between NIH MEN1/ZES patients who died from MEN1-related and nonMEN1-related causes

To investigate further possible prognostic factors that might be associated with an MEN1-related death various clinical, laboratory and tumoral features of MEN1 and ZES were compared for NIH MEN1/ZES patients classified as having either a MEN1-related death or a nonMEN1-related death (Tables 7 and and8).8). Each of the clinical or laboratory features of MEN1 or ZES (Table 7) and tumoral features (Table 8) that were compared between NIH MEN1/ZES patients alive or deceased at the end of the study in Tables 5 and and66 were compared between patients that had either had a nonMEN1 related or an MEN1 related death (Tables 7 and and8).8). There were no significant differences for any of the 34 clinical or laboratory characteristics compared between patients with or without a MEN1 related death (Table 7). In particular, there was no significant difference in fasting gastrin level (median-610 vs 2000 pg/ml, p=0.38), duration or other features of various MEN1 related manifestations (Table 7), many of which have been reported to have prognostic significance in some studies 46,54,71,141,151,151,152,414,465. In contrast, for a number of the tumoral features in NIH MEN1/ZES patients, there was a significant difference between patients who died with or without and MEN1-related death (Table 8). Specifically, of the 42 tumor features compared between NIH MEN1/ZES patients with or without a MEN1 related death (Table 8), those significantly associated with a MEN1 disease related death (Table 8) included: an increased primary tumor size (p=0.0203), particularly >3 cm (p=0.0042); the presence of liver metastases (p=0.0180), bone metastases (p=0.0180) or any distant metastases (p=0.0180); the number of PET lesions initially imaged, particularly if ≥2 were seen (p=0.0180); a younger age of developing liver metastases (p=0.028); the development of any new lesions during follow-up (p=0.0180); the development of liver metastases during follow-up (p=0.0180); or the presence of tumors demonstrating aggressive growth (p=0.0001). Whether a previous PET resection occurred is reported to be an important tumor feature reported in some studies of NIH MEN1/ZES patients 22,150,195,217,217,234 and to have prognostic significance, however we did not find it to be important in our study as a prognostic factor for an MEN1 related (p=0.30) (Table 8). Similarly, in contrast, to sporadic ZES a number of tumoral features (Table 8) reported to have prognostic value for disease related death 118,191,201,279,287,320,459,476 were not found to be associated with an MEN1/ZES related death in our study including: the presence of a pancreatic PET rather than a duodenal PET (p=0.47); the presence of any pancreatic PET (p= 0.44); the failure to undergo a PET resection (p=0.30) or the presence of lymph node metastases (p=0.56).

Table 7
Comparison of clinical MEN1 and ZES features in deceased NIH MEN1/ZES patients with or without MEN1-related death.
Table 8
Comparison of various MEN1 clinical features and tumoral features in deceased NIH MEN1/ZES patients with or without a MEN1-related death.

Comparison of MEN1 and tumoral features (Table 9) between the 227 literature MEN1/PET patients who died from MEN1-related and nonMEN1-related causes

A similar analysis to identify possible prognostic factors determining a MEN1-related death to that performed above for the NIH MEN1/ZES patients was carried out on the 227 literature MEN1/PET patients (Table 9). For various MEN1 features there was no significant difference between the percentage of the MEN1/PET literature patients who died from an MEN1-related or unrelated cause with HPT (95–96%); pituitary disease (20–23%); with an adrenal abnormality (8.7–8.9%); ZES (66–75%); another functional PET (17–22%); a nonfunctional PET (18–29%); or a CNS, skin or smooth muscle tumor (0–3.5%). In contrast, pooled literature MEN1/PET patients with a MEN1-related death more frequently had a carcinoid tumor (26 vs 9%, p=0.0048) and in particular a thymic carcinoid tumor (22 vs 3.3%, p=0.006), but not a gastric, lung or intestinal carcinoid. Almost reaching significant was the presence of other PETs than gastrinomas in patients with a MEN1-related death (47 vs 33%, p=0.058), whereas thyroid disease showed a trend towards high occurrence in patients with a non-MEN1-related death (0 vs 2.95, p=0.050) (Table 9).

The pooled MEN1/PET literature patients having an MEN1-related death, died at a younger age than patients having a nonMEN1-related death (51.1 ± 1.2 vs 53.0 ± 2.1) with 51% dying before age 46 years compared to 29% of the nonMEN1-related deaths (p=0.002) (Table 9). In contrast, there was no difference in the age at diagnosis of MEN1 (44.9 ± 1.2 vs 49.0 ± 2.4) with 79–83% of both groups >45 years at diagnosis, nor in the age of onset of ZES (43.9 ± 1.2 vs 46.6 ± 2.2) with 50–66% >44 years at the time of diagnosis (Table 9). Similarly, there was no difference in gender frequency in patients dying from a MEN1-related or nonMEN1-related cause (60–62% males) however; a family history of MEN1 was significant more frequent in patients dying from a MEN1-related cause (91 vs 77%, p=0.019, Table 9). Furthermore, the occurrence of liver metastases was much more frequently reported in patients dying from a MEN1-related cause compared to a nonMEN1-related cause (72 vs 20%, p<0.0001, Table 9).

Table 9
Comparison of MEN1 features in 227 deceased literature MEN1/PET patients with or without MEN1-related death.

Effect of different MEN1 gene mutations on total and MEN1-disease related survival for 106 NIH MEN1/ZES patients (Table 10)

Although in most studies no genotype-phenotype correlations are reported in MEN1 patients with the different manifestations or tumor features 143,419,420,457, in a few studies the presence or absence of certain MEN1 gene mutations (i.e. exon 2 or nonsense/frameshift mutations in exon 2, 9, 10) 22,217 is reported to have prognostic significance. To explore this possibility in the 106 NIH MEN1/ZES patients we correlated the presence or absence of various types and locations of MEN1 gene mutations with both total survival and MEN-disease related survival (Table 10). For the 89 patients who underwent MEN1 gene testing the location of the MEN1 gene mutation (exon 2, 8 or exon 9) did not have prognostic significance nor did the presence of a mutation that was not predicted to inactivate menin (missense, non frameshift changes). However inactivating mutations overall showed a trend to being more frequent in patients who died of any cause (p=0.084), and were borderline more frequent in patients dying from a disease related cause (p=0.047) both in all patients and in those with only familial MEN1 (p=0.047)(Table 10). The presence of frameshift mutations showed a similar result (Table 10).

Table 10
Comparison of MEN1 gene sequencing results with overall survival and with presence or absence of a MEN1-disease related death.

Total and MEN1-disease related survival for 106 NIH MEN1/ZES patients (Table 11, Fig. 2)

To assess the total survival as well as MEN1-disease related survival for the 106 prospectively studied NIH MEN/PET patients, both types of survival was analyzed in the form of Kaplan-Meier plots (Fig. 2) using time from onset of MEN1 (24.5 ± 1.2 [range-3.6–59.3 yrs]) or the time from the diagnosis of MEN1 15.5 ± 0.9 [range-0.96–44.3 yrs]. The 5-year survival was excellent (97–100%) for each of the four NIH groups (i.e., total survival from MEN1 onset or diagnosis, and MEN1 disease related survival from the onset of MEN1 or diagnosis of MEN1) (Table 11). The total survival curve for the NIH MEN1/ZES patients for time from MEN1 onset was not significantly different than the MEN1 disease-related survival (hazard ratios for onset or diagnosis, 1.7 [CI .9–3.2] (Fig. 2, panel A). The median survival time from time of MEN1 onset for total survival was 42.8 yrs [CI-25–69 yrs], whereas for MEN1 disease-related survival the median survival time was >50 years (Fig. 2, panel A). For the time from diagnosis for the NIH MEN1/ZES patients the median survival time for total survival was 36.5 yrs [CI-11–73] and was similar for the MEN1-disease related survival (Fig. 2, panel B). For the NIH MEN1/ZES patients the disease related survival either from diagnosis or onset of MEN1 remained excellent with values of 80% and 93% respectively, at 20 years, whereas the total survival at 20 years was 67.5% and 90%, respectively. In contrast, when a similar survival analysis was performed for the 227 MEN1/PET literature patients from the pooled case reports and small series, both the total survival and the disease-related survival were much poorer with 5 year survivals of 60 and 68%, respectively and 20 year survivals of 5 and 15 %, respectively (Fig. 2, panel C; Table 11). The median survival times were also shorter for the pooled literature data than with the NIH data with a mean of 6.1 years [CI-5.7–7.0] for the total survival for pooled literature patients and 8 years [CI-7.5–9.3] for disease related survival, which were significantly different, (p=0.0011).

Figure 2
Total and disease-related survival for the two groups of MEN1/PET patients studied

DISCUSSION

Classically, patients with MEN1 develop adenomas or hyperplasia of multiple endocrine glands with hyperparathyroidism due to parathyroid hyperplasia the most frequent abnormality [90–100%], followed by functional [20–70%] or nonfunctional PETs [80–100%], pituitary adenomas [20–65%], adrenal tumors [10–73%] and thyroid adenomas (0–10%)48,102,140,195,228,239,262,280,374,388,390,418. Recently it is increasingly recognized that these patients develop additional tumors including carcinoid tumors (thymic [0–8%], gastric [7–35%], bronchial [0–8%], rarely intestinal); characteristic tumors of the skin (angiofibromas (88%), collagenomas (72%), lipomas (34%), melanomas); CNS tumors (meningiomas, ependymonas, schwanomas)[0–8%]; and smooth muscle tumors (leiomyomas, leiomyosarcomas) [1–7%] 6,13,14,34,46,48,49,56,66,74,111,131,151,176,195,209,228,261,274,368,371,388,390,393,413,428,465.

