MULTIPLE ENDOCRINE NEOPLASIA TYPE 1

Carolina R.C. Pieterman MD, PhD, Endocrinologist, Department of Endocrine Oncology, University Medical
Center Utrecht, Utrecht, the Netherlands. [email protected]. corresponding author
Rachel S. van Leeuwaarde, MD, PhD, Endocrinologist, Department of Endocrine Oncology, University
Medical Center Utrecht, Utrecht, the Netherlands. [email protected]
Medard F. M. van den Broek, MD, PhD, Endocrinologist in training, Department of Endocrine Oncology,
University Medical Center Utrecht, Utrecht, the Netherlands. [email protected]
Bernadette P.M. van Nesselrooij, MD, Clinical geneticist, Department of Medical Genetics, Wilhelmina
Children’s Hospital, University Medical Center Utrecht, Utrecht, the Netherlands.
[email protected]
Gerlof D. Valk, MD, PhD, Endocrinologist, Department of Endocrine Oncology, University Medical Center
Utrecht, Utrecht, the Netherlands. [email protected]

Received December 20, 2021

ABSTRACT mainstay of treatment, and is indicated in non-

gastrinoma functional PanNETs and NF-PanNETs
Multiple Endocrine Neoplasia Type 1 (MEN1) is a rare >2cm or with progression during follow-up. No
autosomal dominantly inherited endocrine tumor consensus exists on the surgical treatment of MEN1-
predisposition syndrome, caused by mutations in the related gastrinoma. MEN1-related dpNETs are
MEN1 gene. Cardinal manifestations are primary currently detected at earlier stages and more indolent
hyperparathyroidism (pHPT), pituitary adenomas small dpNETs are seen. The main challenge is to
(PA), and neuroendocrine tumors (NETs) of the identify patients at risk for an aggressive disease
pancreas (PanNET) and duodenum. Other course. Thymic NETs (2-8%) occur predominantly in
manifestations are NETs of thymus, lung, and males and have a poor prognosis. Bronchopulmonary
stomach, adrenal tumors, and an increased breast NETs are more frequent than previously thought,
cancer risk in women. Malignant NETs are the most occur in both sexes, and are usually indolent although
important cause of disease-related mortality, mainly cases with a deviant progressive course occur.
NF-PanNETs, gastrinomas and thymus NETs. MEN1 Adrenal tumors are mostly indolent non-functioning
can be diagnosed genetically and a clinical diagnosis adenomas, but adrenocortical carcinomas and
in patients with negative comprehensive testing has pheochromocytomas do occur. Women with MEN1
been debated. Timely recognition of MEN1, referral for have an increased (RR 2.8) risk of breast cancer, at a
genetic testing and swift cascade screening is younger age than the general population. Given the
essential. MEN1-related pHPT (penetrance >95%) is complexity of the disease, it is strongly advised that
a multiglandular disease and recurrence after initial patients, whenever possible, be followed and treated
operation is to be expected. Subtotal in centers of expertise.
parathyroidectomy is the preferred initial operation.
Prolactinomas are the most prevalent PA in MEN1,
followed by non-functioning (NF) PAs. Treatment and
treatment results do not differ from sporadic PAs. Life-
time penetrance of duodenopancreatic NETs is >80%.
NF-PanNETs are most frequent, followed by
gastrinomas and insulinomas. Surgical resection is the

www.EndoText.org 1
INTRODUCTION duodenum (dNET) (2). These tumors are considered
the cardinal manifestations of the syndrome. Besides
Multiple Endocrine Neoplasia Type 1 (MEN1) is an the cardinal manifestations, patients with MEN1 are at
inherited endocrine tumor predisposition syndrome. a higher risk for developing NETs of the thymus, lung,
The prevalence is estimated at 1 in 20.000 to 1 in and stomach. In addition, there is a higher risk for
40.000, and is therefore considered a rare disease (1). adrenal tumors and a higher risk for developing breast
The syndrome predisposes mutation carriers to cancer in women (3, 4). Next to these endocrine
develop several endocrine tumors (Figure 1) with a manifestations, patients are at risk for developing
high lifetime incidence of primary hyperparathyroidism several non-endocrine lesions of the skin and
(pHPT), pituitary adenomas (PA), and neuroendocrine subcutaneous tumors such as lipomas.
tumors (NETs) of the pancreas (PanNET) and

Figure1. Manifestations of MEN1

After identification of the causative MEN1 mutation an Because of paucity of scientific evidence, these
intensive lifelong surveillance program follows, if guidelines were mainly based on expert opinion.
possible, starting at childhood because of the high life- Although more evidence was available, the updated
time risk for developing tumors (2). This intensive clinical guidelines of Thakker, et al. which were
follow-up is aimed at early detection of tumors to published in 2012 were also written in the absence of
enable timely interventions in order to prevent robust scientific evidence (2). However, publishing the
complications and metastases of tumors and thereby clinical practice guidelines led to more structured care
preventing premature death and improving the quality of patients, which facilitated studies of the natural
of the life of patients. In 2001 the first set of clinical course of the disease and the effect of follow-up and
practice guidelines was published by Brandi et al (5). treatment strategies. Therefore, in the last two

www.EndoText.org 2
decades large and sometimes nation-wide MEN1 When a sequence variant is identified in the MEN1
cohort studies were initiated which led to new insights gene this is classified by the genetic laboratory as
into the course of the disease and knowledge about either benign or likely benign (which is considered a
more optimal follow-up and treatment. However, to “negative” result i.e., no disease-causing variant is
date there remains a paucity of prospective data from found, clinically similar to no sequence variant
interventional trials designed specifically for MEN1 identified), as a VUS (uncertain if the variant is disease
patients. causing) or as pathogenic or likely pathogenic (which
is considered a “positive” result, a disease-causing
GENETICS variant is found). Especially new non-truncating
(mostly missense) mutations may be difficult to
The MEN1 gene (OMIM 613733 (gene) and OMIM classify (12).
131100 (phenotype)), identified in 1997 (6, 7),
consists of 10 exons and is localized on chromosome The approximate prevalence of MEN1 has been
11q13. Exon 1, the 5’ region upstream of exon 2 and reported as 1 in 30,000 individuals with no apparent
the 3’ region of exon 10 are non-coding, so there are gender bias. MEN1 follows an autosomal dominant
9 coding exons (exons 2 through 10). The MEN1 gen pattern of inheritance with >95% penetrance by age
encodes the protein menin, a 610 amino-acid nuclear 40–50 years (11). The cardinal clinical manifestations
scaffold protein that regulates gene transcription by of MEN1 are primary hyperparathyroidism (pHPT),
coordinating chromatin remodeling. anterior pituitary adenomas (PA), and NET of the
duodenum and pancreas, the so called three P’s.
In 2008, Lemos and Thakker published an overview of
the 459 different germline mutations reported in the If a patient is diagnosed with MEN1, he or she should
first decade since the discovery of the gene (8). In be advised to undergo screening to detect
2016, Concolino, et al. identified an additional 208 manifestations and remain under lifelong surveillance
novel germline variants, of which 76 were reported as in a center of expertise where care is provided by
Variant of Unknown Significance (VUS) (9). Around multidisciplinary teams (MDTs) comprising relevant
40% of all identified mutations are frameshift specialists with experience in the diagnosis and
mutations, 25% nonsense, 20% missense, 10% treatment of patients with endocrine tumors (2).
splice-site, and the remainder 5% are rarer mutations
such as in-frame deletions/insertions and partial or Single center cohorts have identified certain
whole gene deletions (10). Frameshift, nonsense, and genotypes that are associated with a more aggressive
splice-site mutations, which are the majority, are course of the disease (especially related to
predicted to be loss of function mutations that lead to duodenopancreatic NETs), such as mutation in the
truncated forms of menin (8). The variants are JUND (13) or the CHES1 (14) interacting domain or
scattered throughout the MEN1 gene with no evident nonsense/frameshift versus missense mutations (15),
hotspots, although some mutations are found in but since none of these associations have been
apparently unrelated families. This is considered to be independently validated, genotype cannot be used to
a founder effect (11). Sequence analysis of the MEN1 individualize surveillance.
gene will reveal most of the variants. Since 1-2% of
the variants are (partial) deletions of the MEN1 gene Evaluation of 10 Dutch families suggest genetic
(8), multiplex ligation-dependent probe amplification anticipation (decreased age of disease onset or an
(MLPA) or Copy Number Variation (CNV) analysis increased disease severity in successive
should also be included in the diagnostic DNA testing. generations), a known phenomenon which to date
cannot be explained in autosomal dominant inherited

www.EndoText.org 3
disease genes without trinucleotide repeat expansions MEN1-related tumorigenesis is likely to be the result
(“growing genes”) (16). Somatic mosaicism with of aberrant tumor suppressive gene expression due to
subsequent germline inheritance has been described the loss of menin. Restoration of the expression of
(17). menin target genes in MEN1-affected tissues could
therefore have therapeutic consequences. This has
Function of the MEN1 Gene been shown in a preclinical study in mice, where
MEN1 replacement in pituitary tumors of Men1 (+/-)
MEN1 is considered to act as a tumor suppressor mice led to a decrease in proliferation of the pituitary
gene which is demonstrated by the identification of tumors (21).
inactivating mutations, together with loss of
heterozygosity (LOH) in MEN1-related tumors. DIAGNOSIS AND GENETIC TESTING
Biochemical, proteomics, genetics and genomics
approaches have identified various potential roles, Diagnosis of MEN1
which converge on the regulation of gene expression.
The most consistent findings show that menin Patients with MEN1 are at risk to develop different
connects transcription factors including JUND (OMIM endocrine and non-endocrine manifestations. The
165162), NFKB (OMIM 164011), and SMAD3 (OMIM most important of which are (with approximate lifetime
603109) and modulates their activities. In the nucleus, prevalence in parentheses):
menin acts as a scaffold protein to regulate gene • Cardinal manifestations/Major criteria: pHPT
transcription by coordinating chromatin remodeling (>95%), duodenopancreatic NETs (dpNETs)
interacting with chromatin regulatory proteins in the (>80%) and anterior pituitary tumors (50–65%)
MLL1 /MLL2 complex. Menin is implicated in both • Minor clinical criteria: adrenal adenomas (11–
histone deacetylase and histone methyltransferase 35%) and bronchopulmonary, thymic, and gastric
activity (HMT), and via the latter it regulates the NETs (20–30%) (22, 23).
expression of cyclin-dependent kinase inhibitor (CDKI)
and homeobox domain genes (18, 19). While the Additionally, there might be an association with
MEN1 gene functions as a tumor suppressor gene in meningioma (<10%). Cutaneous manifestations such
MEN1, it has an oncogenic role in sporadic breast as subcutaneous lipomas (but visceral, pleural, or
cancer cells (18). Some excellent reviews on the retroperitoneal lipomas have also been described),
function of the MEN1 gene can be found elsewhere facial angiofibromas (22-88%) and collagenomas (0-
(11, 18, 20). 72%) are also seen (2). Women with MEN1 have a 2-
3-fold elevated risk of developing breast cancer (3, 4).
Potential Therapeutic Opportunities (18)
Presently, MEN1 can be diagnosed genetically by
Loss of menin in MEN1-associated tissues, leads to identifying the germline heterozygous (likely)
the disruption of anti-proliferative gene expression pathogenic variant in the MEN1 gene through DNA
programs and to the development of endocrine analysis. According to the guidelines, a diagnosis of
tumors. Restoration of the epigenetic perturbations or MEN1 can also be made on familial grounds in a
correction of the function of aberrantly expressed patient with one of the cardinal MEN1 manifestations
genes in the absence of menin hold promise for and a first-degree family member with MEN1 (2).
molecular mechanism-based means to treat or Additionally, a clinical diagnosis can be made in
prevent MEN1-related tumors. The fate and function individuals with two of the three cardinal
of a cell are determined by its gene expression manifestations (2). However, with modern-day
signature. As menin is a transcriptional regulator, sensitive DNA testing, the value of the clinical criterion

