Abstract
Multiple endocrine neoplasia type 1 is a rare autosomal inherited disorder associated with a high risk for patients to simultaneously develop tumors of the parathyroid glands, duodenopancreatic neuroendocrine tumors and tumors of the anterior pituitary gland. Early identification of MEN1 in patients enables presymptomatic screening of manifestations, which makes timely interventions possible with the intention to prevent morbidity and mortality. Causes of death nowadays have shifted toward local or metastatic progression of malignant neuroendocrine tumors. In early cohorts, complications like peptic ulcers in gastrinoma, renal failure in hyperparathyroidism, hypoglycemia and acute hypercalcemia were the primary causes of early mortality. Improved medical treatments of these complications led to a significantly improved life expectancy. The MEN1 landscape is still evolving, considering the finding of breast cancer as a new MEN1-related manifestation and ongoing publications on follow-up and medical care for patients with MEN1. This review aims at summarizing the most recent insights into the follow-up and medical care for patients with MEN1 and identifying the gaps for future research.
Introduction
Multiple endocrine neoplasia type 1 (MEN1) (OMIM 131100) is a rare autosomal inherited disorder associated with a high risk for patients to simultaneously develop tumors of the parathyroid glands, duodenopancreatic neuroendocrine tumors (NETs) and tumors of the anterior pituitary gland (Chandrasekharappa et al. 1997). Patients with MEN1 are also at risk of developing adrenal tumors and NETs of lung, thymus and stomach, lipomas, angiofibromas and collagenomas (Kouvaraki et al. 2002). Recently, females with MEN1 were found to have a 2–3 times higher risk for breast cancer at a younger age as compared with the general population (Dreijerink et al. 2014, van Leeuwaarde et al. 2017) (Fig. 1).
Nowadays, in approximately 90% of patients, a germline mutation of the MEN1 gene located on chromosome 11q13 is found (Machens et al. 2007, Goudet et al. 2011, Ito et al. 2013, de Laat et al. 2016). Early identification of MEN1 in patients enables presymptomatic screening of manifestations, which makes timely interventions possible with the intention to prevent morbidity and mortality (van Leeuwaarde et al. 2016). The guidelines for clinical practice, which were originally published in 2001 and updated in 2012 led to more clarity for medical professionals on how to take care of patients with MEN1. In the guidelines, it is advised to perform MEN1 mutation analysis in the offspring of patients carrying the MEN1 mutation already at the young age of 5 years (Brandi et al. 2001, Thakker et al. 2012).
Survival and cause of death in MEN1 patients have dramatically changed over the past decades. In early cohorts, complications like peptic ulcers in gastrinoma, renal failure in hyperparathyroidism, hypoglycemia and acute hypercalcemia were the primary causes of early mortality in MEN1 patients (Ballard et al. 1964, Vasen et al. 1989, Goudet et al. 2010). With improved medical treatments, these complications have become rare and life expectancy has significantly improved. Notwithstanding, approximately two-thirds of MEN1 patients still die from MEN1-related causes in the late stage of the disease. Cause of death nowadays has shifted toward local or metastatic progression of malignant NETs. In recent years, studies based on larger MEN1 cohorts have sought for further evidence to support the clinical practice guidelines with regard to follow-up and interventions to ultimately improve the prognosis of patients with MEN1. The present review aims at summarizing the most recent insights into the follow-up and medical care for patients with MEN1 and identifying the gaps for future research.
Genetic testing of MEN1 in index cases
Endocrine diseases associated with MEN1 such as primary hyperparathyroidism (pHPT) and pituitary tumors (PIT) are relatively common in the general population. Moreover, an increasing number of incidentalomas in endocrine organs is found on imaging studies (Golden et al. 2009, Molitch 2009, Scangas & Laws 2014). In patients who are not from known MEN1 families, apparently sporadically occurring tumors might actually be caused by a not yet identified MEN1 mutation. It is important to timely identify index cases, because subsequent early detection of MEN1-related tumors is associated with improved outcomes and survival (Lourenço et al. 2007, Pieterman et al. 2009, de Laat et al. 2016). In addition, the presence of a MEN1 mutation also has important implications for family members of the index case (van Leeuwaarde et al. 2016).
The clinical practice guidelines present a consensus recommendation when to screen potential index cases for MEN1 mutation (Newey & Thakker 2011, Thakker et al. 2012). Genetic screening for index cases is advised when clinical criteria for diagnosing MEN1 are met or when there is high suspicion for (atypical) MEN1. High suspicion for MEN1, which is defined as: parathyroid adenoma below the age of 30 years (or multigland parathyroid disease at any age); gastrinoma or multiple pancreatic NET at any age or individuals who have two or more MEN1-associated tumors that are not part of the classical triad of parathyroid, pancreatic islet and anterior pituitary tumors (e.g. parathyroid tumor plus adrenal tumor) (Newey & Thakker 2011, Thakker et al. 2012).