Although many aspects of MEN1 have been well studied, one of the most important clinical areas, that affect many aspects of the management of these patients, is a clearer understanding of the natural history of patients late in the course of their disease 140,141,276. At present there is little prospective information on these patient’s current history late in the disease’s course, particularly related to causes of death and prognostic factors that are important for various disease courses of patients at the late stages of MEN1 195. This lack of information in this area has occurred for a number of reasons including the occurrence of a number of changes over the last few years that have markedly altered the natural history of MEN1 and likely the causes of death. First, most studies in the literature are retrospective, many contain only small numbers of cases limiting analyses, and most of the larger studies contained pooled data from different centers leading to data variation and frequent use of historical records or retrospective data to determine causes of death and therefore have limitations. Second, in various studies, in which 20–70 % (mean 54%-18 series) of the MEN1 patients developed Zollinger-Ellison syndrome 15,49,63,73,102,152,189,208,212,261,264,298,348,387,418,436,436,444, the most common functional PET seen in patients with MEN1 140,195,261,418, the uncontrolled gastric acid hypersecretion, which is characteristic of ZES 200,201,279,364, was a leading cause of early death 15,43,72,73,83,88,158,180,224,225,240,254,307,353,366,386,399,438,444,458,461,465,466. Gastric acid hypersecretion accounted for up to 73–91% of all deaths in some early series 15,195,224,254,444. At present the situation is entirely different with the development of effective means to treat the gastric acid hypersecretion; first surgically with total gastrectomy described in the 1950–1960s 108,424,483, followed by increasingly effective medical therapy, first with histamine H2-receptor antagonists 69,135,178,193,197,266,272,278,295 and later with H+, K+ ATPase inhibitors [proton pump inhibitors, (PPIs)] 123,171,189,192,227,270,278,284. At present PPIs are the drugs of choice controlling the acid hypersecretion in almost every ZES patient, both acutely and long-term 123,171,189,192,227,266,270,278,281,284,295,350, because tachyphylaxis does not develop 123,171,189,192,227,270,278,281,284. The availability of PPIs has almost completely eliminated the lethal complications of peptic ulcer disease (perforation, bleeding, penetration) in MEN1/ZES patients which were so frequent in older studies 15,17,43,72,73,83,88,107,129,140,158,180,180,189,195,224,225,240,254,307,310,353,366,386,399,438,444,458,461,462,465,466,474, and therefore their use has changed the current natural history of MEN1 patients in regard to times and causes of death. At present there are no prospective studies of MEN1 patient’s natural history and causes of death that reflect these changes in the control of acid hypersecretion. Third, in other older studies, uncontrolled hyperparathyroidism, leading to nephrolithiases and renal failure 3,245,465 was not an uncommon course of death 15,32,68,88,129,224,285,438,444,465,466. With the increased understanding of the diffuseness of the parathyroid disease (hyperplasia effecting all glands) requiring either a 3.5-gland parathyroidectomy or 4-gland parathyroidectomy with a parathyroid implant to effectively control the HPT long-term 11,42,44,104,169,211,328,330,352,376, renal failure due to uncontrolled HPT is now a rarely reported cause of death (Table 12)54,57,78,129,149,150. Fourth, recently it has become increasing apparent that MEN1 patients develop a number of tumors, which are different than the classical endocrine tumors/hyperplasia originally described to occur (i.e. parathyroid, PET, pituitary, adrenal). These include both other endocrine tumors (carcinoids of thymus, stomach, lung, rarely intestinal) and nonendocrine tumors [CNS tumors (meningiomas, schwanomas, ependymonas), skin tumors (angiofibromas, collagenomas, lipomas, melanomas) and smooth muscle tumors (leiomyomas, leiomyosarcomas)] 13,14,34,56,66,74,111,131,151,176,195,228,261,274,368,388,390,393,413,428,465. Of these, particularly thymic carcinoids, which occur primarily in males, occur characteristically later in the MEN1 course (mean age 42–46 years), are generally very aggressive and hence are an increasing cause of death 111,130,131,151,408,413,414,465. Similarly in some studies lung carcinoid tumors as well as gastric carcinoids/neuroendocrine tumors also can pursue an aggressive course 34,40,94,150,253,326,360,465. The fact that MEN1 patients are living longer 150 is raising the likelihood that a number of these newer described tumor types in MEN1 patients will play an increasing role in long term survival as most occur later in the course of patients with MEN1 13,131,195,261,280,326,418, and their effect has generally not been evaluated. Fifth, genetic diagnosis and family screening is being increasing used to diagnose patients with MEN1 and have resulted in its diagnosis at earlier times 42,150,215,246,309. This earlier diagnosis combined with increasing effective treatments of the various hormone excess states, HPT, and PETs 466 will likely have important effects on the natural history and causes of death compared to older studies.

To address the issue of the largely unclear course of MEN1 patients late in their disease history at present, as well as the causes of death at present and to attempt to identify prognostic factors for different causes of death, the present study of the long-term courses of 106 MEN1 patients with PETs who were prospectively follow-up over a 24 ± 1.2 [range 3.6–59.3] year period from MEN1 onset was analyzed. Furthermore, these results were compared to results of a literature review of small series (<7 patients) or case reports of patients who had MEN1 with a PET who died of non-gastric acid related cause. Only patients with MEN1 and PETs were included in the literature review to allow a better comparison with the NIH series who all had PETs. These literature cases were largely from 1980 on when effective medical control of gastric acid secretion became widespread. In the pooled series of literature patients the majority (67%) had ZES and therefore most patients in this comparative group resembled those in the NIH series, although 1/3 had a PET without ZES and therefore differed. To compare our results with a typical general population of MEN1 patients with advanced disease, an additional comparison was performed. In this analysis we compared our series results to that of MEN1 patients reported in series >10 cases of MEN1 with follow-up data (Tables 12, and and13).13). In this group 60% had a PET and 54% had ZES which are similar percentages to that reported in most large series of MEN1 patients 140,167,182,189,254. This study has none of the limitations reported in previous studies outlined above. It involves a large number of cases (n=106) of patients with MEN1/ZES. The patients were prospectively studied and reassessed at regular intervals and using a standardized protocol. All patients received standard treatments to control hormone excess states and to deal with potentially malignant tumors or with advanced malignant disease; therefore the results are representative of current acceptable treatment of these patients. Specifically, gastric acid hypersecretion in all patients with active ZES was controlled and no complications of peptic disease developed and no patients died from a peptic ulcer disease related complication. Other hormone excess states due to other PETs or NETs was also treated with either by surgery or medical therapy (octreotide, interferon, other medical therapies)194,196,221. Hyperparathyroidism was treated by multi-gland parathyroidectomies as outline previously 104,211,317,328 and no patients developed renal failure due to nephrolithiases. Furthermore other NETs such as thymic, gastric or lung carcinoid tumors were treated as described previously 131,326,368. Lastly the cause of death could be established in all patients that died during follow-up and classified as MEN1-related or nonMEN1-related using the criteria outlined in Methods.

Survival data in the NIH MEN1/ZES patients, pooled literature MEN1/PET patient groups and comparison with data in the literature for other series

Whether patients with MEN1 have premature death with shortened survivals is controversial in previous studies 78,88,101,129,465. In two studies 88,101 the survival of patients with MEN1 did not differ from non-affected individuals, however three other studies 78,129,465 concluded that that MEN1 patients had premature death with shortened survivals. In one of the latter studies 129 the mean age at death of MEN1 female patients was 47 years and for male patients was 55 years, which was significantly lower than the age of death of Dutch control non-MEN1 females which was 75.6 yrs (p=0.032) or nonMEN1 control males which was 70.1 yrs (p=0.001). A second series reporting premature death 78 was a large, retrospective study of 228 MEN1 patients from the Mayo Clinic whose age at diagnosis of MEN1 was very similar to those of our 106 NIH MEN1/ZES patients (39.2 vs 38.3 yrs). In that study 78 the expected survival at 20 years from age of diagnosis of the MEN1 for a matched control group was 80%, however for their MEN1 patients, the 20-year survival from diagnosis was 64 %, which was significantly less (p<0.001) than their controls. The survival of their MEN1 patients 78 is similar to our overall survival for a our 106 MEN1/ZES patients prospectively followed which was 67.5% at 20 years from diagnosis, suggesting our patients also had a premature death.

However, in our prospective study a number of the results suggest that these patients are living longer than reported in many previous series. First, during the long follow-up [mean 15.5 years from MEN1 diagnosis, 24.5 yrs from MEN1 diagnosis], 23% of the 106 NIH MEN1/ZES patients died, which is comparable to the 28 ± 3 %, reported in 12 general MEN1 series in the literature (1386 patients, Table 12) reporting percentage deaths. However, the deaths in the NIH MEN1/ZES patients occurred over greater than twice as long a follow-up period than that reported in the literature cases [15.5 (NIH) vs 7.7 ± 1.0 yrs, from diagnosis of MEN1, n=6 series]. Similarly in the 227-pooled MEN1/PET deceased patients whose data came from 108 separate reports, they represented 18.8 ± 1.9% (data -36 reports) of the total MEN1 patients being followed in these reports. However, similar to the 12 general MEN1 literature series, this percentage of patients that died in the pooled literature series, occurred over less than half of the follow-up time (6.9 ± 1.3 yrs) of that of the NIH series. Second, if one compares the data from different series, the mean age of MEN1 patient’s death varies markedly. In our 106 NIH MEN1/ZES patients the mean age of those dying was 55.1 ± 2.8 yrs. This age of death is older than reported in a number of series in the literature with a mean ages of death of 31.7 15, 43.3 444, 45.1 254, 4788, 50.3 46,57, 50.9 465 and 51 yrs 129. However, it is similar to that reported in other studies with mean ages of death of 53.2 54, 55 yrs (males)[47 yrs-females] 129, 60 yrs 448 and 55 yrs 88. Third, in terms of survival calculated using the Kaplan-Meier method, the 106 NIH MEN1/ZES patients had a much better overall survival at 5, 10, 20 years and 30 years post diagnosis than the 227 pooled MEN1/PET literature patients [at 5 yrs 97.3% vs 60%; at 10 yrs 89% vs 21%; at 20 years 67.5% vs 5%; at 30 years 55% vs 0%, p<0.01). Similarly the NIH MEN1/ZES patients survival was significantly better than the average of 22 series in the literature 54,57,78,94,106,153,166,181,217,233,276,289,303,311,367,424,425,440,481,482 which had mean 5- and 10-year survivals of 89 ± 1.9% and 78 ±3.6%, respectively, compared to 97% [CI-92–100] and 89% [CI-81–94%](p<0.05), respectively in the NIH MEN1/ZES patients. If a similar comparison is made just for the MEN1/ZES patients the survival of the NIH/MEN1/ZES patients was also significantly better (p<0.05) that that of 10 series in the literature 54,106,166,181,217,276,303,311,367,424,440,481,482 of MEN1/ZES patients with 5- and 10 year overall survivals of 88 ± 2.9% and 80 ±4.2%, respectively compared to 97% [CI-92–100] and 89% [CI-81–94], respectively for the NIH/ZES patients.