www.EndoText.org 4
in patients with negative DNA testing is under debate. The authors developed a nonogram for clinical
There is mounting evidence that patients who have practice, allowing the clinician to calculate the risk of
clinical MEN1, but negative DNA testing have a MEN1 in patients suspected of MEN1 with
different clinical course from patients with positive sporadically occurring endocrine tumors (29).
DNA testing (24, 25). The same could also be argued
for patients with a familial diagnosis with negative DNA DNA Testing
testing for the family mutation, as these may have a
sporadically occurring endocrine tumor. This subject is According to current practice guidelines diagnostic
discussed in more detail in the paragraph on genetic DNA testing for MEN1 should be offered to (2):
heterogeneity. • all patients fulfilling the diagnostic criteria of a
clinical or familial MEN1 diagnosis
Patients with MEN1 suffer from high morbidity and a • all patients with a pHPT under the age of 30 or
decreased life expectancy. In the present day and multiple (synchronous) parathyroid adenomas
age, MEN1-related malignancy is the main MEN1- under the age of 40 or recurrent parathyroid
related cause of death, particularly due to adenomas
duodenopancreatic and thymic NETs (26, 27). A • patients with a gastrin-producing NET (irrespective
timely and accurate diagnosis of MEN1 is paramount the age of presentation)
to improve disease outcomes. This enables early • patients with multiple PanNETs (irrespective the
identification of tumor manifestations allowing timely age of presentation)
treatment to reduce morbidity and improve survival • patients with two different minor criteria
(28). • a patient with an MEN1-related tumor with a
positive family history of MEN1-related tumors
It is therefore important for clinicians to consider the
diagnosis of MEN1 not only in those patients meeting Once MEN1 is diagnosed in the proband, genetic
clinical or familial criteria, but also in patients with a counseling and DNA testing should be offered to
suspicious family or personal medical history, but not family members, preferably by means of cascade
meeting clinical or familial diagnostic criteria. In screening. Data from the DutchMEN Study Group
patients presenting with an endocrine tumor within the (DMSG) emphasize the importance of timely genetic
MEN1 spectrum, taking a family history of MEN1- testing of family members and prompt clinical
related tumors is very important. Additionally, a young screening according to MEN1 guidelines. In a study
age at presentation or multifocality of tumors within a determining lag time between MEN1 diagnosis in
single organ may point to a diagnosis of MEN1. The index cases and their non-index family members, they
combination of a major and minor criterion or two found a median lag time of 3.5 years (range 0-30)
minor criteria should also raise suspicion of MEN1. In years, in which clinically significant manifestations
all these cases of suspected MEN1, the patient should occurred in the non-index family members with MEN1
be referred to a clinical geneticist or genetic counselor (30). Genetic testing in asymptomatic family members
for counseling and consideration of DNA testing. For of MEN1 patients is called pre-symptomatic or
patients presenting with sporadically occurring predictive genetic testing and involves testing the at-
endocrine tumors, de Laat, et al. developed and risk family members for the familial MEN1 mutation.
validated a prediction rule to predict the presence of This is single-site testing, and outcome is whether the
an MEN1 mutation (29). In this model, recurrent pHPT, family mutation is present or absent in this particular
non-recurrent pHPT, dpNETs, PA, NET of the family member.
stomach, lung and thymus, a positive family history for
a NET and age, predicted the risk of having MEN1.

www.EndoText.org 5
Genetic Heterogeneity MEN1-related disease. Although not specified in the
current guidelines, these patients may benefit from a
Some studies have reported that between 5% and separate classification with alternative surveillance
10% of patient who fulfill the clinical criteria for MEN1 recommendations based on the clinical picture, as has
will not harbor mutations in the coding region or been suggested by Pieterman, et al. (25). Important
adjacent splice sites. In some of these patients a baseline considerations for an alternative surveillance
(likely) pathogenic variant can be found in the are genetic counseling, comprehensive genetic testing
CDKN1A (OMIM 600778 ), CDKN1B (OMIM 116899 based on the personal and family history, and baseline
), CDKN2B (OMIM 600431 ) or CDKN2C gene (OMIM screening to identify any unrecognized manifestations.
603369 ). Mutations in CDKN1B are the cause of the In these patients, there is generally no cause for
MEN4 syndrome, the latest of the MEN syndromes surveillance of the first-degree relatives, although
and most rare, with <50 cases reported in the literature these decisions should be individualized and
to date (31-33). Rather than being a separate discussed in multidisciplinary teams.
phenotype, (likely) pathogenic variants in these genes
are more likely to cause a MEN1 phenotype, with GN-MEN1 patients with a positive family history of
pHPT, PA and gastroenteropancreatic NETs as the clinical MEN1 or a foregut NET and those presenting
main features, and are best met with the same with all three main MEN1-related tumors, should be
guidelines for surveillance, until more is known about followed according to MEN1 guidelines as should their
the phenotype of this rare syndrome. relatives. In these patients, a “false-negative result” of
DNA testing should also be considered. This may
Recent data have shown that patients with a clinical either be because deletion/duplication analyses are
diagnosis of MEN1, in whom no (likely) pathogenic not performed, a sequence variant exists outside of
variant in the MEN1 gene can be found (genotype- the assayed region, or polymerase chain reaction
negative MEN1/GN-MEN1), and who do not have primer selection led to selective amplification of wild-
another known germline mutation, have a different type DNA (25). Additionally, somatic mosaicism or
phenotype and clinical course compared to mutation alternative mechanisms of MEN1 gene silencing could
positive patients (24, 25). Genotype-negative patients lead to inactivation of normal menin (25).
develop MEN1 manifestations at higher age, rarely
develop a third main MEN1 manifestation, and have a Depending on the presenting clinical picture and the
life expectancy comparable with the general family history, other hereditary syndromes causing
population (24, 25). endocrine tumors should also be considered.

Additionally, regarding the individual manifestations, it If pHPT is the primary phenotype, other genes
seems that GN-MEN1 patients have less recurrent or associated with hereditary pHPT are for example
multigland pHPT, less multifocal PanNETs, and more CDC73, CASR and RET (MEN2). Germline CDC73
somatotrophinomas and less prolactinomas (formerly HRPT2) (OMIM 607393) analysis is
compared to genotype-positive patients (25). Most recommended in individuals with (suspected)
patients with GN-MEN1 present with the combination Hyperparathyroidism-Jaw Tumor (HPT-JT) syndrome,
of pHPT and PA, followed by pHPT/dpNET and familial isolated pHPT, atypical or malignant
dpNET/PA (25). The apparent differences in clinical parathyroid histology, and young individuals with
course suggest that GN-MEN1 patients do not have pHPT. These criteria would increase germline CDC73
true MEN1, but another MEN1-like syndrome or mutation detection, enabling optimal clinical
sporadic co-incidence of two NETs (2, 33). In these management of pHPT as well as genetic counseling
patients there is usually a negative family history for

www.EndoText.org 6
and surveillance for family members at risk for CDKN2B, CDKN2C, CDC73 and AIP can be added to
developing CDC73-related disorders(34). the panel using NGS techniques, also to be completed
with CNV analysis, depending on the clinical picture.
If PAs are the primary phenotype, mutations in the AIP In case of panel testing, the patient must be prepared
gene (OMIM 605555) should be considered as these for the possible findings in the different genes,
can cause (familial) pituitary adenomas. Predictors of differentiation of the consequences, and implications
a genetic cause of sporadic pituitary adenomas are of these findings.
young age of diagnosis, and also in AIP pathogenic
variants there is an association with gigantism and In case of testing for a familial (likely) pathogenic
macroadenomas (35). variant (so-called presymptomatic or predictive DNA
testing) presence or absence of the familial mutation
PanNETs can also be seen in neurofibromatosis type can be ascertained, but the differences in expression
1 (NF1), Von Hippel-Lindau (VHL), and Tuberous of the MEN1 syndrome, both within and between
Sclerosis Complex (TSC). families must be emphasized.

Pretest Counseling In case of future pregnancy the possible options like

invasive prenatal diagnostics and Preimplantation
Before DNA testing, pretest counseling is of utmost Genetic Diagnosis (PGD) should be discussed so the
importance. The patient should be informed by genetic prospective parents can make an informed decision
counseling about all aspects (medical, psychological, about the desired pregnancy.
social, and familial implications) of the possible
outcome of genetic testing. This should lead to an Periodical Screening
individual decision whether or not to opt for DNA
testing. In case of DNA testing in minors the The identification of an MEN1 mutation in patients and
counseling should be offered to the parents, and family members at risk is followed by the advice to
include the minor if possible (which is obligatory over remain under lifelong surveillance, with at least annual
the age of 12 in the country where the authors practice clinic visits including history, physical examination,
(the Netherlands) to obtain informed consent for biochemical screening, and radiological screening at
testing. specific intervals (2). This should preferably be carried
out in centers of expertise with a dedicated
In case of diagnostic testing the patient must be multidisciplinary team well versed in management of
informed about the possible outcomes of the DNA test patients with MEN1. In MEN1 there are no
(finding an (likely)pathogenic variant, finding a VUS, prophylactic treatments, so the goal of this screening
and not finding (likely) pathogenic variants) and the & surveillance program is early detection of MEN1-
implications of these findings for the patient and family related tumors to minimize morbidity by hormonal
members. hypersecretion and to prevent malignant NETs by
timely intervention. In the absence of known genotype-
In diagnostic DNA testing the MEN1 gene should be phenotype correlations and with a heterogeneous
analyzed, for which Sanger sequencing can be used, clinical course, even within families, the specific
or Next Generation Sequencing (NGS) techniques. To mutation or family history cannot solely guide the
exclude deletions MLPA or CNV analysis must be surveillance program. In the following sections
performed. As mentioned earlier there is genetic screening and surveillance is discussed within each
heterogeneity and panel DNA diagnostics can be manifestation.
considered. In particular CDKN1A, CDKN1B,