Several studies have raised concerns that these recommendations might be too conservative, resulting in a delay in the diagnosis of index cases (Cardinal et al. 2005, Ellard et al. 2005, Klein et al. 2005, Tham et al. 2007, Lassen et al. 2014). Therefore, risk factors for MEN1 mutation in potential index cases were recently assessed in the Dutch and Swedish population (Tham et al. 2007, de Laat et al. 2012). The results showed that clinicians in both the Netherlands and Sweden already frequently referred patients for genetic counseling and testing for MEN1 who did not meet the criteria for genetic testing as provided by the current practice guidelines (64 and 81% of individuals tested in both cohorts respectively). Mutations were also identified in patients who did not fulfill the suggested criteria for mutation analysis. Altogether, a mutation was identified in 15.9 and 13.2% of the Dutch and Swedish cohort respectively. The main risk factors for a MEN1 mutation were recurrent or multiglandular primary hyperparathyroidism (odds ratio (OR) 162.40); non-recurrent hyperparathyroidism (OR 25.78); pancreatic and duodenal NET (OR 17.94); pituitary tumor (OR 4.71); NET of stomach, thymus or bronchus (OR 25.84) and positive family history (up to third degree relatives) for any neuroendocrine tumor (OR 4.53). Interestingly, in the current practice guidelines, family history other than family members with proven MEN1 is not included to assess the risk for MEN1. The study confirmed that the risk for having a MEN1 mutation decreases with increasing age of first manifestation. A clinical prediction model for estimating the risk for a MEN1 mutation in the individual patient was formulated, that can be used in genetic counseling when considering testing for MEN1 (de Laat et al. 2012).
Familial management
Since the identification of the MEN1 gene in 1997, familial screening of the MEN1 gene in eligible family members after identification of the index case has become possible. The autosomal dominant inheritance pattern leads to a 50% risk of MEN1 carriership for first-degree family members (Chandrasekharappa et al. 1997). The current clinical practice guidelines recommend to offer mutational analysis for first-degree relatives of known MEN1 mutation carriers. Performing genetic testing in family members will identify MEN1 carriers that require screening for early tumor detection and treatment. Family members who do not harbor the MEN1 mutation will not undergo unnecessary screening and are secured from future worry of tumor development (Thakker et al. 2012). Due to genetic testing, family members have an earlier MEN1 diagnosis in comparison with the index case, with mean ages at diagnosis of respectively 42 and 34 years in the Dutch MEN1 cohort (van Leeuwaarde et al. 2016). This age difference was confirmed in an Italian multicenter study with an age difference of 47 and 36.5 years at MEN1 diagnosis in index cases and family members (Marini et al. 2017). However, there is no current advise on timing of familial screening. One study advocates for timely genetic screening of family members after MEN1 diagnosis of the index case. In this study, the median lag time between diagnosis of a family member was 3.5 years, with a maximum lag time of 30 years. At the time of MEN1 diagnosis in family members of the index cases, patients with metastases had a longer lag time compared with patients without metastases. Non-index cases with a pituitary tumor at the time of MEN1 diagnosis with a macroadenoma also had a longer lag time compared with patients with a microadenoma. Ten non-index cases died because of a MEN1-related cause that developed during or before the lag time. These findings stretch the need for prompt genetic screening in all eligible family members (van Leeuwaarde et al. 2016).
Management for patients without a confirmed MEN1 mutation
Traditionally, a MEN1 gene mutation was not identified in up to 25% of MEN1 patients who meet the clinical criteria for the diagnosis of MEN1 (Thakker et al. 2012). With recent new techniques such as multiplex ligation-dependent probe amplification (MLPA), new mutations of the MEN1 gene are uncovered, which increases the sensitivity of genetic analysis (Raef et al. 2011, Giacche et al. 2012). Sensitivity is expected to further increase by the introduction of next-generation sequencing techniques. Despite these new techniques, a MEN1 mutation is not found in approximately 10% of patients with a clinical diagnosis of MEN1, a phenomenon also referred to as ‘phenocopies’ (Lemos & Thakker 2008).
In the past few years, a discussion arose whether these patients are correctly diagnosed as having MEN1. Research was initiated to identify other genes that might cause a MEN1-like phenotype (Georgitsi et al. 2007, Ozawa et al. 2007, Agarwal et al. 2009). Newly found mutations in the cyclin-dependent kinase inhibitor (CDNK1B) are of particular importance. Mutations in the CDNK1B gene caused, both in experimental animal studies and observational studies, a syndrome of parathyroid and anterior pituitary tumors (Thakker 2014). Patients with a CDNK1B gene mutation have a clinical course different from patients with MEN1 mutations and have a lower risk to develop the pancreatic neuroendocrine tumors (pNET). For this reason, after identifying these mutations, a new endocrine tumor syndrome was referred to as MENX or, more recently, MEN4 (Thakker 2014).