MEN1-related survival in the NIH patients, pooled literature MEN1/PET patients and comparison with data in the literature for other series (Table 1,,22,,1111,,12,12, Fig. 1)

In the 106 NIH MEN1/ZES patients during the follow-up [mean 15.5 years from MEN1 diagnosis, 24.5 yrs from MEN1 diagnosis], 24 (23%) of the 106 NIH MEN1/ZES patients died, with 14/106 (13 %) of the total patients (58% of deaths) dying from a MEN1-related cause. This is similar to the results for the 227 MEN1/PET patients from the pool literature series in which 66% of the deaths were due to a MEN1-related cause. In contrast, in the various larger series of MEN1 patients in the literature (Table 12), the percentage of deaths due to an MEN1 related cause varied considerable although the mean of 68 ± 6 for 14 series reviewed was similar to our results (Table 12). In 5 of the large MEN1 series in the literature (Table 12) the percentage of MEN1 related deaths were less than in our NIH patients and the 227 pooled literature series (28–47%) 54,78,88,378,379,448,465; in three literature series it was similar to our results (67%) 129,150,371 and in 8 series it was a higher percentage (75–100%) than in our series 15,57,217,224,226,251,254,289,367,444 (Table 12). Our results are consistent with the results of 5 large series of MEN1 patients published in the last 10 years, which reported 60 ± 9 % [range-28–81%] died from an MEN1-related cause consistent with the conclusion than at present approximately two-thirds of MEN1 patients are dying from an MEN1 related cause. These results are lower than a mean MEN1 death percentage of 88 ± 5 % reported in 5 large early MEN1 series from the years 1960–80 15,224,226,254,444,474, with the difference primarily due to occurrence of acid-related deaths in the earlier series. This data demonstrates that at present approximately two-thirds of MEN1 patients will have a MEN1-related death.

While there have been a number of studies reporting overall survival in MEN1 patients the results of which were discussed in the previous paragraph, there has been only retrospective studies, 88,217 assessing disease-related survival in MEN1 patients. One study assessed disease-related survival in MEN1 patients as a function of the patient’s age 88 and the other as a function of time of follow-up time 217. The former study found that MEN1 patients who had an MEN1-related death had a shortened survival with a mean death age of 47 yrs compared to MEN1 patients dying from non-MEN1 related causes (age-60 yrs, p<0.02) or non-MEN1 carriers (age-55 yrs, p<0.05). However, there was no significant difference between the overall survival and the MEN1-disease related survival (mean age 47 yrs vs 50 yrs). In the second study 217 the 10-year median MEN1 disease related survival was 73% (95% CI, 58–95), which was not significantly different from the overall survival from diagnosis at 10 years of 73% (95% CI, 58–89%), with a median overall survival of 19.5 months. Our disease specific survival rates for 106 NIH MEN1/ZES patients as well as the 227-pooled MEN1/PET literature patients have similarities and differences from those of this latter study 217. Our results are similar in that there was no significant different between the overall survival rate and the MEN1-disease specific survival rates either for time from diagnosis or time from onset of the MEN1 (Fig. 2, Table 11). Our results with both our patient groups differ in that our MEN1-disease related survival for the NIH MEN1/ZES was much better than that reported in the above study 217, with a 10 year survival rate from diagnosis of 93% (95%, CI, 85–97) and a 30 year survival rate of 75%, whereas our 10 year and 40 year disease specific survival rate from onset of MEN1 was 99% and 72 %. In contrast, the disease specific survival rate of the pooled MEN1/PET patients was much worse that that of the NIH MEN1/ZES patients or those reported in the above study 217 with 10 year survival rates from diagnosis of 31% (95% CI, 27–35) compared to 93% in the NIH patients and 75% in the patients in the above study 217. Many factors could be contributing to these markedly different MEN1-disease survival rates in these different groups of MEN1 patients including the differences in study design (retrospective vs prospective); differences in the features of MEN1 patient populations studied; differences in definitions of important variables such as time of diagnosis and differences in definitions of causes of death. The NIH population has the advantage of being studied prospectively, under a fixed protocol with preset definitions allowing standardization of the results, and thus could be used as a template for further comparative studies.

Causes if MEN1-related death in the NIH patients, pooled literature MEN1/PET patients and comparison with data in the literature for other series (Table 1,,22,,1111,,12,12, Fig. 1)

In both our 106 NIH MEN1/ZES patients and the 227 pooled literature MEN1/PET patients, all of the MEN1-related deaths were due in some way to a neuroendocrine tumor (NET), either because of its malignancy, complication of its treatment (postoperative death, etc) or due to the hormone excess state associated with it (i.e. PET hormone secretion, hyperparathyroidism, etc). (Table 2). Of the MEN1-related deaths, 79% and 83% in the two groups of patients were due to the malignant nature of the NET, 14–17% due to a NET hormone excess state and in 4–7% due to an NET-related problem not due to progressive metastatic disease or the hormone excess state (Table 2). The malignant NET deaths (79–83% of MEN1 deaths) were primarily due to deaths from malignant PETs (57–58% total MEN deaths) or to deaths from thymic carcinoid tumors (19–21% of MEN1 deaths) (Table 2).

To compare our data to MEN1 series in the literature all causes of deaths were expressed as percentage of the total deaths, as was done in most of these series (Table 12). When expressed in this form our data demonstrated the main single cause of death was due to PETs accounting for 38% (NIH) and 44% (pooled literature series) of the total deaths, followed by death from thymic carcinoid tumors (12–13%) (Table 12). For 15 large series of MEN1 patients in the literature (Table 12) the average percentage of death due to a PETs-related illness was 53.1 ± 7% of all deaths, however this percentage, as well as the exact causes of the PET death, varied widely in the individual series, with the total percentage varying from 19% of all deaths 78,251 to 91% of all deaths 254. In the NIH and pooled literature series the major cause of a PET-related death was the malignant nature of the PET, responsible for 36% of the total 44 % PET related deaths in the pooled literature series and for all 38% of the PET related deaths in the NIH patients. In 14/15 of the large MEN1 literature series (Table 12), PET related illnesses were also the major cause of death (mean 56 ± 7%), however in one series 251 the main cause of death was related to malignant thymic carcinoid tumors (24% of all deaths)(Table 12). Similar to our two groups of MEN1 patients, in eight of the 14 literature MEN1 series where PET related illnesses were the leading cause of death 57,78,88,129,150,217,378,379,448,465, the major cause of the PETs-related death was the malignant nature of the PET averaging 39 ± 9 % of all deaths with a range 14%% to 83% of all deaths (Table 12). In our two series death due to a malignant PET was most frequently due to a malignant gastrinoma (60 and 100% of cases). This result is similar to reported in 6 series in the literature 54,78,224,226,251,289,367,444 where the percentage of malignant gastrinomas responsible for the PET related malignant deaths could be assessed, however it different from results in 4 series 129,150,378,379,448,465 wherein malignant gastrinomas were only responsible for an average of 16% (range 0–38%) of the malignant PET deaths. It is unclear from the data available in these latter reports whether this low percentage of malignant gastrinomas contributing to the overall number of malignant PETs is clearly reflective of the actual findings in these patients, because in most of these series the specific nature of the malignant PET is poorly described. Therefore, while our data and most recent literature series clearly establish that the malignant nature of the PET is now the leading cause of death in MEN1 patients, it is not clearly established what type of PET is responsible for this: particularly whether they majority of these malignant PETs are nonfunctional PET (NF-PETs), or gastrinomas.

In 6 of the 14 literature series where a PET-related illness was the leading cause of death 15,54,224,226,254,289,367,444(Table 12), the hormone excess state was the leading cause of death and in each case it was primarily due to uncontrolled gastric acid hypersecretion in patients with Zollinger-Ellison syndrome. These series generally included patients prior to the widespread availability of effective medical management for the gastric acid hypersecretory state of patients with ZES (i.e. 1980s). Even though a number of studies have reported that the gastric acid hypersecretion in patients with MEN1/ZES, especially those with uncontrolled hyperparathyroidism, may be difficult to control, compared to patients with sporadic ZES 140,140,189,273,281,317, the data from our NIH patients and from a number of the recent MEN1 literature studies reviewed in Table 12, support the conclusion that current medical gastric antisecretory treatments in these patients are very effective. Specially, compared to earlier series prior to effective medical treatment of the gastric acid in MEN1/ZES patients, there was a low rate of deaths due to gastric acid hypersecretion in 10 of the most recent MEN1 series since 1990 (3.7 ± 1.3) 54,57,150,217,251,286,378,379,448,465, which is similar to our results in the 106 NIH MEN1/ZES patients in which 0% of patients died due to gastric acid hypersecretion.