www.EndoText.org 7
Screening at the Pediatric Age Primary hyperparathyroidism in MEN1 is a
multiglandular disease, affecting all parathyroid
The current clinical guidelines for MEN1 suggest glands, although often asymmetrically and
starting clinical and biochemical screening at the age asynchronously. Parathyroid tumors in adults with
of 5 years (2), which is based on the earliest reported MEN1 usually represent mono- or oligoclonal
case of a patients with a clinical MEN1 manifestation proliferations that probably arise independently in
(36). For radiologic screening in asymptomatic each parathyroid gland (50). Tumorigenesis is initiated
children, pituitary imaging is suggested from age 5 when the remaining normal allele of the MEN1 gene is
years onward (every 3 years), with abdominal imaging lost (the second hit), and as this cumulative chance
starting at age 10 years (every 1-3 years) and thoracic increases with age, normal parathyroid tissue is less
imaging starting at age 15 years (every 1-2 years) (2). often seen with increasing age (51). Supernumerary
However, this intensive surveillance at the pediatric glands (that is, more than four parathyroid glands) are
age has been questioned by some groups who frequently seen in MEN1, with reported ranges
suggest postponing routine screening of between 12-30% (52). Parathyroid glands at ectopic
asymptomatic patients until ages 15 or 16 years while locations are also not uncommon in MEN1, especially
counseling parents about typical clinical signs of in the thymus.
MEN1 manifestations and contacting providers if they
occur (37). The diagnosis of primary hyperparathyroidism can be
made when there is hypercalcemia in combination
PRIMARY HYPERPARATHYROIDISM with an elevated or inadequately normal parathyroid
hormone (PTH). In patients with MEN1 who follow a
Primary hyperparathyroidism (pHPT) (Figure 1) is one prospective screening program from an early age, the
of the cardinal manifestations of MEN1 and has an diagnosis is often made while they are still
almost complete lifetime penetrance (24, 38). It is asymptomatic. Classic objective symptoms of pHPT
often the first clinical manifestation of the disease and include polyuria and polydipsia, gastro-intestinal
biochemical (asymptomatic) pHPT can be diagnosed complaints (nausea, abdominal pain, constipation,
several years before symptoms arise. The reported pancreatitis), (symptomatic) urolithiasis, and
mean age of pHPT diagnosis in published MEN1 decreased bone mineral density (BMD) which can
cohorts is in the fourth decade of life (39-45), with wide lead to pathological fractures. Non-specific symptoms
ranges. When interpreting these mean ages at occurring in pHPT are fatigue, musculoskeletal
diagnosis it is important to realize that these cohorts complaints, neuropsychiatric symptoms such as
often span multiple decades, are made up of both anxiety, depression, concentration disturbance and
index cases and family members, and contain patients sleep-disturbances, and a general decrease in quality
who did and did not follow prospective screening of life.
programs. Recent studies reporting on MEN1 at the
pediatric age show that in a screened population at The diagnosis of pHPT in patients with known MEN1
least half of the pediatric patients already have primary or from a known MEN1 kindred is straightforward.
hyperparathyroidism, although rarely seen before the However, pHPT can also be the first clinical clue to an
age of 10 (46-49). In most cases, patients diagnosed MEN1 diagnosis in a patient or family without prior
at a pediatric age are asymptomatic and the diagnosis MEN1 diagnosis or suspected history. The prevalence
is made biochemically by screening (46-49). Clinical of pHPT in the general population can be up to 1% (53,
and symptomatic pHPT is usually seen in the third 54) and among cohorts of patients with pHPT,
decade of life. depending on the characteristics, the incidence of
MEN1 is 1-18% (2). Considering MEN1 in patients

www.EndoText.org 8
presenting with pHPT is extremely important, because most affected, so including this location in dual-energy
the diagnosis alters the management and prognosis of X-ray absorptiometry (DEXA) should be considered in
pHPT, allows screening and surveillance for other patients with MEN1 (62, 64). Parathyroidectomy
endocrine tumors associated with MEN1, and allows improves BMD (59, 65), although in one small study
for cascade screening within the family to identify improvement was less for patients with MEN1
MEN1 germline mutations carriers. Important clues to compared to patients with sporadic pHPT (59). A
an MEN1 diagnosis in a patient presenting with pHPT factor contributing to the earlier and more severe bone
are young age of onset, a family history of pHPT or involvement in MEN1-related pHPT may be the early-
other MEN1-related tumors, a personal history of other onset of the disease thereby also influencing peak
MEN1-related tumors, and multiglandular disease or bone formation. In addition, other MEN1-related
persistent/recurrent pHPT (29). Recurrent pHPT is diseases may also contribute to bone loss such as
one of the strongest predictors for the presence of an pituitary insufficiency caused by pituitary adenomas or
MEN1 mutation (29). Compared to sporadic pHPT, their treatment, hypercortisolism (although infrequent
patients with MEN1-related pHPT present at an earlier in MEN1), and gastro-intestinal surgery (66).
age, have an almost equal gender distribution
compared to female predominance in sporadic pHPT, Urolithiasis is also frequently seen and at a young age
and present with lower levels of calcium and PTH (55, in patients MEN1-related pHPT (55, 62, 64). In
56). Even though they have biochemically milder addition, a recent study showed that patients with
disease, BMD seems to be lower in patients with MEN1 age 20-59 had a higher prevalence of chronic
MEN1-related pHPT and renal involvement similar kidney disease stage 3 compared to the general US
compared to patient with sporadic pHPT, which may population (67).
reflect longer standing disease (55). MEN1-related
pHPT is a multiglandular disease, as already It is therefore important to perform Dual-energy X-ray
stipulated, while sporadic pHPT is predominantly absorptiometry (DEXA) to assess BMD as well as a
caused by single-gland adenomas (56, 57). This also renal ultrasound and 24-hour urine for calcium
affects recurrence rates which are much higher in excretion to asses risk of urolithiasis in patients with
MEN1-related pHPT (56, 57). The American MEN1 diagnosed with pHPT. And if initial observation
Association of Endocrine Surgeons (AAES) guidelines is chosen, DEXA should be repeated every 2 years
advise genetic counseling for patients younger than 40 (68).
years with pHPT and multiglandular disease and to
consider this for those with a family history or In patients with MEN1 and pHPT, the interplay with
syndromic manifestations (57). The European Zollinger-Ellison Syndrome (ZES; increased gastric
guidelines slightly differ suggesting genetic testing for acid section due to gastrinomas) is also relevant, as
MEN1 in patients with pHPT before the age of 40, calcium can increase gastrin levels. In a study among
multiglandular disease, or persistent/recurrent pHPT 84 patients with MEN1-pHPT and ZES, successful
(58). parathyroidectomy resulted in biochemical cure of
ZES without any resection of duodenal or pancreatic
When comparing, several studies show that patients NETs in 20% of the patients (69). In a recent
with MEN1-related pHPT have lower BMD compared perspective paper Hackeng and colleagues propose a
to patients with sporadic pHPT (55, 59, 60), although parathyroid-gut axis arguing that hypercalcemia may
a Chinese study found no significant difference (61). promote the gastrin-cell hyperplasia to neoplasia
In patients with MEN1-related pHPT, decreased BMD sequence through the calcium-sensing receptor (70).
is frequently seen and already present at a young age The reverse, a more severe form of pHPT among
(62-64). When measured the 1/3 distal radius seems patients with MEN1-ZES has also been suggested,

www.EndoText.org 9
because in the aforementioned study of 84 patients made others suggest and prefer early intervention to
with MEN1-pHTP and ZES, patients had a higher prevent downstream disabilities (71).
frequency of urolithiasis at presentation, higher serum
PTH, and higher recurrences rates after initial subtotal For initial parathyroidectomy in patients with MEN1
parathyroidectomy compared to the literature (69). there are theoretically four different strategies:
focused parathyroidectomy (removing a single
Parathyroidectomy affected parathyroid gland), unilateral clearance
(resection of all parathyroid tissue on one side,
The treatment of hyperparathyroidism in MEN1 is including unilateral cervical thymectomy), subtotal
surgical. Intervention is aimed at achieving parathyroidectomy with concomitant cervical
eucalcemia for as long as possible, while preventing thymectomy, or total parathyroidectomy, cervical
permanent hypoparathyroidism and facilitating thymectomy and immediate auto-transplantation of
potential subsequent surgery. parathyroid tissue (usually to the non-dominant
forearm).
The optimal timing of the initial operation is still a
matter of debate, especially in (asymptomatic) The initial operation recommended by most experts
children and young adults. The guidelines for the and guidelines is a bilateral cervical exploration,
management of asymptomatic pHPT recommend identifying all four parathyroid glands and performing
surgical intervention in case of significant a subtotal parathyroidectomy (leaving a vascularized
hypercalcemia (1 mg/dL or 0.25 mmol/L above the remnant about 1.5-2 times the size of a normal gland)
upper limit of normal), skeletal abnormalities (a T- with concomitant cervical thymectomy (2, 57, 58, 71-
score of < -2.5 at the Lumbar Spine, Total Hip, 73). The latter serves the dual purpose of removing
Femoral Neck or 1/3 Distal Radius or a vertebral any ectopic/supranumerary parathyroid glands and
fracture), risk of renal complications (creatinine potentially decreases the risk of subsequent
clearance below 60 ml/min, 24-h urine calcium development of thymic NETs. This approach offers the
excretion of >400 mg/d (>10 mmol/L)), the presence best balance between persistence (persisting pHPT
of nephrolithiasis/nephrocalcinosis, or age below 50 after operation or recurrence within 6 months after
(68). However, these guidelines are not intended for operation) and recurrence (recurrent pHPT 6 months
patients with MEN1 and most patients with MEN1 will or more after the operation preceded by a eucalcemic
meet the age-criterion regardless of other values. In period) on the one hand and permanent (lasting >6
patients with MEN1 surgery is indicated in case of months after the operation) hypoparathyroidism on the
symptoms, significant hypercalcemia, and renal or other hand. Persistence is infrequent in subtotal (0-
skeletal complications. In addition, concomitant 22%) and total parathyroidectomy (0-19%), but rates
gastrinoma may also provide an indication for surgical range from 0-53% in less than subtotal
intervention of pHPT. For patients not meeting any of parathyroidectomy(58, 72). Recurrence rates are also
these criteria, there is no evidence to determine timing significantly higher after less than subtotal
of surgery. Arguments have been made in favor of parathyroidectomy (0-100%) compared to subtotal (0-
observation to avoid the risk of symptomatic 65%) or total parathyroidectomy (0-56%) (58, 72) and
hypoparathyroidism, multiple operations, and by occur earlier (74). Permanent hypoparathyroidism on
allowing the disease to progress a little bit more, the other hand is rarely seen after less than subtotal
making the glands more easily identifiable upon parathyroidectomy. When comparing subtotal with
intervention. However, on the other hand, data total parathyroidectomy, hypoparathyroidism is
showing early bone and renal complications have significantly more frequent after total
parathyroidectomy (RR 1.61 (95%CI 1.12-2.31) (72).