In a recent nationwide study, major differences in the clinical course were found between 30 mutation-negative MEN1 patients and 293 mutation-positive patients (de Laat et al. 2016). Only one of the mutation-negative patients appeared to have a CDKN1B mutation confirming the rarity of this mutation. The median age for developing the first main MEN1 manifestation was ten years later in mutation-negative patients and a third primary MEN1 manifestation did not occur in this patient group. In addition, those patients hardly ever developed other associated tumors. Median survival in mutation-positive patients was estimated at 73.0 years compared to 84.0 years in mutation-negative patients. These results suggest that, instead of having the MEN1 syndrome, many mutation-negative patients have a syndrome that is caused by a yet unknown genetic predisposition or co-incidentally have two sporadically occurring endocrine tumors. Consequently, systematic follow-up for early detection of endocrine tumors according to the MEN1 screening protocol appeared to be not necessary for most mutation-negative patients.
Primary hyperparathyroidism
Primary hyperparathyroidism (pHPT) is the hallmark disease of MEN1. With a prevalence of around 90% (Goudet et al. 2010, Thakker et al. 2012, de Laat et al. 2016), it is the most common manifestation and often the first clinical feature of MEN1 (Pieterman et al. 2009). It is also responsible for most MEN-related surgeries (Berglund et al. 2003, Wilson et al. 2008).
As presymptomatic screening for MEN1 became possible in 1997 and patients could be identified at an early age before symptoms occurred, more insight is gained about the clinical manifestations of MEN1 in children. In an Italian study, prevalence of pHPT in children and adolescents was 50%. In this study, 11/22 children (median age 12) were asymptomatic at the end of the study. Eleven of the twelve children that did develop a manifestation of MEN1 were diagnosed with pHPT (Vannucci et al. 2017). Another study shows that of the children and adolescents that develop MEN1-related disease before the age of 21 (n = 160), 75% (n = 122) has pHPT. Most cases of pHPT before the age of 21 years occur after the age of 10, are asymptomatic and detected by biochemical screening. However, 9–14% presented with urolithiasis and 22–30% of the patients underwent parathyroid surgery before the age of 21 either because of symptoms or because of the height of serum calcium (>2.75 mmol/L) (Goudet et al. 2015).
Due to the genetic background of MEN1-related pHPT, patients are younger at diagnosis, more often have multiglandular disease and there is an equal gender distribution compared to patients with sporadic pHPT. Anecdotally, parathyroid carcinomas are described in MEN1, but this remains rare (del Pozo et al. 2011, Lee et al. 2014, Christakis et al. 2016, Singh Ospina et al. 2016).
Although MEN1 patients often have lower parathyroid hormone (PTH) and calcium levels compared to patients with sporadic pHPT, early and severe bone involvement as well as more frequent renal complications have been reported (Lourenço et al. 2012). Even after surgical intervention, one study showed that bone recovery was better in patients with sporadic pHPT in patients with MEN1 after one-year follow-up. Risk of bone and renal complications is higher in patients with uncontrolled hyperparathyroidism (Silva et al. 2017).
MEN1 patients without pHPT are monitored with annual calcium and PTH measurements (Thakker et al. 2012). If the diagnosis of pHPT is established and the decision to proceed with surgical treatment is made, preoperative localization studies seem to be of little added value, since a bilateral neck exploration is the surgical procedure of choice (Thakker et al. 2012, Nilubol et al. 2016). One study showed that preoperative localization studies for primary parathyroidectomy in MEN1 may only alter the surgical approach in 7% of the cases, which the authors deemed insufficient to recommend this on a routine basis (Nilubol et al. 2012). When surgery is considered for persistent or recurrent pHPT, localization studies are necessary to guide surgical approach, with ultrasound and sestamibi being the most sensitive conventional imaging studies (Keutgen et al. 2016). Fluorine-18 fluorocholine PET-CT should be considered when conventional imaging studies are inconclusive (Kluijfhout et al. 2016).
The optimal timing of surgical intervention is under debate and should be evaluated individually. With severe hypercalcemia and symptomatic pHPT, the indication for surgery is obvious. However, when hypercalcemia is mild and the diagnosis is made by presymptomatic screening in young patients, the optimal timing is less clear. Early surgery can be more difficult because glands are only minimally enlarged, which might predispose the patient to recurrence and reoperation at an early age. On the other hand, longstanding elevated PTH might predispose the patient to more severe bone disease (Giusti et al. 2012).
The cornerstone in treatment of pHPT is surgery. There is still a debate on the most effective type of surgery depending on the number of parathyroids, which are surgically removed (Montenegro et al. 2012, Pieterman et al. 2012, Fyrsten et al. 2016). In this time of shared decision making, patient may weight risks and benefits of the extensiveness of surgery differently than doctors do and might opt for more conservative approaches with clear understanding of failure risks.
One of the most important challenges after initial parathyroidectomy is managing the frequently occurring postoperative hypocalcemia. This might be severe and symptomatic requiring extended hospital stay for i.v. calcium, but also the milder cases, which can be managed by administering oral active vitamin D (alfacalcidol or calcitriol) and calcium require careful and frequent monitoring. Often medication can be tapered and stopped, but this may take over one year (Pieterman et al. 2012).