Even though gastric acid hypersecretion is now being controlled in almost every MEN1/ZES patient, in contrast to some older studies 15, other hormone excess states per se are an uncommon cause of death in our series and in recent series. Specifically, in the NIH patients only 1/106 (0.9%) patients died from another hormone excess state (insulinoma), and in the 227-pooled MEN1/PET literature patients 2.2 % (5/227) died from another non-gastrinoma hormone excess state (8-insulinomas, 1-VIPoma). Even this may be an overestimation because 3 of the 8 pooled literature insulinoma patients had malignant insulinomas and it is unclear whether they died of progression of the malignant disease or refractory hypoglycemia. With the 5 patients in the pooled literature series with glucagonomas who died from a MEN1-related cause, all died from progressive metastatic disease. These data support the conclusion that death from the hypersecretion of a PET other than gastrinoma is an uncommon cause of death in MEN1 patients at present. These conclusions are supported by the data from 11 various large literature MEN1 series wherein 8 series, reporting 257 deaths of MEN1 patients 57,129,251,254,277,299,371,444 no patients died from insulinoma and in 3 other series 54,78,448 comprising 161 deaths of MEN1 patients, only 2 deaths (1.2%) were due to a insulinoma. Furthermore in the GTE MEN1 series comprising 758 patients the presence of an insulinoma was not associated with an increased mortality in contrast to the presence of other PETs in MEN1 patients 71,150. These data are at some variance with some older studies. Ballard in his sentinel study in 1964 of MEN1 15 where he reviewed findings in an extensive MEN1 kindred as well as 74 additional cases previously reported in the literature, concluded that hypoglycemia suggesting a possible insulinoma was frequent in MEN1 patients occurring in 36% of cases and that 5 patients (6%) died of insulinomas, suggesting that it was not an infrequent cause of death. Subsequently most studies show that insulinomas occur less frequently than this in MEN1 patients occurring in 11.8% of 758 MEN1 patients in the GTE study 148,150 and in 18% in a recent review of MEN1 cases in a number of series 102,174,189,195,212,261,348,418,436. Both the surgical curability and more effective medical control of the rare MEN1 patient with an insulinoma are contributing to the current low rate of insulinoma as a cause of death in recent MEN1. In recent large series only a small percentage (0–15%) of insulinomas in MEN1 patients are reported to be malignant 22,71,82,153,195,205,247,279,330 and the remaining 80–100% of the MEN1 patients with insulinomas are cured post resection 21,22,71,75,82,82,153,195,247,319,330,425. Short term medical control with diazoxide, diet or somatostatin analogues prior to surgery is effective in controlling hypoglycemia in most patients 76,81,82,144,196 and therefore uncontrolled hypoglycemia resulting in death is primarily restricted at present to the small percentage with a malignant insulinoma (<1% of all patients) and to even a smaller group comprised of the few patients with malignant insulinomas not controlled by medical therapies (diazoxide, somatostatin analogue, mTor inhibitors (everolimus, rapamycin) 76,144,196,221 or more recently by peptide radio-receptor therapy using radiolabeled somatostatin analogues 76,144,441.

Other functional PET syndromes [not including insulinomas or gastrinomas) were a rare cause of death in our two study groups causing no deaths in the 106 NIH MEN1/ZES patients and 1 death (0.4%) (a VIPoma) in the 227 pooled literature MEN1/PET patients. This data is in agreement with the results reported in 13 large literature series 54,57,78,129,224,251,254,367,371,444,448,474 which contain data of 463 MEN1 patient’s death where only 2 deaths (0.4%) were reported due to a glucagonoma and one death (0.2%) to a GRFoma. These rare PETs are frequently malignant when present in MEN1 patients (33–50% of cases) 51,125,195,233,334. In the large GTE series comprising 758 MEN1 patients 150,233 in which glucagonomas/Vipomas/somatostinomas were present in 3.3% of all patients, their presence was associated with decreased overall survival (HR=4.29, CI 95%–1.54–11.9) and with a decreased 10 yr survival (54%) compared to patients with gastrinomas or insulinomas (82–92%) and was similar to patients with only NF-PETs (62%). While this latter data show these the presence of these rare PETs can affect survival in MEN1 patients, in our series, as in most of the recent literature series reviewed above, the low frequency of deaths caused by these rare PET in the MEN1 patients is likely due to their low rate of occurrence in MEN1, reported as 1.6%–3% for glucagonomas, 1–3% for VIPomas and 0.65% to <1% for GRFomas or somatostatinomas 102,152,174,189,195,212,233,261,308,348,418,436.

The second largest single cause of MEN1 death in our two groups of patients was thymic carcinoid tumors (12% of the NIH MEN1/ZES patients and 12.5% of the pooled literature series). This finding has both similarities and marked differences from the findings in the 15 large MEN1 literature series reviewed in Table 12 and other recent literature series 111,150,371,373 reporting assessment of thymic carcinoids in MEN1 patients. Our results are similar to two series 129,217, which report thymic carcinoids as the second leading cause of MEN1 death (6–13% of all death) behind PET-related deaths. However, they differ from one study reporting thymic carcinoids as the most frequent cause of MEN1 related deaths (i.e. 24% compared to 10% for malignant PETs), and from 12 series in which either thymic carcinoids did not cause death of any patients 15,54,57,78,88,226,254,289,367,394,463 or caused only a small percentage of MEN1 related deaths (5–6%) 150,378,379,465 which was much less than seen with malignant PETS. Almost all of these latter series not reporting thmic carcinoids in MEN1 patients were older series. Specifically, they including patients followed before 2000 and the likely reason that thymic carcinoids were not reported, is because thymic carcinoids were not recognized as part of MEN1 until 1972 363 and not as a major cause of death until the 1990s 131,378,465 and thus were not specifically sought for or considered as a cause of death in many of these older series. Since the 1990s a number of studies have called attention to the increasing importance of thymic carcinoids as a cause of death in MEN1, particularly in men, because >90% occur in males 45,111,131,151,414,465,477,479. These tumors are particularly aggressive, associated with a poor prognosis, with more than one half of patients having metastases in some series at diagnosis and even more developing them during follow-up, particularly to the bone 45,111,131,151,363,414,477,477,479. The aggressive nature of these tumors is supported by the results of large, retrospective GTE study composed of 758 MEN1 patients, in which the presence of thymic carcinoids was reported to be associated with a higher risk of death compared with unaffected patients [HR=4.64 95% CI-1.7–12.4]. The malignant nature of the thymic carcinoid itself is responsible for almost all deaths in MEN1 patients with these tumors, because MEN1 patients with thymic carcinoids rarely develop a hormone excess state 111,130,131,151,414,470,479. In this sense thymic carcinoids in MEN1 patients differ from those occurring in patients without MEN1 (i.e. sporadic thymic carcinoids), because a hormone excess state due to the thymic carcinoid, is very infrequent (only 4 cases reported)111,130,408,470 and the hormone excess state was only Cushing’s syndrome when it occurred, whereas in patients with sporadic thymic carcinoids, a hormone excess state is more frequent (up to 40%) and more varied, with Cushings syndrome, carcinoid syndrome, and acromegaly being reported 38,111,131,185,342,392. Our results and those from a number of studies in the literature support the increasing importance of thymic carcinoids as a cause of death in MEN1 patients. In our series they occurred in 6% of all NIH patients and in various retrospective studies they occurred in 2.6% 151, 3% 45,57,151, 4.2% 305 and 4.9 % 479 of all MEN1 patients, however in our series they accounted for 12% (NIH) and 12.5% (pooled literature series), and in some recent series for up to 24% 251 of all MEN1 deaths, demonstrating their increasingly important role as a cause of death in MEN1patients.

In addition to PETs and thymic carcinoid tumors, other MEN1 features have also been reported to be an important cause of MEN1 related death in a number of studies, particular some older series. Complications of uncontrolled hyperparathyroidism including renal failure and hypercalcemic crises are reported to contribute to MEN1 related deaths in 10–12% of patients in three older series of MEN1 patients 224,226,378,379,444,465 and in occasional patients in other reports 78,150. In more frequent series 54,57,129,217,251,371,448,474, including all of the NIH patients in the current series, death from complications of uncontrolled hyperparathyroidism were not seen, because of the greater understanding of the hyperplasic nature of the parathyroid disease and the need for subtotal/total parathyroidectomy to control the hyperparathyroidism 42,104,149,168,211,328,330. Pituitary diseases (pituitary apoplexy, tumor invasion) are reported to either be a cause of or contribute to MEN1 related death in 3–6.5 % of patients in a few older series 49,129,150,222,378,379,465. Pituitary tumors in MEN1 patients are more aggressive, more frequently multiple and invasive than in patients with sporadic pituitary tumors 49,147,435,447. However, in the NIH prospective series as well as most current series, although pituitary adenomas are frequently present (i.e. 20–65% of patients) they are recognized and adequately treated, so they rarely cause death at present 54,57,78,88,195,217,251,448. This latter conclusion is also supported from the findings of the GTE study involving 758 MEN1 patients where the presence of pituitary disease was not associated with an increased risk of death in MEN1 patients (HR=1.17, CI 95%-0. 72–1.90, p=0.54) 150.

Adrenal disease is present in 10–73% of MEN1 patients on imaging studies 23,48,128,228,374,388,390,453 and is reported to cause MEN1 related deaths in occasional series (0.4% 150, 4% 465) and case reports 161,385. Adrenal tumors in MEN1 patients are reported to cause a number of functional hormone excess syndromes including Cushings syndrome, hyperaldosteronism, pheochromocytoma, androgen secretion or feminization 8,27,48,57,128,157,228,228,261,276,385,388,390,436,453. Functional hormone excess states caused by the adrenal tumors are rarely a cause of MEN1-related death, because in most series >90% of the adrenal lesions are not associated with a functional syndrome (except one series 228 where 38% with adrenal lesions had Cushings syndrome)48,388,390. In various series 0–6% % of MEN1 patients 23,48,128,140,157,374,385,390,453 develop adrenal cortical carcinomas, which can be aggressive, invasive and associated with a functional syndrome such as Cushing’s syndrome, and which can contribute to or cause death in these patients. However, in both our series including the 106 NIH MEN1/ZES patients and the 227 literature MEN1/PET patients, no patient died of adrenal disease, similar to reported in a number of recent large MEN1 series 23,78,129,157,217,448, supporting the conclusion that it is an uncommon cause of death at present in MEN1 patients. This conclusion is also supported by the results from the 758 patient GTE study of MEN1 patients in which those with adrenal tumors had a trend toward an increased risk of death compared to unaffected patients, but it did not reach significance (p=0.064) (HR=1.72, 95% CI-0.97–3.06) 150.