www.EndoText.org 10
 excision and in retrospective studies these are often
Pre-operative imaging plays a limited role at initial lumped together under “less than subtotal” resections.
parathyroidectomy in patients with MEN1, because Thirdly, the success of such an approach is dependent
the recommended initial operation always constitutes on the sensitivity of pre-operative imaging and in most
bilateral neck exploration( 58). In addition, data has retrospective studies, more sensitive imaging
shown that pre-operative imaging (consisting of neck modalities such as 18F-fluorcholine positron emission
ultrasound and sestamibi scan as first line and tomography (PET)/CT have not been used. Finally,
parathyroid computed tomography (CT) or magnetic since in MEN1 inherently all parathyroids are affected,
resonance imaging (MRI) as second line) only although asynchronously, such an approach may be
identified 68% of the largest glands pre-operatively more successful in younger patients, where there may
(75). Pre-operative imaging may have some use for still be normal parathyroid glands (51). Currently this
identifying ectopic glands (7% of ectopic glands were approach is controversial. Therefore, prospective data
identified by pre-operative imaging in one series) and are needed to determine if and when unilateral
for identifying concomitant thyroid abnormalities that clearance can benefit patients with MEN1 at the time
need attention (71, 75). Similar, intra-operative PTH of their initial parathyroidectomy.
monitoring seems of little value during the initial
parathyroidectomy (76). Currently, subtotal parathyroidectomy remains the
initial procedure of choice, but total parathyroidectomy
Recently, several groups have advocated unilateral or unilateral clearance can be considered depending
clearance as an initial operation, especially for young on individual circumstances. Single gland excision is
patients with MEN1 (74, 77-79). The rationale behind generally not recommended.
this approach is to provide several years of
eucalcemia during acquisition of peak bone mass, After initial subtotal parathyroidectomy, the 10-year
while preventing hypoparathyroidism and allowing recurrence rate is approximately 50% (2). Reoperation
subsequent reoperations to be performed in a non- is therefore a frequent necessity in patients with
operated neck (the contra-lateral side). A prerequisite MEN1. Recurrence can be caused by parathyroid
for this strategy is that pre-operative imaging glands missed during the initial operation, parathyroid
concordantly shows unilateral disease. Intra-operative glands intentionally left in situ, growth of the remnant
PTH monitoring should be used to ensure there is an of a partially resected gland, supranumerary and/or
adequate drop in PTH after the resection. Although ectopic glands, and hyperplasia of autotransplanted
persistence rates between 10-15% after unilateral parathyroid tissue. As reoperations are more complex
clearance or single-gland excision have been reported and have a higher risk of complications (12% not
by these groups (74, 77), others state that less than including hypoparathyroidism in one study of
subtotal parathyroidectomy has an unacceptable reoperative parathyroidectomy in MEN1 (81)), the
failure rate (69% in one study) (80). Several remarks timing of the reoperation is individualized and patients
must be made when using retrospective studies to with mild biochemical recurrence are usually initially
evaluate this strategy. The first being that intentional observed. When reoperation is indicated, careful
less than subtotal resection is a different entity from an examination of the operation notes and pathology
intended subtotal or total resection in which not all reports of previous procedures, if available, is very
glands were identified (78). Secondly, true unilateral important. In contrast to the initial surgery, pre-
clearance in which all parathyroid tissue on one side operative imaging is essential for surgical planning in
of the neck is removed including unilateral cervical reoperations. First-line imaging studies are neck
thymectomy is a very different operative strategy from ultrasound and Tc99m-sestamibi scan, although this
minimal invasive parathyroidectomy/single gland may not show all enlarged glands. Second-line

www.EndoText.org 11
imaging studies are 4-dimentional CT or MRI and PET Non-Surgical Interventions
(18F-fluorocholine or 11C-methionine) (82, 83). In a
small study 18F-fluorocholine PET-CT has also shown For those patients who require intervention, but who
to be of added value in MEN1-related pHPT (84). If are not surgical candidates, cinacalcet, an allosteric
first- and second-line studies are inconclusive more agonist of the calcium receptor, can be used. It has
invasive localization studies can be considered such been shown to reduce/normalize calcium and PTH in
as arteriography, venous sampling, and neck small studies in patients with MEN1, although it has no
ultrasound with fine needle aspiration and PTH effect on bone and renal complications(87-89).
measurement (83). The exact operative strategy Cinacalcet should be used with great caution in
(bilateral or unilateral neck exploration or focused children, as a death from acute hypocalcemia has
resection) is individualized based on previous been reported in a 14-year-old (90). Another
operation(s) and results of preoperative imaging. If the alternative may be ethanol ablation of enlarged
thymus was not removed during the initial operation, parathyroid glands. A study from the Mayo Clinic
its removal is recommended at reoperation (81). Intra- reported results from 37 patients who had an average
operative PTH monitoring is valuable for the of 2.2 treatments and a mean duration of eucalcemia
reoperative setting in MEN1 as it can inform when the of 25 months. Complications were hypocalcemia in
exploration can be ended (71, 81). 8%, hoarseness in 5%, and cough in 1% (91).

As a consequence of the extended initial operation Parathyroid Carcinoma

necessary, as well as frequent reoperation, life-time
risk of postoperative hypoparathyroidism is relatively Parathyroid carcinoma is a very rare endocrine
high for patients with MEN1. Transient malignancy seen in <1% of all patients with pHPT (92).
hypoparathyroidism, defined as lasting less than six It is likewise very rare in patients with MEN1, with only
months after parathyroidectomy, may be seen in more 21 reported cases in the literature (based on a review
than 50% of patients and its absence after subtotal published in 2020) (93). In three large series from The
parathyroidectomy may even be associated with University of Texas MD Anderson Cancer Center, the
recurrence (85, 86). Rates of permanent Mayo Clinic, and The Peking Union Medical College
hypoparathyroidism are dependent on the procedure Hospital the prevalence of parathyroid carcinomas
performed and vary greatly between series. It is was 2/242 (0.8%), 1/348 (0.3%) and 1/153 (0.7%)
important to realize that, unless patients are truly respectively and the prevalence of atypical parathyroid
aparathyroid, recovery of parathyroid function can neoplasm was 1/242 (0.4%), 0, and 2/153 (1.3%)
occur after 6 months up to several years, and respectively (93-95).
permanent hypoparathyroidism may therefore be
more aptly termed “prolonged” hypoparathyroidism Conclusion
(86). To prevent hypoparathyroidism immediate
autotransplantation is used when it is suspected that In conclusion, pHPT in MEN1 has an almost complete
all parathyroid glands are resected or when there is penetrance and is responsible for most MEN1-related
concern about parathyroid tissue viability in situ (57). surgeries. It is a multiglandular disease and
Cryopreservation with delayed autotransplantation recurrence after initial operation is to be expected.
can also be used as a rescue from permanent End-organ damage (bone, renal) can occur early and
hypoparathyroidism, but is not available everywhere in asymptomatic patients and should be systematically
and its use has been under debate (57). looked for. Recognizing MEN1 in a patient presenting
with apparently sporadic pHPT has important
consequences for both the patient and his/her family.

www.EndoText.org 12
Surgical decision making is complex both for initial and presenting with a PA (2, 35). Obviously, MEN1 should
reoperations and patients with MEN1 should be considered in a patient with a family history of
whenever possible be treated in centers of expertise MEN1-related tumors or presenting with other MEN1-
by a high-volume endocrine surgeon. Treatment related tumors. For patients with apparently sporadic
decisions are made by multidisciplinary teams in PAs (no suspicious family history or syndromic
shared decision making with the patient taking into features), a recent systematic review has shown that
account not only medical information but also the MEN1 mutation analysis is recommended in patients
patient’s individual situation, such as but not limited to, ≤ 30 years, although this was a weak recommendation
ability to adhere to follow-up and insurance issues. based on low quality of evidence (35).

PITUITARY ADENOMAS Characteristics of Pituitary Adenoma in MEN1

In 1903, the first description of a case with MEN1 was From the earliest descriptions of MEN1 in the 1950s
published by Erdheim. The necropsy report of a PAs have been recognized as one of the main
patient with acromegaly revealed a pituitary adenoma characteristics of the syndrome. However, since the
and enlarged parathyroid glands (96). Pituitary original description of MEN1, the clinical picture of
adenomas (PAs) are one of the three cardinal features MEN1-related PAs has changed. In a summary of the
associated with MEN1 and part of the so-called ‘three first 85 reported cases of MEN1 (many of which were
Ps’ (Figure 1). PAs are in general benign lesions and autopsy cases), Ballard found a very high prevalence
do not seem to negatively affect survival in patients of 65% of PA, with 42% being chromophobe
with MEN1(26), although cases of mortality due to PAs adenomas and more than one in four being
have been reported (27). However, they can cause acromegaly/eosinophilic adenoma (108). With the
significant morbidity due to mass effect on the optic discovery of prolactin, it was soon realized that in fact
chiasm or hormone secretion leading to functional prolactinomas were the most frequently occurring PA
symptoms or hormone deficiency. in patients with MEN1. The discovery of the MEN1
gene in 1997 (6, 7), and more advanced genetic
As in other main manifestations of MEN1, loss of testing techniques such as NGS and MLPA, have
heterozygosity (LOH) at the MEN1 locus has been allowed better identification of patients as having
demonstrated in pituitary adenomas in patients with MEN1. This has led to the recognition that patients
MEN1, confirming the role of MEN1 in the with a clinical diagnosis of MEN1 because they have
pathogenesis of these tumors (97-100). However, in two out of the three main MEN1-related tumors, but
contrast to PanNETs, the role of MEN1/menin in negative mutation analysis, have a different clinical
tumorigenesis of sporadic PAs seems to be limited. course than mutation positive patients and arguably
Although initially, before the identification of the MEN1 do not have true MEN1, but rather an MEN1-like
gene, 19-33% of sporadic PAs showed allelic loss on syndrome or a co-occurrence of two sporadic tumors
chromosome 11 (101, 102), subsequent studies (24, 25). Most patients in this group have a clinical
investigating LOH, somatic mutations, and messenger MEN1 diagnosis based on the combination PA and
mRNA expression found limited involvement of MEN1 pHPT. As these patients may have been included in
in sporadic PAs (103-107). older MEN1 cohorts, before the widespread
availability of genetic testing, and these patients seem
As the prevalence of clinically relevant PAs is 68- to have macro-adenomas and somatotrophinomas
98/100,000 in the general population and in general more often, this can be one of the reasons of the
<3% of patients with a PA will have MEN1, the changing clinical picture of MEN1-related PAs.
question is when to think of MEN1 in a patient Additionally, imaging techniques have markedly

www.EndoText.org 13
improved over the last decades and guidelines have was the first manifestation (111). In the most recent
been developed for the screening and surveillance of GTE cohort, 88/202 patients with a PA were the index
patients with MEN1 including regular pituitary imaging case in their family and in 84% of these patients a PA
and biochemical screening using Insulin-like Growth was (one of) the first manifestation(s) (114).
Factor-1 (IGF-1) and prolactin (2, 5). All this has led to
earlier identification of PAs in patients with MEN1 and Prolactinomas are the most prevalent PA in patients
more frequent detection of (small) non-functioning PA with MEN1 and account for 30-80% of adenomas
(NFPAs). diagnosed in patients with clinically evident disease
(42, 43, 109, 111-114). Second most prevalent are
After the discovery of the MEN1 gene (1997), six non-functioning PA comprising 36-48% in the most
cohorts of MEN1-PA have been published, the first recent cohorts (111-114). Other functioning PAs are
two by the French multicenter Groupe d’étude des seen in <10%, and are in decreasing order of
Tumeurs Endocrines (GTE) in 2002 (109) and 2008 prevalence somatotropinomas, ACTH-producing
(110), in 2015 the DutchMEN Study Group (DMSG) adenomas (Cushing’s disease), and TSHomas and
published the results from their national population- gonadotropinomas (the latter two being equally rare)
based database (111), which was followed by two (109, 111-114). Co-secreting tumors are seen in less
single-center cohort from China (112) and the Mayo than 10% (109, 111-114).
Clinic respectively (113). Recently, the GTE have
published an update to their previous study, only Multifocal PAs are rare in MEN1, and are found in
including patients diagnosed since January 1st 2000 1.5% in the most recent GTE cohort (114) and in 4%
(114). in the 2008 GTE cohort of surgically resected MEN1-
related PAs (110). In this latter cohort the prevalence
As in sporadic PAs, PAs in patients with MEN1 show of multifocal tumors was compared to that in non-
a slight female predominance (52-69%) (109, 111- MEN1 resected PAs and was found to be significantly
114). With exception of the Chinese cohort, where the larger. Additionally, MEN1-related resected PAs were
mean age of diagnosis was 54 years (112), the more often plurihormonal on immunostaining (110).
mean/median age of diagnosis of MEN1-related PAs
is in the fourth decade. Lifetime prevalence of a PA in Signs and symptoms in MEN1-related PAs (Table 1)
patients with MEN1 is 49-58% (38, 111). are not different from those observed in sporadic PAs
and are caused by size effects (chiasm compression,
Although not as frequent as pHPT, PAs are often the compression of nerves in the cavernous sinus,
first clinical manifestation of the MEN1 syndrome. In hypopituitarism) and effects of hormonal
the Dutch cohort, in 29% of the patients with a PA, it hypersecretion in functioning tumors.