If surgery is not feasible because of inoperability of the patient, patient refusal or the inability to demonstrate the source of persistent pHPT, the calcimimetic agent cinacalcet can be used. Cinacalcet is registered for the use in patients with pHPT who, though meeting the criteria for surgery, cannot be operated. Small series have shown that cinacalcet is effective to achieve reductions in serum calcium in MEN1 patients with (recurrent) pHPT (Whitley et al. 2008, Falchetti et al. 2008, Akker et al. 2010, Giusti et al. 2016). However, results of long-term use in MEN1 patients are still lacking.
Duodenopancreatic neuroendocrine tumors
Neuroendocrine tumors of the pancreas (pNETs) are the second most frequently occurring tumors among patients with MEN1 (Vasen et al. 1989, Shepherd 1991, Trump et al. 1997, Carty et al. 1998, Vierimaa et al. 2007, Pieterman et al. 2009). The median age of patients at pNET diagnosis is around the forth decade but tumors can already occur in childhood (Carty et al. 1998, Goudet et al. 2015). At the age of 80 years, the penetrance of pNETs is over 80% and metastatic pNET is the most important cause of MEN1-related mortality (Triponez et al. 2006, Ito et al. 2013, de Laat et al. 2016, Conemans et al. 2017). Pancreatic NETs can either lead to a clinical syndrome because they are hormonally active (functional) or can be non-functional. The most frequently occurring functional tumors secrete gastrin or insulin, respectively leading to a high gastric acid secretion (Zollinger–Ellison syndrome) and hypoglycemia. Gastrin secreting NETs are mostly located submucosally in the duodenum and then often occur as multiple tumors (Gibril et al. 2001, Norton et al. 2001, Pieterman et al. 2014). Rates of pancreatic gastrinomas are only 0–18% in series that include immunohistochemistry in the classification of pNETs (Tonelli et al. 2006, Dickson et al. 2011, Imamura et al. 2011, Lopez et al. 2013). Insulinomas occur in about 2–24% of patients (Vierimaa et al. 2007, Waldmann et al. 2009, Goudet et al. 2011, Sakurai et al. 2012). Glucagonomas, glucagon-secreting tumors, occur in less than 3% of patients with MEN1 (Dralle et al. 2004, Giudici et al. 2012). Vipomas, ViP-secreting tumors, have been reported in a few patients with MEN1 (Åkerström & Hellman 2007).
In the clinical practice guidelines, it is suggested to annually screen for pNETs using plasma hormonal measurements and by imaging to identify tumors for timely interventions with the aim to prevent morbidity and mortality because of metastasized disease (Lourenço et al. 2007, Thakker et al. 2012). For screening for gastrinomas, fasting plasma gastrin appears to be useful to identify those patients who have to undergo further imaging to confirm and localize the gastrinoma (Thakker et al. 2012). In patients with complaints of hypoglycemia, a 72-h fast is the cornerstone of the diagnosis of an insulinoma (Thakker et al. 2012). The diagnostic accuracy of the tumor markers glucagon, pancreas polypeptide and chromogranin A, which up until now are recommended in the clinical guidelines, even if measured in combination, turned out to be too low, making these measurements unsuitable for the annual screening for pNETs (de Laat et al. 2013, Qiu et al. 2016). In addition to plasma hormonal assessments, yearly radiological imaging studies are advised (Thakker et al. 2012). However, one must keep in mind the life-time cumulative radiation exposure when CT scans are used especially for young patients (Casey et al. 2017). Therefore, expert centers preferably use magnetic resonance imaging (MRI) (Newey et al. 2009, Thakker et al. 2012). Endoscopic ultrasound is more sensitive for identifying small tumors compared with CT scan and MRI (Langer et al. 2004, Camera et al. 2011, Van Asselt et al. 2015). However, by using EUS mainly the smaller tumors are identified, which are generally of no clinical consequences (Kappelle et al. 2017). When taking the slow growth rate of MEN1-related non-functioning-pNETs, less than two centimeters into account, one might consider a less frequent radiological surveillance schedule once tumors appear to be stable in size (Pieterman et al. 2017). The recently introduced imaging using 68Gallium-somatostatin receptor positron emission tomography (PET) seems to be suitable for identifying small tumors and metastasized disease. In addition, 18F-FDG PET/CT appeared to identify tumors of increased malignant potential. However, the clinical utility of PET imaging is not yet clear and more studies are needed (Sadowski et al. 2015, Morgat et al. 2016, Albers et al. 2017, Kornaczewski Jackson et al. 2017).
The optimal treatment for single non-metastasized functioning pNET is surgery since this offers the highest chance for definitive curative therapy. However, non-functioning pNETs are the most frequent type and the pancreas usually harbors multiple tumors (Thompson et al. 1984, Triponez et al. 2006). Functioning pNETs occur mostly in combination with other pNETs making the decision, which tumor should be removed, difficult. In addition, especially small (<2 cm) non-functioning pNETs detected through periodical screening pose a challenge for the physician. Although pNETs have an indolent course, these tumors can metastasize (Triponez et al. 2006). To prevent metastasized disease, the current clinical practice guideline suggests follow-up for NF-pNETs smaller than one centimeter unless tumors exhibit significant growth and to consider surgery for larger tumors (Thakker et al. 2012). However, since MEN1-related pNETs are often multiple and occur throughout the lives of patients, this strategy leads to multiple operations. In addition, pancreatic surgery in patients with MEN1 is associated with a high rate of short- and long-term complications (Nell et al. 2016). Recent evidence from the Dutch and French cohorts pointed out that a conservative approach for tumors up to 2 cm does not lead to a higher chance of metastasis for patients (Nell et al. 2017, Triponez et al. 2017). Therefore, a watchful waiting strategy for patients with pNETs smaller than 2 cm appears to avoid major surgery without losing oncological safety.