In addition to thymic carcinoid tumors, patients with MEN1 have an increased incidence of pulmonary [0–8%] 47,140,190,195,261,368,378 and gastric carcinoid tumors [7–35%] 34,140,187,195,232,326,360, which are reported to be a MEN1 cause of death in a few series in the literature and in some case reports 39,150,326,378,379,448,465. In the 106 NIH MEN1/ZES patients, neither gastric nor pulmonary carcinoid tumors caused any MEN1 deaths, however, in the 227 pooled literature series, 1 patient died from a gastric carcinoid (0.4% of all deaths) and 1 patient died from a pulmonary carcinoid (0.4 % of all deaths). This data suggests, although these tumors can be malignant and also cause a hormone excess syndrome [carcinoid syndrome] 40,94,98,190,360,437, they are an uncommon cause of MEN1-related death at present. This conclusion is supported by results of 15 MEN1 series (Table 12) and a detailed series on only pulmonary carcinoids in MEN1 patients 368 in which pulmonary carcinoids were reported to be a cause of death in a mean of 0.5 ±0.4% of total deaths (range 0–5%) and gastric carcinoids in 1.2 ±0.8 (range 0–10%), with 11 series reporting no deaths from either gastric or pulmonary carcinoids. This conclusion for bronchial carcinoids was also supported by the GTE study on 758 MEN1 patients in which the presence of a bronchial carcinoid did not increase the death rate compared to unaffected controls (HR=1.55, 95% CI-0.64–3.77, p=0.332)150.

Prognostic factors for survival in the NIH patients, pooled literature MEN1/PET patients and comparison with data in the literature for other series (Tables 39)

We attempted to identify prognostic factors for overall survival in the NIH patients, as well as survival from a MEN1-related death in both groups of patients in our study. We analyzed overall survival in addition to MEN1 disease related survival for a number of reasons. In the literature almost all studies on prognosis in MEN1 patients report overall survival and therefore to allow comparison, we also included overall survival. Secondly, by including overall survival, MEN1’s effect on all disease processes leading to death can be reviewed. This is an important point because at present there is little information on what is now described as non-MEN1 related deaths and it is unknown whether MEN1 patients have increased occurrences of any of the diseases currently include in this category. Although the exact role of menin, the protein altered in patients with MEN1, in causing many of the abnormalities seen in MEN1 patients is not known is not clear, it is clear it is involved in many important cellular processes such as cell cycle regulation, transcriptional control, cell division and genomic stability, any of which if altered could lead to many different diseases including various common neoplasms 16,50,195,419,469.

For overall survival in the 106 NIH MEN1/ZES patients none of five general disease features analyzed differed between surviving and deceased patients including gender; race; age at first NIH assessment or age at last follow-up; or duration of MEN1 to death/last follow-up or duration of follow-up at NIH. Similarly, for MEN1 disease related survival for either the NIH patients or the 227 MEN1/PET patients from the pooled literature series gender, age at diagnosis of MEN or onset of ZES or time to death/ last follow-up did not differ between patients with or without and MEN1 related death. However, the age at death was earlier for the pooled literature patients with an MEN1 related death compared to those with a non-MEN1 related deaths (51 vs 53 yrs, p=0.002). These results differ from a number of MEN1 series in the literature where decreased survival was associated with older age 46,54,152,217, and in two studies males had a decreased survival compared to females 54,150. They also differ from a study 54, which assessed the presence of liver metastases as a surrogate marker of survival in MEN1 patients, because their presence is a strong negative prognostic factor in MEN1 and in nonMEN1 patients with NETs or PETs 21,37,54,103,105,141,191,217,252,291,398,433,459,471,476,481, which reported liver metastases were more frequently in males with MEN1 than females. Our results are similar to those in various studies of MEN1 patients where survival was not affected by age 150,152,217, gender 152, and another study, which also found that MEN1 deaths occur at an earlier age than death due to nonMEN1-related deaths in MEN1 patients 87. Our results differ from those in some studies of patients with sporadic PETs or sporadic ZES in which a worse prognosis is associated with female gender and shorter disease histories to diagnosis 191,459,476. However, our results are similar to most studies of sporadic PETs which show no effect of gender on survival 100,105,258,338,400,429,446,471. Nevertheless, our result showing a lack of gender effect on survival (total or MEN1 disease related) is somewhat surprising, because even though the most common cause of MEN1 death, PETs, occur approximately equal in males and females, the second most common cause of MEN1 death, thymic carcinoids occur in >90% males, thus this would be expected to lead to a gender effect on survival 111,131,148,151,414,465,477,479. A likely factor contributing to our failure to see the gender effect of thymic carcinoids reflected in our survival results is the fact that thymic carcinoids are diagnosed relatively later in the course of MEN1 (mean age mean 42–50 yrs) 131,151,204,362,414,479 and these patients may have a prolonged survival, therefore their full effect on mortality may require even longer follow-up than that in our study.

Previous studies suggest that a number of clinical and laboratory MEN1 related features can be predictive of survival 46,46,141,150,152,367,465(Tables 4,,5,5, ,77,,9,9, ,10).10). For the 106 NIH MEN1/ZES patients most non-PET related features of MEN1 (HPT, pituitary, adrenal, thyroid, carcinoid) were not significantly associated with decreased overall survival, except for the occurrence of other functional syndromes than ZES [either PET-related (p=0.031) or non PET-related (p=0.0033)], the requirement for a high number of parathyroidectomies (>3)(p=0.008), a higher fasting serum gastrin level (>20 fold increase)(p=0.022) or the need for previous gastric acid reducing surgery (p=0.0261). Almost reaching significance for overall survival was the presence of a higher percentage of patients with family history of MEN1 among patients who died of any cause (p=0.052) and the presence of thymic carcinoids (p=0.098). In contrast, the presence/absence of none of these variables correlated with the presence of disease-related survival in the NIH patients. However, with the 227 literature MEN1/PET patients, a MEN1 disease related death was highly correlated with the presence of thymic carcinoid tumor (p=0.0006), the lack of presence of a family history of MEN1 (p=0.019) and borderline correlated with the presence of thyroid disease (p=0.050) or other PETs than ZES (p=0.058). These results are consistent with the conclusion that a worse survival prognosis occurs when an MEN1 patient has severe hyperparathyroidism requiring more parathyroidectomies; higher functional expression of gastrinomas resulting in higher gastrin levels, with more severe gastric acid hypersecretion requiring more frequent need for gastric acid reducing surgery prior to the availability of PPIs; the presence of additional functional hormone excess states than ZES, and the presence of a thymic carcinoid tumor. These conclusions are consistent with a number of previous findings in various studies on MEN1 patients and sporadic PET patients. They are consistent with studies that have shown the development of liver metastases, which are associated with decreased survival in patients with PETS such as gastrinomas 37,54,103,105,252,291,398,405,459,471,476, more frequently occur in gastrinoma patients with higher gastrin levels 19,33,36,46,96,184,191,241,405,459,476 and in some studies with higher basal acid outputs 476. Our findings that more resistant hyperparathyroidism is associated with a poorer survival prognosis is consistent with studies that propose that the present of uncontrolled hyperparathyroidism in these patients increases the risk of developing PETs 47, that it may act as a prerequisite for the development of other neoplasms in MEN1 29 and that it may be an important factor in the release of mitogenic factors that are found in the serum of MEN1 patients, including a basic fibroblast growth factor-like substance 263,480.

Our results for the prognostic value of various MEN1 clinical and laboratory features show a number of similarities and differences from other series of MEN1 patients. The are similar to almost all other studies in demonstrating that the frequency of occurrence of many of the features of the MEN1 syndrome including HPT; adrenal or pituitary disease; smooth muscle or CNS tumors; bronchial/ gastric carcinoids; or dermatological lesions does not correlate with survival and thus they are not prognostic factors for survival 78,129,150,152,217,251,289,433,444. In contrast, almost all studies similar to our pooled MEN1/PET literature series, report the presence of thymic carcinoids carries a worse prognosis, due to the aggressive nature of these tumors 111,131,131,150,151,331,413,414,465. While our NIH MEN1/ZES series showed a trend toward significance for thymic carcinoid patients having a worse prognosis (p=0.098), a number of factors likely contributed to it not reaching full significance as a prognostic factor. These include that we made an early diagnosis of thymic carcinoid because all patients were prospectively followed with regular imaging 131 and their treatment was aggressive, because of the known progressive nature 131 of these tumors, resulting in prolonged survivals. A number of large studies of MEN1 patients report that the presence of any PET (except insulinomas), is associated with decreased survival 150,331,389,465. In our study this could not be evaluated because both groups of our MEN1 patients studied (the 106 NIH patients and the 227 patients from the pooled literature series) all the patients had PETs. The characteristics of the PETs as prognostic factors could be studied and are dealt with in the next section. Our finding that in the pooled MEN/PET literature patient series that a family history of MEN1 carried a better prognosis agreed with the large French GTE study which reported similar findings 150. These findings are at odds with the results from a study 46 that reported the presence of a first degree relative with MEN1 was associated with an increased risk of developing a PET 46, which was associated with a worse prognosis.