www.EndoText.org 14
 Table 1. Signs and Symptoms of Pituitary Adenomas in MEN1
Related to tumor size/ growth headache, visual field defects (usually bitemporal
hemianopsia), diplopia, hypopituitarism
Prolactinoma females: amenorrhea, galactorrhea, infertility
males: hypogonadism, impotence, lack of libido,
galactorrhea (rare), infertility
Somatotrophinoma Acromegaly: local overgrowth of bone (most often
mandible, skull), soft tissue growth (acral enlargement,
coarse facial features), hyperhidrosis, fatigue,
hyperglycemia, hypertension, sleep apnea, skin tags,
hypogonadism.
Corticotrophinoma Cushing syndrome: central obesity, hypertension,
hyperglycemia, gonadal dysfunction, moon facies,
plethora, osteoporosis, proximal muscle weakness,
psychological disturbance, wide purple striae, easy
bruising
Thyrotropinoma heat intolerance, unintentional weight loss, anxiety,
tremor, palpitations, frequent bowel movements
Gonadotropinoma hypogonadism, ovarian hyperstimulation in women
Pediatric specific delayed or halted pubertal development, primary
amenorrhea (females), accelerated linear growth, poor
growth velocity, decline in school performance

Presently, most non-functioning PAs in MEN1 are macro-adenomas and ACTH-secreting tumors are
microadenomas detected by prospective screening. generally microadenomas.
These micro-adenomas show indolent behavior during
follow-up. In the Dutch series after a median follow-up Although the youngest patient with a clinical
of 5.3 yrs, 9.7% showed minimal tumor growth which manifestation of MEN1 described in the literature is a
was without clinical significance in all and none 5-year-old boy with gigantism and a lactosomatotroph
progressed to macro-adenoma (111). In the Mayo macro-adenoma (36), PAs are rare in patients with
Clinic cohort, in those with asymptomatic non- MEN1 below the age of 10 (37, 46-49). However,
functioning PA (size not specified) progression to pediatric cohorts show that in children and
surgery was seen only in 1.7/100yr (113). In the most adolescents who have clinical manifestations of MEN1
recent GTE cohort, after a median follow-up of 2 years up to 1/3 have PAs (37, 47-49). As in adults, most PAs
(IQR 0-4), progression in Hardy classification was only the pediatric and adolescent age are prolactinomas
seen in 1 out of 63 patients with a non-functioning followed by non-functioning PAs and more rarely GH
micro-adenoma (2%) (114). In the Chinese cohort, of or ACTH producing tumors (37, 46-49, 115). In the two
the 19 patients with non-functioning micro-adenomas, largest pediatric cohorts, PAs were symptomatic in
no progression to macro-adenomas was seen during 50% of the cases and were macro-adenomas in 33-
a median follow-up of 3 years (112). 51% (47, 48).

Prolactinomas are also mostly micro-adenoma, while Treatment

30-38% are macro-adenomas (111, 113, 114). As in
sporadic PAs, GH-secreting tumors are more often The treatment of MEN1-related pituitary adenomas

www.EndoText.org 15
follows the same strategy as sporadic pituitary the pituitary gland every three years from the age of
adenomas. Management is aimed at tumor reduction, five years, and an annual blood test of IGF-I and
normalization of hormone secretion, and preservation prolactin concentrations, together with a clinical
of pituitary function. assessment (2). The young starting age – which was
based on a single case-report – has been disputed,
Dopamine agonists are the first line of treatment for given that PAs are rarely seen before the age of 10.
patients with prolactinoma (116), in which cabergoline
has proven to be most effective at restoring normal The aim of surveillance imaging is to detect the PAs in
prolactin concentrations and achieving tumor an early phase before clinical symptoms become
shrinkage than other dopamine agonists. With regards apparent. In general, surveillance leads to detection of
to adverse effects, cabergoline shows fewer side smaller non-functioning PAs (111, 113, 114).
effects than bromocriptine. In case of treatment However, early diagnosis by surveillance is not
resistance, or treatment intolerance, surgery or associated with smaller prolactinomas, but treatment
radiotherapy are considered as second-line treatment is required less frequently and a longer safe
options (116). observation period can be conducted (111). There are
currently no specific recommendations for the follow-
In Cushing’s disease(117) and acromegaly(118) up of MEN1-related (micro-)adenomas under
surgery is the first treatment option. In addition, non- observation, on medical treatment or after surgical
functioning PAs with mass effect or rapid progressive resection.
adenomas will also benefit from surgery.
DUODENOPANCREATIC NEUROENDOCRINE
MEN1-related functional PAs were initially considered TUMORS AND GASTRIC NETS
more resistant to medical treatment than those with
sporadic disease (109). However, the latest reports do General
not confirm this (111, 114) and treatment results seem
to be in line with what is reported in sporadic PAs. The Duodenopancreatic neuroendocrine tumors (dpNETs)
latter cohorts consist of a population with meticulous (Figure 1) are one of the cardinal features of MEN1
surveillance and therefore PAs are detected in an and highly penetrant, with a prevalence of over 80% at
early phase (111, 114). the age of 80 in recent cohorts (24, 38, 124). Malignant
dpNETs are the most important cause of MEN1-
Pituitary Carcinoma related death (26, 125).

Pituitary carcinoma is extremely rare, and this is Duodenopancreatic NETs in MEN1 can secrete
equally so in patients with MEN1. Although at higher hormones that produce a clinical syndrome or be
risk for PA than the general population, there does not functionally silent (non-functioning, NF). Due to
seem to be an increased risk of pituitary carcinoma. improved imaging techniques in the past decades,
Single cases of malignant, metastatic prolactinoma including endoscopic ultrasound (EUS) and
(119, 120), gonadotropinoma (121), thyrotropin somatostatin receptor (SSTR) imaging, non-
secreting adenoma (122), and non-functioning PA functioning pancreatic NETs (NF-PanNETs) are now
(123) have been reported. recognized as the most frequent type of dpNET in
patients with MEN1. Of the functional dpNETs,
Surveillance for Pituitary Adenoma gastrinomas are the most frequent, seen in
approximately 30% of patients with dpNETS. In
Current guidelines recommend examination by MRI of patients with MEN1, gastrinomas are almost

www.EndoText.org 16
exclusively of duodenal origin (126). Insulinomas onset of gastrinomas is usually later, with a reported
(pancreatic in origin) are the second most common mean age of onset around 30-35 years in the National
functional dpNET and occur in approximately 10-15% Institutes of Health (NIH) MEN1-ZES cohort (133, 134)
of patients with MEN1. More rare functional PanNETs to 51 years in the Dutch MEN1 cohort (135). The
such as glucagonomas, vipomas, somatostatinomas occurrence of MEN1-related gastrinoma in childhood
(127) or even rarer PanNETs secreting GHRH (128), or adolescence is rare.
calcitonin or PTH-related peptide (129), can also
occur. Upon histological examination of the duodenum Duodenopancreatic NETs can be the first
in patients with MEN1, small somatostatin-positive manifestation of MEN1, both in patients from known
tumors can also be found (130) although they do not MEN1 families but also in the index case.
seem to give rise to the somatostatinoma syndrome. Approximately 20-25% of all patients with gastrinoma
have MEN1 (136), a rate much lower for insulinomas
The hallmark of duodenopancreatic involvement in (approximately 5%) (2). Therefore, genetic testing for
MEN1 is multifocality, with the pancreas usually MEN1 is recommended in all patients diagnosed with
containing multiple NETs <5mm, called micro- gastrinoma (137). For patients presenting with a non-
adenomas, combined with one or more macroscopic gastrinoma dpNET without a family history of MEN1,
PanNETs (130). These micro-adenomas already have referral for genetic testing should be guided by the
loss of heterogeneity (LOH) of the MEN1 locus and are individual clinical characteristics, such as patient age,
considered precursors to PanNETs (130). Similarly, concomitant other MEN1-related tumors, multifocality
duodenal gastrinomas in MEN1 are usually multiple of dpNETs, and family history of endocrine tumors. If
and accompanied by gastrin cell hyperplasia, although a new diagnosis of MEN1 is made in a family, cascade
LOH was demonstrated in duodenal gastrinomas, but screening and subsequent screening and lifelong
not in gastrin cell hyperplasia (131). This multiplicity surveillance of affected family members is of utmost
sets MEN1-related dpNETs apart from sporadic importance, as delays may lead to preventable
duodenal and pancreatic NETs, which are usually morbidity and mortality in non-index cases in the
single tumors. family (30).

For patients with MEN1, the cumulative probability of Distant metastases occur in approximately 15-30% of
having a dpNET increases with age, however the age MEN1-related dpNETs and are the most important
of onset varies somewhat per tumor type. In a recent prognostic factor for disease-related survival (125,
study from the Dutch MEN1 cohort, the modeled 134, 138, 139). In the Dutch MEN1 cohort, 5- and 10-
cumulative probability of having developed a NF- year overall survival rates were 95% and 86% for
PanNET was 8.6% (95%CI 0.8-15.3%) at age 15, 12% patients with dpNETs without liver metastases,
(95% CI 5.9-17.0) at age 18, 16.1% (11.2-21.5) at age compared to 65% and 50% for those with liver
21 and rising to 80% at age 70 (72.2-97.0)(15). metastases (139). Non-functional pancreatic NETs
Insulinomas can also occur at a young age and the and duodenal gastrinomas are the most frequent
prevalence of insulinoma among the larger (n>50) cause of distant metastases. Regional lymph node
cohorts describing pediatric and adolescent MEN1 metastases are seen more often, but the exact
ranges from 6-25% (37, 46-48). Data from a recent reported prevalence highly depends on the type of
multicenter cohort study show that half of the patients cohort, primary dpNET, and the manner of diagnosis
with MEN1-related insulinoma were diagnosed before (i.e., surgical cohorts versus observational cohorts,
the age of 30 (96 patients who underwent surgery for surgery with or without systematic lymph node
MEN1-related insulinoma from 46 centers in Europe dissection, imaging with or without SSTR-PET
and North-America between 1990-2016) (132). The imaging, etc.). In a recent publication from the Dutch