Reducing acid output in patients with gastrinomas can be achieved with proton pump inhibitors. Since the introduction of these agents, the Zollinger–Ellison syndrome is no longer the main reason for premature MEN1-related death. At this time, evidence for medical therapy from RCTs or controlled studies of sufficient size and methodological quality for the effectiveness of agents to prevent growth or metastatic behavior of small pNETs in patients with MEN1, such as somatostatin analogs, is not available. There is also no scientific evidence available for treatment for advanced MEN1-related pNETs. Trials of systemic antitumor therapies and other treatment modalities such as Peptide Radionuclide Receptor Therapy (PRRT) and locoregional therapy of metastasis included mainly patients with sporadically occurring tumors.
At this moment, no known clinical characteristics can predict the growth of individual tumors, which hampers tailored patient care. Therefore, treatment decisions regarding pNETs in MEN1 should be discussed in multidisciplinary tumor boards with special MEN1 expertise and are currently based on ‘simple’ clinical characteristics such as tumor size and growth (Thakker et al. 2012, Yates et al. 2015). However, prediction of tumor behavior for individual patients is not possible. Since liver metastasis caused by pNETs are an important reason for premature death of MEN1 patients, future research should focus on identifying driving factors for tumor behavior as well as the identification of those patients at risk for future liver metastases (Conemans et al. 2017). Future research should therefore be based on the earlier recognized need of circulating multianalyte biomarkers and the clinical use of miRNA and circulating tumors cells that would allow for accurate characterization of the evolution of these tumors (Oberg et al. 2015).
Pituitary tumors
Pituitary tumors (PIT) are the third most common MEN1 manifestation with a reported prevalence of 20–65 (Ballard et al. 1964, Vasen et al. 1989, O’Brien et al. 1996, Verges et al. 2002, de Laat et al. 2015) The median age for development of PIT is around the fourth decade, although cases as young as five years of age have been described (Carty et al. 1998, Stratakis et al. 2000, de Laat et al. 2015, Giusti et al. 2017). In general, these tumors are mostly benign, but can cause significant morbidity. Clinical symptoms depend on the type and presence of hormonal hypersecretion, the presence of hypopituitarism and the size of pituitary tumors. Pituitary macroadenoma can cause ophthalmologic symptoms, especially visual impairment because of compression of the optic chiasm (Dekkers et al. 2006, 2007). Symptoms related to hormone secretion comprise reduced fertility, amenorrhea, galactorrhea in women with prolactinoma and reduced fertility and impotence in men with prolactinoma. Other hormone secretion-related manifestations include Cushing’s disease and acromegaly caused by corticotroph and somatotroph adenomas, respectively.
Pharmacological treatment of PIT depends on the type of hormone secretion. Treatment for prolactinomas is by dopamine agonists, whereas somatotroph adenomas can be medically treated by somatostatin analogs and the newer growth hormone receptor antagonist Pegvisomant (Trainer et al. 2000).
MEN1-associated PIT were considered more aggressive than sporadic PIT, and more often unresponsive to medical treatment (especially in prolactinomas) necessitating earlier surgery (O’Brien et al. 1996, Verges et al. 2002, Trouillas et al. 2008, Thakker et al. 2012). For this reason, screening for PIT was introduced in the clinical practice guidelines for MEN1 (Thakker et al. 2012).
According to the current clinical practice guideline, screening for PIT is performed by annual testing of prolactin and IGF-1, and MRI every three years (Thakker et al. 2012). Intensive radiological screening appears to reveal pituitary incidentalomas, significance of which is still largely unknown (Dekkers et al. 2006, de Laat et al. 2015). Incidental microadenomas are reported in up to 10% of normal population (Molitch 2009, Freda et al. 2011, Scangas & Laws 2014). In a recent study, the impact of screening for PIT among MEN1 patients was evaluated. PIT was diagnosed in approximately 40% of the MEN1 patients, of whom 50% were diagnosed by MEN1-related screening. The incidence of PIT in the screening program was 34 per 1000 patient years (de Laat et al. 2015). Almost 50% of pituitary tumors diagnosed during screening, were non-functioning microadenomas. Only very few microadenomas showed minimal growth and the prolactinomas responded very well to medical treatment (de Laat et al. 2015).
These findings were confirmed in a recent Italian cohort in which 178 (44.0%) patients developed PIT. In 56 patients, PIT was the first MEN1 manifestation. In patients in whom a PIT was diagnosed in the course of follow-up, both small microadenomas (63%) and non-functioning tumors (20.2%) were found. Most patients were successfully managed by pharmacological treatment (57.3%) or a watchful waiting strategy (25.3%) (Giusti et al. 2017).