A number of studies of MEN1 patients report that various tumoral aspects, primarily associated with PETs have prominent prognostic significance. These include in various studies the primary PET size54,141,217,234,247,315,324,433,434, whether the PET is functional or nonfunctional 150,217; the functional type of PET 46,150; whether liver metastases are present or not 54,141,152,217,276 and the effect of various treatments, particularly whether the patient underwent surgical resection of the PET or not 152,217,217,433. In the 106 NIH MEN1/ZES each of these variables could be analyzed and assessed for their effect on both overall survival and MEN1-specific survival. In contrast, because of incomplete data, only a few of these variables could be assessed in the 227 MEN1/PET pooled literature patient series. In the NIH series of MEN1/ZES patients decreased overall survival (OS) (p=0.0203) and disease related survival (DRS) (p=0.022) occurred in patients with increasing primary PET tumor size; in patients with liver metastases initially (OS-p=0. 011, DRS-p=0.0180); bone metastases (OS, p=0.0002; DRS, p=0.0099), but not lymph node metastases (OS, p=0.057; DRS, p=0.56); for patients who develop liver metastases (OS, p=0.001; DRS, p=0.0180) and for patients whose PETs show aggressive growth (OS, p<0.00001; DRS, p=0.0001). Decreased overall survival also was associated with increasing number of PETs (p=0.032), however for MEN1-disease related survival this did not reach significance (p=0.097). Conversely, the development of any new lesion was associated with decreased MEN1-disease related survival (p=0.0180), but it effects on overall survival did not reach significance (p=0.124). A number of these results are consistent with findings reported in other studies of MEN1 patients or patients with sporadic PETs. The presence of liver metastases initially or their development with time are associated with decreased survival in a number of studies of MEN1 patients 54,141,217,276, but not in others 152. These results are also consistent with most studies of patients with sporadic PETs, which report liver metastases are associated with a poor prognosis 37,103,105,159,200,252,255,291,338,398,429,459,471,476,481, but some studies report also their development during follow-up and the extent of the liver metastases correlate with decreasing survival 191,459,476. The exact primary source of the liver metastases in almost every study of MEN1 patients is not well defined and it is often unclear whether it is from a PET, thymic carcinoid or another carcinoid tumor (gastric, pulmonary). The liver metastases in MEN1 patients with a PET, without a thymic carcinoid, are almost always attributed to the PET, although this remains unproven. Furthermore, the exact source of the liver metastases becomes even more of an issue in patients with MEN1 with gastrinomas, because many of these patients also have nonfunctioning PETs in the pancreas on imaging studies and in most cases it is unclear which PET metastasized. Lastly, the majority of patients with MEN1 that have thymic carcinoids also have PETs (57–100%) 111,131,151,414, and which is responsible for the liver metastases is usually not resolved. This ambiguity has occurred because until recent many of these different NETs could not be distinguished histologically or immunohistologically and even in more recent studies where numerous methods to distinguish these NETs have been reported 177,237,243,395, detailed histological/immunohistochemical studied were not performed to resolve the primary site that metastasized. Because of this, the true metastatic rate of many of the MEN1 NETs to the liver remains unclear.

The prognostic significance of distant metastases (beyond liver) to bone, etc. has not been specifically studied in MEN1 patients. Similarly, the presence of local metastases to adjacent lymph nodes on survival in MEN1 patients has not been specifically studied. However, the prognostic effect of each of these metastatic sites has been studied in detail in patients with various sporadic PETs. In the case of local metastases to lymph nodes, studies have reported contradictory results, with most reporting no prognostic effect 54,114,145,191,201,252,279,338,377,459, whereas a few other studies have reported a negative effect on survival 37,67,219,429,476, however the impact is much less than seen with the presence of liver metastases. A number of studies report the presence of distant metastases, especially to bone, is a predictor of decreased survival 20,133,133,191,231,338,476. In one study of patients with advanced gastrinomas (sporadic) the presence of bone metastases was associated with a mean survival of only 1.9 years after their detection 476. Therefore, our results with MEN1 patients are similar to most studies with sporadic PETs, which report no effect of lymph node metastases on survival, and other studies, which report decreased survival in patients with sporadic PETs who develop distant metastases to bone.

Our finding that aggressive tumoral growth or the development of new lesions during the follow-up is associated with decreased survival is consistent with results of a few studies on MEN1 patients and a number of studies in patients with sporadic PETs. One prospective study of MEN1 patients with gastrinomas 141 reported than 15 % of patients demonstrated aggressive growth of their PETs and that it was associated with decreased survival. This is a lowered percentage than the 25% of patients with sporadic ZES 459,476 who are reported to develop aggressive tumor growth over time, but nevertheless, it also had similar effect on decreasing survival in both groups of patients. Similarly, a number of single cases reports or small series have reported patients with MEN1 whose tumors demonstrate rapid growth 51,94,160,183,333,354,454 which in most cases leads to decreased survival. Other studies with various sporadic PETs demonstrate that a subset is associated with rapid growth and the development of new lesions, which is associated with a decreased survival 100,337,382,405.

In our 227 MEN1/PET pooled literature patients we did not find a difference in survival between patients with or without a gastrinomas, with or with a NF-PET or with or without another functioning PET. Our results are similar to those in one study of MEN1 patients 150 comparing these different PETs wherein MEN1 patients with various PETs (except insulinomas) all had decreased survival rates [hazard ratios of 1.9–4.3]. In contrast, our results differ from a number of other previous studies in MEN1 patients, which have reported that different PETs have different effects on survival rate 46,195,217. Insulinomas in MEN1 patients are an uncommon cause of death, especially in more recent series, with 20 year survival >90%, in contrast to gastrinomas, NF-PETs, glucagonomas and other rarer functional PETs with 20 year survivals of 52–67% 21,57,71,78,166,195,217,233,330,345,433. In MEN1 patients insulinomas are rarely malignant (0–15%) and in most series 80–100% of the MEN1 patients with insulinomas are cured post resection 21,22,71,75,82,82,153,195,247,319,330,425. In contrast > 50% of gastrinomas and 20–50% of NF-PETs and other rarer functional PETs are malignant 155,195,217,233,247,250. These results also differ from findings in a large Tasmanian MEN1 family 46 in which it was reported the presence of hypergastrinemia was associated with a significant increase of enteropancreatic malignancy and decreased survival. At present it unclear what is the basis for the difference in our data from the finding in this large kindred and whether it could be due to different PET behaviors in different MEN1 kindreds.

Our prospective study of the 106 NIH MEN1/ZES patients demonstrated that patients with large PETs had decreased total and MEN1-disease related survival. There was not sufficient data on the 227-pooled MEN1/PET literature patients to perform a similar analysis. Our results agree with a number of studies 54,141,217,234,315,322,324,433,434, but not all 217,247 studies in the literature on MEN1 patients which have examined this correlation. Most of these studies reported that in MEN1 primary PETs >2–3 cm in diameter are associated with increased development of liver metastases 141,141,217,234,234,433,433,434,434, which in many reports is also shown to be associated with decreased survival. These results in MEN1 patients are in agreement with a number of studies on sporadic PETs which also show a correlation between primary pancreatic tumor size and the development of liver metastases and in some cases an association with decreased survival is shown 37,52,103,159,173,252,339,476, however other studies do not report this association 338,429. Our data on the NIH MEN1/ZES patients did not show an association with the presence of a pancreatic PET or the presence of a duodenal gastrinoma with survival. The situation in patients with MEN1 who develop gastrinomas/ZES is confused by the fact that most of the gastrinomas (80–100%) occur in the duodenum 90,154,250,315,348, however these patients also frequently develop pancreatic PETs, which are nonfunctional in most cases (80–100%) 9,90,315,348. The duodenal gastrinomas in the MEN1 patients are characteristically small, and in contrast to the sporadic case, are invariably multiple 9,90,250,348. Similarly in sporadic ZES, 60–75% of the gastrinomas in MEN1 patients, are now found in the duodenum, with 20–30% in the pancreas 316,321,323,324. Studies on sporadic gastrinomas demonstrate that the duodenal and pancreatic gastrinomas behave differently in that although they are equally malignant with 40–70% of patients having metastases in adjacent lymph nodes 21,22,250,315,459 which have not been shown to affect survival 459, metastases to the liver are uncommon with the sporadic duodenal gastrinomas, whereas the sporadic pancreatic gastrinomas are aggressive and associated with a worse prognosis 324,459,476. There is less data available in MEN1, but a number of studies show that these patients also frequently (30–70% of cases) have lymph metastases associated with their duodenal gastrinomas, however they are uncommonly associated with liver metastases and are not associated with decreased survival in MEN1 patients 54,247,250,315,321,389, similar to the results in the current study.

Causes if nonMEN1-related death in the NIH patients, pooled literature MEN1/PET patients and comparison with data in the literature for other series (Table 13, Fig. 1)

While a number of studies report the frequency of all deaths that were due to nonMEN1-related deaths, there is relatively little data on the exact non-MEN1 related causes of death and it has in general not been systematically studied. In most studies the exact causes of the nonMEN1-related deaths are not specifically stated so that it is in general more difficult to compare our data to that in the literature. In our 106 NIH MEN1/ZES patients the cause of death was determined in all cases, with 42% of the 24 deaths due to a nonMEN1-related death and in the 227 pooled MEN1/PET patients from small series/case reports, 34% of all the deaths (i.e. 73/227 patients) were due to a non MEN1 related cause of death. Whereas the mean overall percentage of deaths due to nonMEN1-related causes in the literature from 13 series 54,57,78,88,129,150,217,251,254,289,378,379,379,444,448,465 was similar to the data on our two series (mean-33 ± 7%), the percentage of all deaths due to an nonMEN1-related death varied widely in the different series from 0% to 72% of all the deaths reported (Table 13). In 4 series the percentage of all deaths due to nonMEN1-related deaths was <20% 57,217,254,289,367, and in five series >50% 54,78,88,378,379,448,465. This marked difference is not due to the time of reporting of the series because the mean percentage of patient deaths reported due to an nonMEN1-related cause for the 4 series reported before the widespread use of PPIs (prior to 1995) 254,289,367,378,379,444,465, and the nine series reported after their widespread use (after 1995) are similar 54,57,78,88,129,150,217,251,448 (25 ± 10 % vs 36 ±9 % all deaths due to nonMEN1-related death). These data demonstrate that approximately one-third of all deaths in MEN1 patients are due to a nonMEN1-related cause.