www.EndoText.org 17
MEN1 cohort, in 350 patients with MEN1-related NF- (15). However, these associations up until now have
PanNETs without metastases at diagnosis, not been independently validated, either because
metastases (regional and/or distant) developed in associations were not confirmed in other cohorts or
18%, while the cumulative probability of having any validation was not performed.
PanNET-related metastases at the age of 70 was
41.2% (95%CI 31.3-50.3) (15). Since patients with In patients with MEN1, dpNETs are usually diagnosed
MEN1 often have multiple concomitant dpNETs and at an early stage, especially in patients from families
most patients with duodenal gastrinomas have with MEN1 or who have had predictive genetic testing.
concomitant NF-PanNETs, it may be difficult to Additionally, even in index cases, benign MEN1
determine the primary tumor for regional and distant manifestations may lead to the diagnosis of MEN1 and
metastases. dpNETs can be diagnosed early. In the French GTE
cohort and the Dutch MEN1 cohort, both spanning
Unlike in MEN2, in MEN1 there is no clear genotype- multiple decades, synchronous metastases were seen
phenotype correlation. Several groups however have in 6.5 and 6.4% of patients with a dpNET respectively
studied the association between MEN1 germline (125, 139). In MEN1-related dpNETs the focus of care
mutation and the disease course of dpNETs in their therefore lies before the onset of metastatic disease
cohorts, to see if genotype might be able to identify a and with a younger population than is seen in sporadic
subset of patients with a more aggressive clinical dpNETs. The goals of follow-up and treatment are to
course. This was in part fueled by the clinical prevent metastatic disease, cure hormonal
observation that in some families dpNETs seem to be hypersecretion, and prevent complication from
more prevalent, occur at a younger age and have a hormonal hypersecretion, while minimizing treatment-
higher proportion of metastatic disease. related complications and preserving Quality of Life. It
is therefore of utmost importance that whenever
Several associations have been reported: in the possible patients with MEN1 and MEN1-related
French GTE cohort mutations in the JUND interacting dpNETs are treated in centers of expertise with a
domain were associated with death (13), in the knowledgeable and experienced multidisciplinary
German Marburg cohort CHES1 loss of interaction team.
was associated with aggressive pNETs and pNET-
related mortality (14), in the Italian Florence cohort Staging and Grading
mutations in exon 8 were associated with higher risk
of progression and mortality (140), in the MD MEN1-related dpNET are graded according to the
Anderson cohort mutations in exon 2 were associated latest WHO classification (Table 2) of digestive system
with a higher risk of distant metastases (141), and in tumors (2019, 5th edition) and the WHO Classification
the Dutch MEN1 cohort nonsense/frameshift of Tumors of Endocrine Organs (2017, 4th edition)
mutations were associated with a higher cumulative (142). Where previously dpNET grading was only
probability of developing metastases in NF-PanNET covered in the Classification of Tumors of Endocrine
(regional and/or distant) compared to missense Organs, it is now included in the classification of
mutations 53.9 (37.8-74.3%) vs 10% (2.6-82.7%)) digestive system tumors as well (142).
.

www.EndoText.org 18
 Table 2. WHO Classification of Digestive Neuroendocrine Tumors
Classification Ki-67 proliferation index Mitotic rate (mitoses/2mm2)
Well-differentiated Neuroendocrine Tumors (NET)
NET, G1 <3% <2
NET, G2 3-20% 2-20
NET, G3 >20% >20
Poorly-differentiated Neuroendocrine Carcinomas (NEC)
NEC (G3) >20% >20
Small-cell type
Large-cell type

Pancreatic NETs are staged according to the AJCC UICC 8th edition Neuroendocrine tumors of the pancreas
(Table 3a and b).

Table 3a. TNM Staging of Pancreatic Neuroendocrine Tumors (AJCC UICC 8th edition)
Primary Tumor (T)
For any T add (m) for multiple tumors e.g., T2(m).
TX Tumor cannot be assessed
T1 Tumor limited to the pancreas*, <2 cm
T2 Tumor limited to the pancreas*, 2-4 cm
T3 Tumor limited to the pancreas*, >4 cm; or tumor invading the duodenum or
CBD
T4 Tumor invading adjacent organs (stomach, spleen, colon, adrenal gland)
or the wall of large vessels (celiac axis or the superior mesenteric artery)
Regional lymph Nodes (N)
NX Regional lymph nodes cannot be assessed
N0 No regional lymph node involvement
N1 Regional lymph node involvement
Distant Metastases (M)
M0 No distant metastases
M1 Distant metastases
M1a Hepatic metastases only
M1b Extra-hepatic metastases only
M1c Both hepatic and extra-hepatic metastases
* Limited to the pancreas means no invasion of adjacent organs or the wall of large vessels. Extension into
peripancreatic adipose tissue is included in “limited to the pancreas”. CBD common bile duct

Table 3b Stage Grouping

Stage I T1 N0 M0
Stage II T2-3 N0 M0
Stage III T4 N0 M0
Any T N1 M0
Stage IV Any T Any N M1

www.EndoText.org 19
Duodenal NETs are staged according to the AJCC UICC 8th edition Neuroendocrine Tumors of the duodenum
and ampulla of Vater (Table 4a and b).

Table 4a. TNM Staging of Duodenal Neuroendocrine Tumors (AJCC UICC 8th edition)
Primary Tumor (T)
If the number of tumors is known use T (#), if unavailable or too numerous T(m) e.g.,
T2(3) or T2(m)
TX Tumor cannot be assessed
T1 Tumor invades the mucosa or submucosa only and is ≤ 1 cm (duodenal)
Tumor ≤ 1 cm and confined within the sphincter of Oddi (ampullary)
T2 Tumor invades the muscularis propria or is >1 cm (duodenal).
Tumor invades through sphincter into duodenal submucosa or
muscularis propria, or is >1 cm (ampullary).
T3 Tumor invades the pancreas or peripancreatic adipose tissue
T4 Tumor invades the visceral peritoneum (serosa) or other organs
Regional lymph Nodes (N)
NX Regional lymph nodes cannot be assessed
N0 No regional lymph node involvement
N1 Regional lymph node involvement
Distant Metastases (M)
M0 No distant metastases
M1 Distant metastases
M1a Hepatic metastases only
M1b Extra-hepatic metastases only
M1c Both hepatic and extra-hepatic metastases

Table 4b. Stage Grouping

Stage I T1 N0 M0
Stage II T2-3 N0 M0
Stage III T4 N0 M0
Any T N1 M0
Stage IV Any T Any N M1

Non-Functioning Pancreatic NETs for NF-PanNETs in MEN1 below the age of 10 by a

combination of biochemical tests and yearly imaging
In patients with known MEN1, screening is advised for (either MRI, CT or EUS) (2).
early detection of NF-PanNETs. When NF-PanNETs
are diagnosed and there is no immediate indication for Since the publication of the guidelines, it has become
intervention, surveillance should be performed at clear that the diagnosis of NF-PanNETs in patients
regular intervals to re-evaluate indications for with MEN1 relies heavily on imaging, since tumors
intervention, as well as to detect newly developing markers chromogranin A, pancreatic polypeptide, and
dpNETs. Current guidelines suggest to start screening glucagon have low accuracy for the diagnosis of NF-

www.EndoText.org 20
PanNETs as summarized in a recent systematic active surveillance imaging should be individualized
review (143). Additionally, since the publication of the according to growth rate. Initial repeat imaging should
guidelines SSTR-PET-CT has emerged as a high- be done after 6-12 months to assess growth rate, but
sensitive diagnostic imaging tool for dpNETs and its afterwards in small stable NF-PanNETs the interval
role within the screening and surveillance of MEN1- can be extended to once every 1-2 years. The imaging
related dpNETs has yet to be determined. modality can be either MRI or alternating with EUS.
EUS alone should always be combined with an
There is currently no consensus regarding the best imaging method for metastases detection, since it
imaging modality and interval for screening and does not offer complete abdominal imaging. The exact
surveillance of MEN1-related NF-PanNETs (144). In a role of SSTR-PET-CT in the screening and
recent systematic review on the diagnosis of NF- surveillance of MEN1-related NF-PanNETs is still to
PanNETs in MEN1, it was concluded that for lifelong be determined, however, based on currently available
screening and surveillance CT was probably least evidence, it is best employed when results may
suitable given the inferior sensitivity compared to EUS change management such as in prevalent NF-
and SSTR-PET-CT in combination with the cumulative PanNETs >10 mm for early detection of metastases,
exposure to ionizing radiation, although head-to-head or as comprehensive staging before planned
comparisons with MRI are not available (143). This interventions (143, 145).
does not mean that a CT scan cannot still be indicated
and be the best imaging for specific clinical situations Another dilemma is when to start radiological
(for example pre-operative imaging). EUS is the most screening for NF-pNET in children with MEN1. As
sensitive method for the diagnosis of NF-PanNETs mentioned before, current guidelines advise initiating
and offers the possibility of obtaining tissue for screening before the age of 10 (2). However, others
analysis pre-operatively. However, it is also invasive, have advocated postponing until the age of 16, in the
operator dependent, clinically significant PanNETs absence of signs and symptoms (37). Recently,
can be missed in the pancreatic tail, and for the modeled data from the Dutch population-based MEN1
diagnosis of NF-PanNETs in MEN1 histological cohort show that the estimated age at a 1%, 2,5% and
confirmation is usually not necessary given the high 5% risk of having developed a clinically significant NF-
pre-test likelihood and the typical appearance on PanNET (≥ 20mm or documented growth of ≥1.6 mm
imaging. On the other hand, tissue-based analysis within one year above a baseline size of ≥ 15mm) is
prior to intervention may become more relevant in 9.5, 13.5 and 17.8 years respectively and they
MEN1 as more novel prognostic factors are identified. conclude that there is medical indication to initiate
MRI has the advantage of performing more radiological screening during the second decade of life
homogenously throughout the pancreas and the and that starting between 13-14 years of age is
absence of ionizing radiation although a significant justifiable (15).
proportion of NF-PanNETs >2 cm is missed. The
authors of the systematic review therefore suggest It is important to remember that each screening and
alternate use of EUS and MRI (143). surveillance schedule should be tailored to the needs
of the individual patient in his or her unique
Given a reported growth rate of 0.1-1.32 mm/year for circumstances, should be based on well-informed
small NF-PanNETs, if initial screening imaging is shared decisions making between providers and
negative, the next imaging can be performed with an patients (and parents if applicable), with
interval of two to three years, providing no clinical multidisciplinary team input when necessary.
reason for earlier imaging. For prevalent NF-PanNETs
without an indication for intervention, the interval for