In conclusion, in contrast to earlier studies, more recent studies on PIT in MEN1 patients show that these tumors usually respond well to medical treatment regimes, in line with PIT occurring in the general population. The benefits of frequent screening for PIT by imaging seem questionable as this mainly results in the detection of incidentalomas that do not require treatment. Non-functioning microadenoma in patients with MEN1 can be treated according to the same guidelines as sporadic incidentalomas of the pituitary gland (Freda et al. 2011).
Thymic neuroendocrine tumors
Prevalence of thymic NET among MEN1 patients is relatively low and reported between 2.8 and 8.0% (Teh et al. 1997, Gibril et al. 2004, Ferolla et al. 2005, Goudet et al. 2009, Pieterman et al. 2009). Most cohorts report that thymic NET occur predominantly in men with a mean age around the fifth decade (Teh et al. 1997, Gibril et al. 2003, Ferolla et al. 2005, Sakurai et al. 2007, Habbe et al. 2008, Goudet et al. 2009, de Laat et al. 2014) in contrast with previous studies, a Japanese study reported a relatively high percentage (36%) of women in their cohort of MEN1 patients with a thymic NET (Sakurai et al. 2013).
Despite the low prevalence, thymic NET has become increasingly important in the epidemiology of MEN1. Thymic NETs are one of the most important causes of MEN1-related mortality, second to metastasized pancreatic NET (Goudet et al. 2010, Ito et al. 2013, de Laat et al. 2016). In a study from the French Groupe d’etude des Tumeurs Endocrines (GTE), malignant thymic NET was the manifestation with the highest risk of mortality among MEN1 patients (Goudet et al. 2010).
Thymic NET is usually asymptomatic until the late stage of the disease, and neuroendocrine tumor markers are generally not elevated (Gibril et al. 2003, Ferolla et al. 2005, Goudet et al. 2009). Therefore, radiological screening every one to two years by CT or MRI scan is currently advised (Thakker et al. 2012). However, up to now, it is unclear if this intensive radiological screening is frequent enough to diagnose the often aggressively behaving thymic NET at an early stage to lead to a survival benefit. At the other hand, the total MEN1 population is exposed to intensive radiological screening for timely diagnosing a thymic NET in very few patients in every year of follow-up (Singh et al. 2016). Because of its aggressive behavior, prophylactic surgery of the thymus is recommended by several authors (Dotzenrath et al. 2001a, Goudet et al. 2001, Lambert et al. 2005, Norton et al. 2008, Thakker et al. 2012, Pieterman et al. 2014). At present, prophylactic thymectomy is usually performed through a cervical incision at the time of parathyroid surgery. In the Dutch cohort, none of the 97 patients who underwent prophylactic surgery of the thymus developed a thymic NET during a median follow-up of 8 years (range 0–40 years), and a median age of 47 years (range 20–78 years) at the end of follow-up (de Laat et al. 2014). However, a cervical thymectomy is often not complete and sporadic cases of thymic malignancies after a prophylactic cervical thymectomy have been reported (Burgess et al. 2001, Lim et al. 2006, Habbe et al. 2008). Thymic NET is primarily treated by surgery. Evidence for both (neo) adjuvant and palliative chemotherapy in thymic NET are scarce and often not specific for MEN1 patients. Chemotherapeutic treatment that has been used for thymic NET include cisplatin, etoposide and 5 fluorouracil (Oberg & Jelic 2009, Singh et al. 2015). Somatostatin analogs might improve the symptoms and are associated with tumor regression in some cases (Tomassetti et al. 2000).
Pulmonary endocrine tumors
Prevalence of pulmonary NET is reported between 1.4 and 13.3%, with a higher incidence of lung NET since the introduction of radiological screening for thymic and lung NET (Dotzenrath et al. 2001a,b, Pieterman et al. 2009, Goudet et al. 2010, de Laat et al. 2014). The prognosis of lung NET is generally favorable and mortality from lung NET is sporadic, in which some series report no mortality after more than 10 years of follow-up (Teh et al. 1997, Dotzenrath et al. 2001a,b, Sachithanandan et al. 2005, Goudet et al. 2010, de Laat et al. 2014, Bartsch et al. 2016). Pulmonary NETs are mainly stable tumors (de Laat et al. 2014, Bartsch et al. 2016). Tumor diameter of pulmonary NETs increased by only 17% per year (doubling time 4.5 years). Doubling time in male patients appeared to be higher than that in female patients (2.5 vs 5.5 years) (de Laat et al. 2014).
Up to now, the treatment of pulmonary NET has primarily been surgical. However, there is no evident survival benefit from surgery in these indolent tumors (de Laat et al. 2014). Recent findings might reveal potential new mechanism for pharmacological control for growth of pulmonary NETs. In a cohort of pulmonary NETs occurring in the general population with a somatic mutation of the MEN1 gene in the tumor, a correlation was found between MEN1 mutations and the overexpression of human epidermal growth factors receptors (HERs) (Lattanzio et al. 2016). If expression of HERs are elevated in MEN1 patients, has not yet been confirmed, but this finding suggests that HER inhibitors might have a potential for clinical use in pulmonary NET. A new class of anti-cancer drugs that might be promising in treatment of pulmonary NETs are inhibitors of epigenetic pathways. In a recent in vitro study, such epigenetic pathway inhibitors demonstrated to be very promising in decreasing proliferation of NET (Lines et al. 2017).