In the NIH 106 prospectively followed MEN1 patients the most frequent nonMEN1-related cause of death was heart disease [i.e. myocardial infarction, arrhythmia or cardiac arrest], followed by death due to nonMEN1-related cancers, cerebrovascular disease and one death due to a cocaine overdose (4% of deaths). The order of the main causes of nonMEN1-related deaths in the 227-pooled MEN1/PET patients from case reports or small series was different with the most common cause being death from other nonMEN1-related cancers. This was followed in descending frequency by death due to a nonMEN1 cause which was not specified in the report, then by heart disease, lung disease (noncarcinoid), cerebrovascular disorders, accidents, other gastrointestinal disorders (non-cancer or MEN1 related), diabetes, neurological diseases and suicide. These results have both similarities and differences from previous reports of the causes of non-MEN1-related death in various large series of MEN1 patients (Table 13). They are similar in that for the 12 different series of MEN1 patients where data on the cause of nonMEN1-related deaths was reported, in four series heart disease either was the most frequent or the second most frequent cause of a nonMEN1-related death 78,88,129,378,379,465. Similarly, in eight series the occurrence of nonMEN1-related cancers was either the most frequent or second most frequent cause of death 54,88,129,150,217,289,367,444,448. In contrast to these results, eight studies do not report heart disease 54,57,150,217,254,289,367,444,448 and two studies a nonMEN1-related neoplasm 57,254 as one of the most frequently seen causes of a nonMEN1-related-death. Two studies of MEN1 patients 289,367,448 report suicide as a frequent cause of death in their patients. However, it was not a cause of death in any of the 106 NIH MEN1/ZES patients and was a cause of death in only 1 death in the 227 pooled MEN1/PET patients from case reports and small series. Cerebrovascular disease was a nonMEN1 cause of death in 4% of the 106 NIH MEN1/ZES patients (10% total nonMEN1 deaths) and 3.5% of the 227 pooled MEN1/PET literature patients (11% of the total nonMEN1 deaths), however it is not reported as a cause of death in 12 large series of MEN1 patients (Table 13) 54,57,78,88,129,150,217,254,289,378,379,379,444,448,465.

The finding that heart disease as one of the most frequent nonMEN1 causes of death in the MEN1` patients in both the 106 NIH MEN1/ZES patients (20% of all nonMEN1 deaths), the 227 pooled MEN1/PET patients from small series/case reports (40% of all nonMEN1 deaths) and in some of the other large series of MEN1 patients (24–48% of all nonMEN1 deaths)78,88,378,379,465 raises the question of whether it is more common in MEN1 patients. Heart disease is a frequent cause of death in nonMEN1 patients and at present without matched controls and more MEN1 deaths, it is unclear whether cardiovascular death is more frequent in MEN1 patients with or without PETs. It has been proposed that MEN1 patients may have an increased risk of cardiovascular disease 442. Furthermore, MEN1 patients frequently develop a number of diseases, which are associated with an increased risk of cardiovascular disease. These include insulin resistance and impaired glucose metabolism which are known important risk factors for cardiovascular diseases 116,163,442, as well as the development of chronic hyperparathyroidism, which is associated with an increased mortality, mainly due to an overrepresentation of cardiovascular death 116,210,259,455. In three studies of MEN1 patients 271,442,452 evidence is provided to support the conclusion that these patients are more frequently insulin resistant compared to their unaffected relatives, that both increased fasting blood glucose levels and diabetes mellitus were more prevalent in MEN1 patients than unaffected family members, that the impaired glucose metabolism was associated with hyperparathyroidism and hypergastrinemia and that MEN1 patients had decreased insulin sensitivity. Studies in patients with primary hyperparathyroidism report that it can be associated with an increased cardiovascular morbidity and mortality 116,210,259,455. Primary hyperparathyroidism is reported to be associated with hypertension, disturbances in the rein-angiotensin-aldosterone system, reduced coronary flow reserve resulting in dysfunction of the coronary micro-circulation, cardiac arrhythmias, as well as changes both functionally and structurally in walls of blood vessels 116,210,259,455. Furthermore, hyperparathyroidism has been related to the development of insulin resistance 271 and post successful parathyroidectomy insulin sensitivity has been reported to improve 65,126. Therefore, by influencing glucose homeostasis through the development of insulin resistance, hyperparathyroidism could also affect cardiovascular function and play a role in the development of cardiovascular disease. While this is unproven in patients with MEN1, these patients almost invariably have hyperparathyroidism 102,140,189,280,418; it can be severe, especially in patients with MEN1 with gastrinomas 245,328; it is frequently long-lasting being present before diagnosis and frequently recurring even if multi-gland parathyroidectomies are performed 11,44,93,104,149,169,179,211,218,257,328,330. These considerations suggest that in future studies of MEN1 patients, the occurrence and mortality of cardiovascular disease should be carefully assessed and compared to a control population to determine whether presence of the MEN1 is having an effect and if so, whether any of the above mechanisms seen in primary hyperparathyroidism are contributing.

Classically. MEN1 is associated with tumors/hyperplasia of the pituitary, parathyroid, duodenum/pancreas, thyroid or adrenal, however over the last few years a wide spectrum of other tumors are reported with increased frequency in MEN1 195,261,418. These include the development of carcinoid tumors in a number of locations (thymic [0–8%], gastric [7–35%], bronchial [0–8%], rarely intestinal); dermatological tumors [angiofibromas (88%), collagenomas (72%), lipomas (34%), melanomas]; various tumors of the central and peripheral nervous systems (meningiomas, ependymonas, schwanomas)[0–8%]; and smooth muscle tumors (leiomyomas, leiomyosarcomas) [1–7%] 6,13,14,34,46,48,49,56,66,74,111,131,151,176,195,209,228,261,274,368,371,388,390,393,413,428,465. These newer tumors show varying degrees of aggressiveness with thymic carcinoids being highly aggressive, gastric and pulmonary carcinoids less commonly aggressive (metastasize <30% of cases), as are most smooth muscle or CNS tumors which rarely metastasize and the skin tumors which all have a benign course, except for the occasional melanoma. Similar to the classical endocrine tumors in MEN patients 80,89,131,170,248,261,419,439, with most of the more recently described tumors associated with MEN1 [smooth muscle tumors including some leiomyomas, leiomyosarcomas], gastric carcinoids, pulmonary carcinoids) 10,26,53,79,89,274,302,336,451, but not all cases [thymic, some angiofibromas, leiomyomas and angiomyolipomas] 89,131,156,170,414, molecular studies of the tumor provide evidence that these are intrinsic MEN1 tumors, because loss of heterozygosity of the MEN1 gene is found in the tumor compatible with the proposal the MEN1 gene functions as a tumor suppressor gene 195,419. These results of the increased development of various tumors in MEN1 patients is consistent with recent results exploring the role of cellular roles of menin, the protein altered in patients with MEN1. It still remains unclear the exact cellular basis for the increased occurrence of these various endocrine and nonendocrine tumors in MEN1 patients. The frequent occurrence of various nonendocrine neoplasms as a cause of death in both our 106 NIH MEN1/ZES patients, the 227 MEN1/PET pooled literature patients from small series and case reports as well as in many of the large MEN1 series from the literature raises the possibly that some of these more common neoplasms could be more frequent in MEN1 patients. At present this remains unclear and because of the small numbers of patients in most of the series, as well as the lack of systematic collection of the data in a prospective fashion in most studies this question cannot be answered definitively by the data available at present.

In the 106 NIH MEN1/ZES patients there were four deaths due to four different nonMEN1 tumors [breast, renal, hematological, oral cancers] which is close to the 3.2 ± 1.1 nonMEN1 tumor deaths per series in 12 large literature series 54,57,78,88,129,150,217,254,289,378,379,379,444,448,465. In the 227 MEN1/PET pooled literature patients from small series/case reports there were 18 nonMEN1 tumor related deaths in a frequency that reflected the common tumors in nonMEN1 patients with lung cancer>prostate, CNS tumors>colorectal cancer. From this limited data only a few trends can be pointed out on the frequency of the individual nonMEN1 tumoral causes of death in the MEN1 patients. For the 12 literature series 54,57,78,88,129,150,217,254,289,378,379,379,444,448,465 and the two series in our study (i.e. 106 NIH MEN1/ZES and 227 pooled literature MEN1/PET patients), the nonMEN1 tumor causing death that appeared in the most series was renal cancer and colorectal cancer (each in 6/14 series=43%), followed by the common neoplasms causing death in nonMEN1 patients (lung cancer=36%=5/14 series, breast cancer=29%=4/14 series), followed in decreasing frequency by oral cancers (29%=4/14 series) and then by hematological, CNS tumors (14%=2/14 series) followed by prostate/ esophageal cancer in 7% of series (1/14 series). Renal neoplasms are reported in a number of MEN1 patients (renal cell cancer, oncocytoma, angiomyolipomas) 53,84,88,89,99,176,186,217,256,289,448 and two reports 84,186 proposed that renal tumors might be a new manifestation of MEN1. Even though renal neoplasms are reported as a cause of nonMEN1 related death in equal frequent to colorectal cancer, which occurs in >3 fold higher frequency than renal cancer in the general population (United States Cancer Statistics, CDC), no definite conclusions can be drawn from the data reported above because of the low numbers of cases, lack of systematic reporting and lack of careful epidemiological comparison. In studies it will important to prospectively assess whether any of the nonMEN1 neoplasms are increased in MEN1 patients with particular attention to renal and oral cavity neoplasms.

One study has proposed that suicide 72 might be an important cause of death in MEN1 patients and another study proposed that cerebrovascular accidents due to MEN1 mediated related effects result in death 2. For the 12 literature series 54,57,78,88,129,150,217,254,289,378,379,379,444,448,465 and the two series in our study (i.e. 106 NIH MEN1/ZES and 227 pooled literature MEN1/PET patients) suicide as a nonMEN1 cause of death was reported in 28% of the studies (i.e. 4/14 studies) 54,289,367,448. It was not a cause of MEN1 death in any of the 106 NIH MEN1/ZES patients prospectively studied and in was a nonMEN1 cause of death in 1 of the 227 pooled MEN1/PET literature patients (0.44%). These later data suggest that suicide is a relatively uncommon cause of death in these patients. Cerebrovascular disease as a cause of nonMEN1 related death was also uncommon. For the 12 literature series 54,57,78,88,129,150,217,254,289,378,379,379,444,448,465 and the two series in our study (i.e. 106 NIH MEN1/ZES and 227 pooled literature MEN1/PET patients), only one patient in any series died from a cerebrovascular accident.

CONCLUSIONS AND SUMMARY OF IMPORTANT POINTS (Table 14)

Table 14
Summary and conclusions of important clinical points from study of death and prognostic factors in 106 NIH and 227 MEN1/PET pooled literature patients from small series/case reports and 1386 patients in 12 large series of MEN1 patients in the literature. ...