www.EndoText.org 21
The only curative treatment for NF-PanNETs in MEN1 thalassemia/mental retardation X-linked (ATRX) and
is surgical resection, and the goal of surgical death domain-associated protein (DAXX), which lead
intervention in NF-PanNETs is to prevent metastases to the alternative lengthening of telomeres (ALT)
and thereby NF-PanNET-related mortality, while phenotype have been found to be associated with
preserving as much pancreatic tissue as possible and decreased disease-free survival and higher rates of
limiting treatment-related morbidity and mortality. distant metastases (146, 151). Mutations in DAXX and
Although theoretically, total duodenopancreatectomy ATRX result in loss of nuclear expressions of their
would prevent metastatic disease altogether, short- proteins by immunohistochemistry (IHC) and ALT can
term morbidity associated with this complex major be identified in tissue-samples by telomere-specific
surgery is high and the subsequent life-long brittle fluorescence in situ hybridization (FISH). Next to
diabetes that follows rarely justifies such major DAXX/ATRX and ALT, the differential expression of
intervention when balanced against the risk of distant transcription factors aristaless-related homeobox
metastases and PanNET-related death. gene (ARX) and pancreatic and duodenal homeobox
1 (PDX1) as assessed by IHC was also found to be
Since the risk of future metastases and disease- associated with risk of metastases (152, 153). In
related death must be balanced against short- and patients with MEN1-related NF-PanNETs, one study
long-term treatment-related morbidity and mortality, showed that liver metastases were only seen in ARX+
information regarding prognosis in MEN1-related NF- or ARX-/PDX1- tumors and that ALT positivity was
PanNETs is of vital importance to make well-informed only seen in ARX+ or ARX-/PDX1- tumors and
decisions regarding timing and extent of intervention. significantly correlated with relapse rate (152).
However, presently there is a paucity of prognostic However, since the publication of these data, a large
factors on which to base these decisions (146). The international cohort of 1322 NETs (not including
most important factor to date is tumor size, with the MEN1-related NETs), was evaluated by
risk of (distant) metastases increasing with increased immunolabelling for ARX/PDX1, ATRX/DAXX and by
size. Recent data from retrospective cohort studies telomere-specific FISH for ALT and it was found that
have shown that small (<2cm) NF-PanNETs generally ATRX/DAXX and ALT, but not ARX/PDX1 were
have an indolent course, that surgical resection of independent negative prognostic factors (151).
small NF-PanNETs does not seem to offer benefit
over active surveillance, and that the risk of A recent study by Fahrmann, et al. identified a 3-
metastases and disease-related death is low, albeit marker polyamine signature that distinguished
not zero (124, 146-150). Most small NF-PanNETs are patients with metastatic dpNETs from controls and
stable during follow-up, but there is a subset with which yield an AUC of 0.84 (95% CI: 0.62-1.00) with
progression in size (150). Generally, size progression 66.7% sensitivity at 95% specificity for distinguishing
is also considered to be a prognostic factor. An cases form controls in an independent test set (154).
important tissue-based prognostic factor is tumor These results form the basis for prospective testing of
grade, with grade 2 tumors being more often plasma polyamines as a prognostic factor for MEN1-
associated with metastases (146). Grade 3 NF- related dpNETs.
PanNETs or NECs are rarely seen in patients with
MEN1, but are associated with a worse prognosis. Further validation of these molecular markers in
More recently, advancements in molecular techniques MEN1, may also change the role of pre-intervention
have identified several potential prognostic EUS-guided aspiration or biopsy.
biomarkers for NF-PanNETs, mostly in sporadic NF-
PanNETs, but limited data in MEN1-related NF- So, when to intervene in MEN1-related NF-PanNETs?
PanNETs is also available. Mutations in alpha- Presently, these decisions are mostly based on tumor

www.EndoText.org 22
size and growth, with the current guidelines hypergastrinemia without the use of antisecretory
suggesting considering surgical resection in NF- drugs. The diagnosis is established if the fasting
PanNETs >10 mm or those that show significant serum gastrin (FSG) is more than tenfold the upper
growth during follow-up (doubling of tumor size over a limit of normal with a gastric pH of less than two (after
3–6-month interval and exceeding 10 mm) (2). Given ruling out retained antrum) (156, 157). When gastric
the emerging evidence that most NF-PanNETs <20 pH is low and FSG is <10-fold upper limit of normal,
mm are indolent in nature as described above, a more additional testing is needed to establish the diagnosis,
recent consensus statement states that surgical such as a secretin provocative test or measuring basal
resection is indicated for NF-PanNETs >20 mm and acid output (156, 157). The latter situation occurs in
those that progress during surveillance (155). 60% of ZES, and this might even be higher in MEN1,
Additionally, the presence of suspicious lymph nodes, given the early detection through prospective
or a higher grade on EUS-guided aspiration may guide screening programs. Due to unreliable gastrin assays,
intervention decisions. In all cases these decisions the limited availability of secretin and therewith the
should be made in multidisciplinary teams and in loss of expertise in performing the secretin provocative
shared decision making with the patient. The extent of test, the wide-spread use of PPIs and the risk
resection depends on multiple patient-, tumor- and associated with cessation of PPI for proper testing, the
MEN1-related factors and should be individualized. diagnosis of gastrinoma is challenging (157, 158).
Additionally, the value of non-biochemical tests in the
Gastrinoma diagnosis of gastrinoma (such as SSTR-PET-CT and
EUS/ esophagogastroduodenoscopy (EGD)-guided
Gastrinomas, NETs secreting gastrin, cause the cytology/biopsy) might also need re-evaluation (157).
Zollinger-Ellison Syndrome (ZES). ZES is a syndrome Recently experts have therefore suggested possible
characterized by tumor-related hypergastrinemia new criteria for diagnosis of ZES in patients with
leading to gastric acid hypersecretion. fasting hypergastrinemia with and without PPI use
(157).
Sign and symptoms of ZES/Gastrinoma are gastro-
esophageal reflux disease (GERD), (proton-pump Patients with MEN1 are screened for the presence of
inhibitor (PPI) responsive) diarrhea, abdominal pain, a gastrinoma by at least annually assessing clinical
nausea/vomiting, weight loss, and peptic ulcer symptoms and fasting serum gastrin (2). If a diagnosis
disease. Complications may arise from the peptic of gastrinoma is established or suspected, EGD
ulcer disease including upper gastro-intestinal should be performed to assess the presence of
bleeding, strictures, and bowel perforation. complications of gastric acid hypersecretion, type II
gastric NETs, and possibly to identify duodenal
Before the introduction of PPIs, complications from gastrinomas. Duodenal gastrinomas in MEN1 are
gastric acid hypersecretion were an important cause small, but despite their small size 70-80% are
of death in patients with MEN1 (134). With the arrival metastatic to the regional lymph nodes at the time of
of proton pump inhibitors, gastric acid hypersecretion diagnosis (159). However, these regional lymph node
can be effectively treated, although higher dosages metastases do not seem to have a negative impact on
are needed than for the treatment of non-ZES overall survival (159). In MEN1, attributing
hyperacidity. locoregional lymph nodes to the correct primary
dpNET is important for adequate treatment planning
The diagnosis of gastrinoma in MEN1 is challenging at and prognostic inferences. It is also challenging
present. The gold standard for the diagnosis is the however, given that most patients with MEN1 and
demonstration of inappropriate fasting duodenal gastrinoma(s) also have concomitant

www.EndoText.org 23
PanNETs, and the duodenal gastrinoma(s) may not be surgical intervention (161). Still, in retrospective
visible on imaging due to their small size. Hackeng, et studies around a quarter of the patients develop liver
al. studied 137 microscopic and macroscopic dpNETs metastases and around 15% shows aggressive
and 36 matched metastases (lymph node and distant) growth (138), and presently there are no good markers
in 10 patients with MEN1 to unravel the relationship to predict which patients with MEN1-ZES will have a
between the multiple primary dpNETs in MEN1 and more aggressive disease course. In a study from the
the metastases (160). They found that most patients NIH age at ZES diagnosis (≤33), FSG levels ≥10,000
had a single NET of origin for their metastases, but pg/mL, pancreatic tumors >3 cm, presence of
multiple metastatic primaries were also seen. In liver/bone metastases and presence of gastric
addition, and very important for MEN1-related carcinoids were associated with aggressive tumor
gastrinomas, in 6 patients with MEN1 and growth (138). In a study from the DutchMEN Study
hypergastrinemia, periduodenopancreatic lymph node Group, overall survival rates of MEN1-gastrinoma
metastases clustered with minute duodenal were 83% and 65% at 5 and 10 years respectively,
gastrinomas and not with larger pancreatic NETs. So which was significantly worse than age- and gender-
a duodenal origin for periduodenopancreatic lymph matched patients without gastrinoma. FSG ≥ 20x
node metastases in patients with MEN1 and upper limit of normal, PanNETs≥ 2cm, synchronous
hypergastrinemia should always be considered (160). liver metastases, EGD suspicious for gastric NETs,
and multiple concurrent NETs were associated with
Although its role still needs to be delineated, in MEN1- decreased overall survival (135). A recent study from
gastrinoma next to EUS/EGD, SSTR-PET-CT may be the French GTE, ZES was independently associated
very useful for staging to visualize duodenal with a higher risk of distant metastases, but did not
gastrinomas, lymph node metastases, and significantly seem to be associated with decreased
concomitant PanNETs. overall survival (125).

Presently, as in other MEN1-related dpNETs, surgery So presently, if surgical intervention should be

is the only potentially curative treatment. And although performed, when surgical intervention should be
MEN1-related ZES has been historically been performed and how (to what extent) surgical
considered a surgically incurable disease, more recent intervention should be performed for gastrinoma in
small studies have shown, that when the correct target MEN1 are all controversial topics. Treatment of
organ is addressed, namely the duodenum and not the patients in centers of expertise with a highly dedicated
pancreas, biochemical cure can be achieved after multidisciplinary team and experienced surgeons is
partial pancreaticoduodenectomy(PD), combined with therefore very important. Treatment decisions for
regional lymph node dissection (159). However, this MEN1-ZES should be made after MDT discussion in
must be balanced against the risk of peri-operative shared decision making with the patient.
and long-term complications and loss of quality of life.
Overall survival is generally good in duodenum- As stands to reason, treatment of MEN1-ZES patients
preserving operations as well, but persistence or with (high-dose) PPI is mandatory and patients should
recurrence of ZES occurs in 6-100% (159). Most often, not cease this treatment without consultation with their
hyperacidity can be adequately controlled with PPIs, provider. If specific testing without PPI is needed this
making the main goal of surgical resection the needs to be performed under close supervision in
prevention of distant metastases and disease-related centers of expertise.
death. The majority of MEN1-ZES patients with
associated small PanNETs have an indolent disease As mentioned in the section on parathyroid tumors, the
course with excellent overall survival even without interplay between pHPT and ZES in MEN1 is

www.EndoText.org 24
important to realize as hypercalcemia can increase therefore the history is probably the most important
gastrin levels. Additionally, a recent paper on the element.
Tasmanian MEN1 cohort showed an association
between H. pylori seropositivity and hypergastrinemia When the diagnosis of insulinoma is made,
and severe ZES-range hypergastrinemia. Further localization in MEN1 can be challenging, if there are
work is needed to fully elucidate this relationship, but multiple PanNETs. These usually are concomitant NF-
testing for H. Pylori and eradication if positive might be PanNETs, since in surgical series multiple insulin-
consider in patients with MEN1-ZES (162). positive PanNETs in patients operated for insulinoma
were seen in 8-40% (132, 164-166).
Insulinoma
For MEN1-related insulinoma, especially if
As already stated, MEN1-related insulinomas occur at conventional imaging shows multiple PanNETs and
a young age and are the most frequent functional correctly identifying the insulinoma(s) among them
PanNET at the pediatric age. Early recognition of would change surgical strategy, 86Ga-Exendin-4 PET-
signs and symptoms of insulinoma is of extreme CT is very promising. Although there is limited data in
importance in both children and adults. Signs and MEN1 patients, a recent meta-analysis showed a
symptoms may be erroneously attributed to epilepsy positive predictive value (PPV) of 94%, with a negative
or behavioral or neurological disorders, especially if predictive value (NPV) of 67%; In MEN1 PPV was
insulinoma is the presenting manifestation of MEN1 in 95% with NPV 96%, although based on a limited
an index case. In children this can lead to decline in number of patients (167, 168).
school performance and in children and adults alike
episodes of hypoglycemia can lead to accidents or Surgical resection is the treatment of choice for MEN1-
irrational behavior. related insulinomas and is associated with a high cure
rate. In a retrospective cohort study of 40 European
As insulinomas secrete insulin inappropriately and and 6 North-American institutes 92 patients with
lead to hypoglycemia the signs and symptoms are MEN1-related insulinomas who underwent surgical
those of hypoglycemia; both adrenergic symptoms resection were followed for a median of 8 years after
(such as fast heartbeat, jitteriness/shakiness, surgery (132). Overall, after different surgical
sweating and pale skin) as well as neuroglycopenic procedures, only 1 patient had persistence of
symptoms (such as mental status changes and hypoglycemia and six had recurrent hypoglycemia,
irritability). Symptoms are relieved with food (glucose) four due to new primaries and 2 due to development
intake. They usually occur during fasting, before meals of liver metastases, leading to a 10-year
or after exercise, but can occasionally occur at other hypoglycemia-free survival of 91% (95% CI 80-96).
times. In patients fulfilling Whipple’s triad (symptoms For those with unifocal insulinoma based on pre- and
and/ or signs consistent with hypoglycemia, a low intra-operative assessment (n=63), 1/46 (2.2%)
plasma glucose concentration, and resolution of undergoing pancreas resection had persistent
symptoms/signs after plasma glucose concentration is disease, while among those who underwent
raised) diagnosis can be established by a supervised enucleation 1/17 (6%) had recurrence of
fast (163). In patients with MEN1, screening for hypoglycemia based on a new primary insulinoma. For
insulinoma is advised from the age of five by careful those with multifocal insulinoma (n=33), of whom 30
history taking and measurement of fasting insulin and underwent pancreatic resection, mostly distal
– more importantly – glucose (2). However, almost all pancreatic resection, and three had multiple
patients with MEN1 and insulinoma are symptomatic, enucleations, 15% had recurrent hypoglycemia (9%