Adrenal tumors
Adrenal involvement has been described in patients with MEN1. The incidence of adrenal involvement varies from 5% in early series to 73% in more recent studies (Trump et al. 1997, Carty et al. 1998, Langer et al. 2002, Vierimaa et al. 2007, Waldmann et al. 2007, Schaefer et al. 2008, Pieterman et al. 2009, Gatta-Cherifi et al. 2012). The majority of adrenal lesions are non-functional and include cortical adenomas, hyperplasia, multiple adenomas, nodular hyperplasia or cysts. Bilateral hyperplasia is also commonly described (Schaefer et al. 2008, Gatta-Cherifi et al. 2012).
ACTH-independent Cushing’s syndrome and primary hyperaldosteronism are the most encountered clinical syndrome in the presence of an adrenal lesion and cortical hyperfunction (Waldmann et al. 2007, Schaefer et al. 2008, Gatta-Cherifi et al. 2012). Pheochromocytomas are reported in patients with MEN1, but remain rare (Waldmann et al. 2007, Schaefer et al. 2008). Adrenocortical carcinomas (ACC) are described in several series and seem to occur more frequently in patients with MEN1 than in a group of sporadic adrenal tumors. In one study, ACC was present in 13.8% of adrenal lesions (Gatta-Cherifi et al. 2012), which is line with other studies (Skogseid et al. 1995, Waldmann et al. 2007). Sporadically, hyperandrogenemia occurs in association with ACC.
The age at diagnosis of adrenal tumors in most series is in the fifth decade (Skogseid et al. 1995, Vierimaa et al. 2007, Waldmann et al. 2007, Gatta-Cherifi et al. 2012), but adrenal involvement has also been described under the age of 20 years (Goudet et al. 2015).
Adrenal lesions are usually identified through CT, MRI or endoscopy in the course of follow-up of screening of MEN1-related manifestations. The clinical guideline suggests annual screening when adrenal lesions are present due to a prevalence of 13% of ACC in MEN1 patients with adrenal lesions reported in one study (Gatta-Cherifi et al. 2012, Thakker et al. 2012). Biochemical testing should be undertaken when an adrenal lesion larger than 1 cm is present or in symptomatic patients with signs of hormonal overproduction. Biochemical investigation consists of a low-dose dexamethasone suppression test, plasma renin and aldosterone concentrations, plasma or urinary catecholamines and/or metanephrines (Thakker et al. 2012).
The majority of patients will only undergo regular follow-up with imaging studies. Since ACC was found to be more prevalent in patients with MEN1 and has a weak, but evident impact on mortality due to aggressive tumors (Skogseid et al. 1995, Schaefer et al. 2008, Goudet et al. 2010, Gatta-Cherifi et al. 2012), management of adrenal lesion should be in line with this finding. Indications for adrenal surgery are adrenal lesions with a diameter greater than 4 cm; lesions with atypical or suspect radiological features or a progressive lesion over a 6-month interval adrenal tumors (Schaefer et al. 2008, Gatta-Cherifi et al. 2012, Thakker et al. 2012).
Breast cancer
In 2014, breast cancer was identified as a MEN1 manifestation. In the Dutch MEN1 population, the relative risk for breast cancer was 2.83 in females with MEN1. In addition, breast tumors from MEN1 patients showed loss of heterozygosity (LOH) at the MEN1 locus. This clinical observation was validated in three independent MEN1 cohorts from France, Australia and the United States (Dreijerink et al. 2014). Further research did not demonstrate that other endocrine risk factors or general risk factors were associated with the increased risk and confirmed that MEN1-related breast cancer is diagnosed at an average age of 48 years, which is significantly younger compared with the general population (van Leeuwaarde et al. 2017).
The MEN1 gene product, menin, appears to have a dual role in breast tumorigenesis. In accordance with the observations in female MEN1 patients, genetic loss-of-function MEN1 mouse models show increased incidence of both in situ and invasive mammary cancer (Seigne et al. 2013). However, in sporadic breast cancer, menin seems to have a proliferative function. In breast cancer cell lines, menin is a co-activator of the estrogen receptor alpha, a critical driver in approximately 70% of sporadic breast cancer cases. Menin has been reported to be involved in resistance to endocrine therapy (Dreijerink et al. 2006, Imachi et al. 2010).
In addition to the LOH in a subset of samples, expression of menin was reduced in 80% of MEN1-related breast cancer samples. In contrast, in only 5% of sporadic breast cancer samples no menin was found by immunostaining (Dreijerink et al. 2014). Silencing of the MEN1 gene in primary human mammary luminal progenitor cells did reveal an anti-proliferative role for menin, further supporting distinct roles in sporadic versus MEN1-related breast cancer (Dreijerink et al. 2017).