From our analysis of causes of death and identification of prognostic factors in 106 NIH MEN1/ZES patients prospectively studied compared to results of pooled data from 227 MEN1/PET patients in case reports/small series and to data from published large series of MEN1 patients 15,53,54,57,78,88,129,150,217,224,226,254,289,378,379,379,444,448,465,465, a number of conclusions can be drawn which will be important in the management of these patients and which are summarized in Table 14.

Our analyses demonstrate that in contrast to the past, in our two series and in recent large MEN1 literature series, MEN1 patients rarely die of causes related to the hormone excess state per se. Therefore, at present death uncommonly is death due to complications of gastric acid hypersecretion which was so frequent in the past 15,43,72,73,83,88,158,180,224,225,240,254,307,353,366,386,399,438,444,458,461,465,466, due to hormone hypersecretion by other PETs such as insulinomas 15,306,334,375,466; due to the complications of untreated hyperparathyroidism such as renal failure or hypercalcemic crises 15,32,68,88,129,224,359,427,438,440,444,461,465,466; due to untreated pituitary disease (apoplexy, hormone excess state, etc) 222,447 or to other uncommon hormone excess states (ectopic Cushing’s from adrenal tumors, other functional PETs, etc)165,228,447,468,475.

Analysis of the survival data of both the NIH/pooled literature series of MEN1/PET patients and comparison with literature data, supports the conclusion that MEN1 patients, even today have a decreased survival compared to the normal population with a mean age of death of 55 yrs. In both the NIH and pooled literature series, 2/3 of all deaths are due to MEN1-related disease which also agrees with the data from 12 large MEN1 series in the literature 15,53,54,57,78,88,129,150,217,224,226,254,289,378,379,379,444,448,465,465. The most frequent causes of MEN1 related deaths are from pancreatic endocrine tumors with the malignant behavior of the tumor being the major factor. Of the different PETs that MEN1 patients develop gastrinomas account for more than one-half of the PET related deaths (60%) and in none of the NIH/pooled literature series patients was death due to the complications of the gastric acid hypersecretion these patients develop, instead to primarily the malignant behavior of the gastrinoma 199,200,290,364. The second most common cause of a MEN1-related death was thymic carcinoids, which accounted for almost 20% of the MEN1 related deaths in the NIH/pooled literature series, but only 5% of the 12 large MEN1 literature series. This marked difference can be largely attributed to the fact that thymic carcinoids have only from the early 1980s been recognized as part of the MEN1 syndrome, their aggressive nature appreciated after this and thus as a cause of death they were only systematically reported in more recent series 45,111,131,150,151,251,413,414,465.

In both the NIH/pooled literature series as well as the average of 12 large literature series 15,53,54,57,78,88,129,150,217,224,226,254,289,378,379,379,444,448,465,465, 1/3rd of the patients died due to nonMEN1-related causes. The most frequent causes of nonMEN1 related death in the NIH/pooled literature series were cardiovascular disease and death due to other nonMEN1 neoplasms, with numerous other causes such as cerebrovascular disease, lung disorders other than lung carcinoid tumors, and accidents making up the remainder. For the other non-MEN1 neoplasms, colorectal and renal cancers as a cause of death were reported in the most series, followed by lung cancer and breast and oral cancers. However, because of low patient numbers and other technical issues with data collection it can not be determined from the available data whether any of these nonMEN1 neoplasms are more frequently seen or have altered behavior in MEN1 patients.

In the NIH and pooled literature series, comparisons of MEN1/ PET patients in different survival categories (alive, deceased, MEN1-related death, nonMEN1-related death) allowed us to identify a number of prognostic factors. These include various clinical features (disease duration, presence of nonZES functional syndromes, parathyroidectomy number, presence of thymic carcinoid, presence of family history, in ZES previous acid reducing surgery); laboratory features (fasting gastrin levels) and various tumoral features (PET size, liver metastases, distant metastases, number lesions imaged, growth behavior of tumor).

The above results lead to a number of general conclusions related to the diagnosis and management of MEN1 patients. Even though survival of these patients has certainly improved from older studies, wherein the hormone excess states of various NETs frequently caused premature death 15,43,72,73,83,88,158,180,224,225,240,254,306,307,334,353,366,375,386,399,438,444,458,461,465,466, it is still shortened compared to the general population and needs to be improved. This will primarily require more systematic and aggressive treatment of various MEN1 aspects, particularly treatment of PETs and carcinoid tumors, which are the principal causes of MEN1-related death. To accomplish this earlier diagnosis of MEN1 is need because the mean delay in diagnosis is 4–7 years from the onset of MEN1 (present study) 55,140,207,357 and aggressive treatment of NETs is needed.

Because malignant PETs were the principal cause of MEN1 related deaths, particular attention will need to be paid to their early diagnosis and effective treatment. Particularly important are the diagnosis and treatment of gastrinomas, which were responsible for most (60–65%%) of the PET-related deaths. In almost 25% of the NIH patients liver metastases were already present at the time of MEN1 diagnosis and therefore earlier diagnosis is essential to prevent their development if possible. Also important is the effective treatment of both gastrinomas and other PETs. Their treatment remains controversial because studies show that patients with MEN1 with small nonfunctional PETs (<2 cm) have a excellent long term prognosis and in the GTE studies their survival did not differ from patients with MEN1 without a pancreatic PET 315,433,434. Patients with duodenal gastrinomas with tumors <2 cm also have an excellent long-term survival with the survival being 100% of patients at 20 years 315. This has led to the recommendation that small PETs (<2 cm) in these patients can be followed without resection either by standard imaging studies or by serial endoscopic ultrasound studies 18,110,195,221,315,423,433,434. The present study as well as others in the literature in MEN1 and sporadic PETs show that tumor size is an important prognostic factor for the development of liver metastases, that liver metastases (either their extent, rate of growth, or development), not lymph node metastases is a very important prognostic factor for long-term survival 191,315,405,459,476. One of the central problems that need to be assessed is the actual source of the liver metastases that these patients develop. The metastases can either be from a gastrinoma if the patient has Zollinger-Ellison syndrome; from a small occult thymic carcinoid; from a pancreatic NF-PET or from a gastric carcinoid, all of which can be aggressive and malignant 111,131,151,195,326,368,413,414. There is little data on well-assessed biopsies from MEN1 patients who do develop liver metastases to allow an accurate assessment of the malignant nature of each of these NETs. At present new treatments for certain NETs (PETs especially) have been described such as with the mTOR inhibitor, everolimus 198,355,472,473; the tyrosine kinase inhibitor, sunitinib 198,356; various liver directed therapies using embolization, chemoembolization or radiolabeled microspheres 61,127,164,343,401 and new chemotherapeutic regimes that are reported to have a high response rate (capecitabine and temozolomide) 343,402. It will be important in the future that the source of the metastatic disease be established so that it can be treated appropriately and aggressively.

Thymic carcinoid tumors are generally a later feature of MEN1 and occur in most series in >90% in males, so that it is important that guidelines for screening/management for these aggressive tumors, that have been proposed in a number of recent papers, be carefully followed 42,111,131,151,196. It has been proposed that the routine use of partial thymectomy (cervical thymectomy) at the time of parathyroidectomy may reduce the occurrence of thymic carcinoids, and at present this is generally recommended, however, cases of thymic carcinoid have still occurred in MEN1 patients who have previous underwent this surgery, therefore careful/regular follow-up is required 45,98,140,151,156,235,412,414,477,479. At present the treatment of advanced metastatic disease in patients with thymic carcinoids is not very effective, therefore the main aim at present is to prevent them if possible (with cervical thymectomy) and for their early diagnosis and aggressive surgical treatment 111,131,151.

In one third of patients with MEN1 1 there is a nonMEN1 cause of death, and at present it is unclear whether any of these causes are actually increased in frequency in MEN1 patients and therefore actually MEN1-related. Heart disease and nonMEN1 related tumors were the main causes in our patients and in those in the literature in large MEN1 series 15,53,54,57,78,88,129,150,217,224,226,254,289,378,379,379,444,448,465,465. In the case of heart disease there are possible MEN1 associated factors that are associated with an increased risk of cardiovascular disease which include hyperparathyroidism and glucose intolerance/diabetes, the latter which is reported to occur with increased frequency in MEN1 116,163,271,442,442,452. Similarly, because of the fundamental role that the menin protein plays in growth related processes 16,50,195,261,419,469,478 it remains possible other neoplasms that are now thought nonMEN1 related, might be affected either in frequency or severity in MEN1 patients. At present neither of the above possibilities can be adequately addressed because of lack of control studies that are prospective in nature addressing either the frequency or severity of cardiovascular disease or other nonMEN1 neoplasms in MEN1 patients. These types of studies will be important in the future to manage these patients and extend their lives.

Acknowledgments

Funding: This research was supported in part by funding from the intramural research program of the NIDDK, NIH.

Abbreviations used in this article

ACTH
adrenocorticotropin
BAO
basal acid output
CNS
central nervous system
CI
confidence interval
CDC
Centers for Disease Control
CT
computed tomographic scan
DRS
disease related survival
FSH
follicle stimulating hormone
GERD
gastroesophageal reflux disease
GI
gastrointestinal
GH
growth hormone
GRFoma
growth hormone-releasing factor-secreting tumor
GTE
Groupe d’etude des Tumeurs Endocrines
HPT
hyperparathyroidism
HR
hazard ratio
MAO
maximal acid output
MEN1
multiple endocrine neoplasia-type 1
MEN1/PET
patients with MEN1 with pancreatic endocrine tumors
MEN1/ZES
Patients with MEN1 and Zollinger-Ellison syndrome
MRI
magnetic resonance imaging
NET
neuroendocrine tumor
NIH
National Institutes of Health
nonMEN1-related
not related to MEN1
NF-PET
nonfunctional pancreatic endocrine tumor
Octreotide-LAR
octreotide-long acting release preparation
OS
overall survival
PCR
polymerase chain reaction
PET
pancreatic endocrine tumor
PPI
proton pump inhibitor
PTH
parathormone
PTX
parathyroidectomy
SRS
somatostatin receptor scintigraphy
TSH
thyroid stimulating hormone
VIPoma
vasoactive intestinal peptide secreting tumor
ZES
Zollinger-Ellison syndrome

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