Currently, there is no guideline regarding breast cancer screening in MEN1 patients. A recent report addressing this issue formulated an advise based on the increased risk, the early age of breast cancer onset and the absence of other breast cancer risk factors or familial risk in females with breast cancer and MEN1 (van Leeuwaarde et al. 2017). Since the majority of MEN1-related breast tumors were of the luminal type, which is prognostically favorable, screening biennially from the age of 40 years is considered justifiable. This advice results from the mean age of breast cancer in the different MEN1 cohorts and is in concordance with a study assessing the harms and benefits of different screening strategies (van Leeuwaarde et al. 2017). Annual screening from the age of 40 years in women with a twofold to fourfold increase in breast cancer risk was found to have similar or even more favorable harm/benefit ratios as biennial screening of women with average-risk from 50 to 74 years of age, which seems directly applicable for women with MEN1 with a relative risk of 2.83. International collaborations should be initiated now to assess the effect of breast cancer screening in females with MEN1 in which the prevention of advanced breast cancer by early diagnosis is weighed against the potential harms as a consequence of overdiagnosis and unnecessary invasive follow-up (van Leeuwaarde et al. 2017).
Future challenges and considerations
Considering the recent update of the clinical guidelines, ongoing MEN1 publications and the finding of breast cancer as a new MEN1-related manifestation, one can conclude that the MEN1 landscape is still evolving. However, there are some challenges in addressing underexposed topics, increasing population sizes by constructing national MEN1 registries, international collaborations and working toward individualized MEN1 care.
Quality of life/psychosocial aspects
A fundamental, but up to now, underexposed topic remains the quality of life and the psychosocial impact of MEN1. The often young age at diagnosis and subsequent life-long screening with inevitable treatments, might lead to psychological distress and perished quality of life. One study reported a mean number of 3.2 surgical treatments for a MEN1 patient and 61% of the patients had 3–7 surgeries (Berglund et al. 2003). Moreover, MEN1 is not solely a disease affecting one individual, but the autosomal dominant inheritance pattern gives rise to a theoretical carrier ship of 50% of family members. In other hereditary cancer syndromes with a similar inheritance patter, such as Li-Fraumeni, patients worried more about affected family members than about themselves. The degree of cancer worry was already considerable in those patients and warrants for more emphasis and care for patients with high levels of worry and psychological distress (Lammens et al. 2010).
Up to now, one single-center study addressed the quality of life in patients with MEN1. In comparison with the general Swedish population, MEN1 patients reported significantly lower levels of General Health and Social Functioning on the Health Related Quality of life Short Form 36 (Berglund et al. 2003). Another study addressed the quality of life in MEN1 patients after pancreatoduodenal surgery. Global quality of life scores showed no difference from the general population, but interestingly, MEN1 patients had more financial difficulties caused by their physical condition and medical treatment (You et al. 2007). These studies give more insight in the impact of MEN1 and stretch out the need for more studies focusing on this topic.
Personalized MEN1 care
Current guidelines for clinical care provide an excellent clinical guidance for diagnosis, screening and treatment of MEN1-related tumors (Brandi et al. 2001, Thakker et al. 2012). However, guidelines are population based and only limitedly suitable for personalized care, which in general comes down to the physician and his team of experts. Future research should ideally focus on biomarkers for early diagnosis and importantly predictors of disease progression. In case of MEN1, these markers should differentiate between the various MEN1-related manifestations, which can be considered challenging. Circulating multianalyte biomarkers, the clinical use of miRNA and circulating tumors cells are promising novel tools to accurately characterize the evolution of these tumors in the future (Oberg et al. 2015). Reducing the number of imaging studies, especially CT scans, would be major improvement in the follow-up.
National registries and international collaborations
Performing research of the highest level of scientific evidence in a rare disease such as MEN1 remains a challenge due to the low incidence and prevalence of the disease. The limited number of patients and low occurrence of disease-specific events complicate performing randomized controlled trials. Therefore, cohort studies, as next best level of evidence are regularly performed to answer relevant MEN1-related research questions. To achieve the most optimal population size in order to gain more scientific power, nationwide cohort studies are indispensable. Recently, results from an Italian nationwide cohort study were published, which included data from 14 referral centers from 12 different Italian cities (Giusti et al. 2017). Other European countries with national MEN1 databases are the Group d’etude des Tumeurs Endocrine in France and the Dutch MEN1 Study Group (DMSG) in The Netherlands. These cohorts comprise respectively 924 and 393 MEN1 patients in their national registries (Goudet et al. 2015, van Leeuwaarde et al. 2016).
To gain more insight in the natural course of the disease, improve management strategies and work toward more targeted treatment, efforts to build and maintain these national registries seem at hand. Ultimately, international collaboration based on these national research groups can be formed, which will lead to larger MEN1 populations and hereby improved scientific possibilities that will lead to better care for the individual patient. Patient advocacy groups should be part of the national study groups since these parties represent the MEN1 patients and are closely involved in MEN1 patient care. In conclusion, collaborations on national and international levels will improve our knowledge and hereby management for patients with MEN1.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this review.
Funding
This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.
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