www.EndoText.org 25
based on new primaries and 6% based on liver weight loss. Tumors producing GHRH, calcitonin, and
metastases) (132). PTHrP lead to acromegaly, diarrhea and
hypercalcemia, respectively. In these rare functional
Therefore, given the better outcomes of pancreatic dpNETs without synchronous distant metastases
function over the long-term and young age of the surgery is generally indicated.
patients, if surgically feasible, enucleation seems the
better option for solitary insulinomas in MEN1, Non-Surgical Treatments of Non-Metastatic
provided of course that concomitant functional and dpNETs in MEN1
non-functional tumors do not make a different strategy
necessary (132). Although for most non-metastatic functional dpNETs
in MEN1 surgery is indicated, there may be a
Among MEN1-related dpNETs, insulinomas have the (temporary) need to control the hormonal syndrome
best oncological prognosis (26, 125, 169). Data from medically. As such gastrinomas are treated with high-
the international MEN1 Insulinoma Study Group and dose PPI, insulinomas with diazoxide or frequent
the DutchMEN Study Group show that for surgically feedings and in all cases somatostatin analogues
resected insulinomas 10-yr liver-metastases free might be considered if needed to control the functional
survival was 87% (72-91%) (169). Malignant syndrome.
insulinoma is rare, both in sporadic and MEN1-related
insulinoma. In the two largest MEN1-insulinoma Local resection of sporadic small dNETs is
cohorts synchronous liver metastases were seen in increasingly considered as an alternative to surgery
3.8-8.1% and metachronous liver metastases in 0- (170), and current European Neuroendocrine Tumor
2.2% after a median follow-up of 8-9 years (132, 165). Society (ENETS) guidelines recommend endoscopic
management for dNETs ≤ 10mm in size, confined to
Rare Functional dpNETS the submucosal layer and without lymph node and
distant metastases (171). However, since in MEN1
Functional dpNETs besides gastrinomas and dNETs are usually multiple, may grow beyond the
insulinomas, are rare in MEN1 and are seen in <1% of submucosa and, in case of gastrinomas, are
patients with dpNETs(2). These include PanNETs associated with lymph nodes in up to 80% of the
producing vaso-active intestinal peptide (VIPoma), cases, this is not generally recommended (159).
somatostatin, glucagon and other (ectopic) hormones
such as growth hormone releasing hormone (GHRH), Similarly, for PanNETs EUS-guided intervention using
calcitonin, or PTH-related peptide (PTHrP). A rare ethanol or radio-frequent ablation has been reported
functional tumor is considered if there are elevated in around 80 and 70 cases respectively in the
hormone levels in conjunction with a fitting clinical literature, with only a handful procedures performed in
syndrome. Without a clinical syndrome, tumors are not patients with MEN1 (172). Whether or not
considered functional but merely hypersecreting. This interventional EUS may play a role in treatment of
is relevant as for example glucagon can be elevated MEN1-related PanNETs is therefore unclear at the
in patients with MEN1 and PanNETs without the present time.
patient having the glucagonoma syndrome. VIPomas
lead to watery diarrhea, hypokalemia, achlorhydria There is much interest in chemoprevention in small
and dehydration, the somatostatinoma syndrome NF-PanNETs using somatostatin analogues (SSA).
consists of diabetes mellitus, diarrhea, steatorrhea SSA have proven anti-proliferative effect in advanced
and cholelithiasis, while glucagonomas give rise to PanNETs (173, 174) and the question has been raised
necrolytic migratory erythema, diabetes mellitus, and if SSA may be used to prevent progression and

www.EndoText.org 26
metastases of small NF-PanNETs in patients with Metastatic dpNET in MEN1
MEN1. In mouse models of Men1 PanNET lanreotide
and pasireotide showed the ability to decrease tumor The treatment of stage IV dpNET in patients with
proliferation. In a retrospective non-controlled study of MEN1 is similar to that of patients with sporadic
20 patients with small NF-PanNETs who received dpNETs(178). There is very limited evidence
long-acting octreotide for 12-75 months 10% had an regarding MEN1-specific outcome data, and from the
objective tumor response, 80% stable disease, and limited evidence available there seems to be no
10% showed progression (175). In another small (n=8) difference with sporadic NETs. In landmark studies
prospective series patients with small NF-PanNETs leading to approval of lanreotide (173), everolimus
were treated with SSA for up to 72 months, with stable (179), sunitinib (180) and peptide receptor
disease in all, however again without a control group radionuclide therapy (PPRT) (181), patients with
(176). In a recent observational cohort study MEN1 were either excluded, only single cases
lanreotide was compared with standard of care active included or MEN1-status was not mentioned (182).
surveillance in n=42 patients with pNETs <2 cm (N=23 With the advancing molecular understanding of
lanreotide vs n=19 active surveillance) during a MEN1-related NETs, MEN1-specific targeted
median follow-up of 6 years (177). The study showed therapies might be possible in the future, which in turn
improved RECIST-defined progression-free survival might benefit the almost 50% MEN1-mutated sporadic
(PFS) in the lanreotide group. In both groups however, PanNETs (182).
one patient developed distant (liver) metastases (177).
Limitations include sample size, non-experimental and Gastric NETs in MEN1 (Type II Gastric NETs)
therefore non-randomized design, and non-blinded
outcome evaluation. In addition, improved RECIST NETs of the stomach (Figure 1), formerly called gastric
PFS is not yet known to predict longer overall survival carcinoids or carcinoids of the stomach, are classified
for MEN1 patients with small NF-PanNETs. Ideally this into three different types(171):
is further evaluated in a randomized double-blind trial. • Type I, associated with atrophic gastritis
The most important challenge in the design of such a • Type II, associated with MEN1/ZES
study however, is the definition of appropriate • Type III, without associated conditions
surrogate endpoint for distant metastases and overall
survival (144). Gastric NETs are graded according to the latest WHO
classification of digestive system tumors (2019, 5th
edition) as described above for dpNETs (Table 2)
(142). TNM staging is shown in Table 5a and b.

www.EndoText.org 27
 Table 5a. TNM Staging of Neuroendocrine Tumors of the Stomach (AJCC UICC 8th
edition)
Primary Tumor (T)
For any T, add (m) for multiple tumors, for multiple tumors with different Ts, use the
highest (e.g., if three tumors’ sizes 0.5, 0.5, and 1.5 cm, T stage should be T2(m).
TX Tumor cannot be assessed
T0 No evidence of primary tumor
T1 Invades lamina propria or submucosa and ≤ 1 cm
T2 Invades muscularis propria or >1cm
T3 Invades through the muscularis propria into subserosal tissue without
penetration of overlying serosa
T4 Invades visceral peritoneum (serosal) or other organs or adjacent
structures
Regional lymph Nodes (N)
NX Regional lymph nodes cannot be assessed
N0 No regional lymph node involvement
N1 Regional lymph node involvement
Distant Metastases (M)
M0 No distant metastases
M1 Distant metastases
M1a Hepatic metastases only
M1b Extra-hepatic metastases only
M1c Both hepatic and extra-hepatic metastases

Table 5b. Stage Grouping

Stage I T1 N0 M0
Stage II T2-3 N0 M0
Stage III T4 N0 M0
Any T N1 M0
Stage IV Any T Any N M1

Gastric NETs are tumors of the gastric entero- of hypergastrinemia (185, 186). ECL-cell hyperplasia
chromaffin like (ECL) cells, which develop in MEN1 is considered a precursor lesion for gastric NETs
due to the trophic effect of gastrin on ECL-cells (187).
combined with the predisposing germline MEN1
mutation. Both components seem to be necessary for In the NIH-ZES cohort, 57 patients were extensively
the development of gastric NETs in patients with studied for gastric ECL-cell changes. All of the patients
MEN1. Gastric NETs are rarely seen in sporadic ZES were found to have proliferative ECL-cell changes,
patients and loss of heterogeneity was demonstrated with advanced changes in 53% and gastric NETs in
in 75% of MEN1-related gastric NETs (183, 184), 23% (188). More recently, data on ECL-cell changes
while in patients with MEN1 gastric NETs occur almost in patients with MEN1 was reported from the Marburg
exclusively in patients with gastrinoma and regression MEN1 database (185). They reported on 38 MEN1
of gastric NETs has been reported after normalization patients who underwent regular screening including

www.EndoText.org 28
EGD, regardless of gastrinoma status. Sixteen of
these patients had a gastrinoma diagnosis, 13 of Conclusion
whom had biochemical ZES at the time of first EGD.
They found that ECL-changes and gastric NETs were In conclusion, dpNETs are highly prevalent in patients
exclusively seen in patients with MEN1-gastrinoma with MEN1 reaching a more than 80% penetrance at
albeit in a lower percentage than in the NIH. They the age of 80. NF-PanNETs are most frequently seen,
found ECL hyperplasia in 62.5% of patients with a followed by gastrinomas and insulinomas. Most
gastrinoma diagnosis, versus 0% in those without MEN1-related dpNETs are diagnosed at an early
gastrinoma. No advanced ECL-cell changes were stage and NF-PanNETs <2 cm generally have an
seen and gastric NETs were found in 12.5% of indolent course. However, distant metastatic dpNETs
patients with a gastrinoma diagnosis (185). These (mostly NF-PanNETs and gastrinoma) are the most
differences might also reflect practice changes with important cause of MEN1-related mortality. Treatment
earlier gastrinoma diagnosis due to screening and goals for MEN1-related dpNETs are therefore to
surveillance and more frequent surgical treatment of prevent metastatic disease, cure hormonal
gastrinoma in the Marburg cohort compared to the NIH hypersecretion, and prevent complication from
cohort. hormonal hypersecretion, while minimizing treatment-
related complications and preserving Quality of Life.
In the NIH cohort, higher levels of FSG as well as Surgical resection is the mainstay for treatment, and is
longer duration of ZES were associated with a higher indicated in non-gastrinoma functional PanNETs and
risk of advanced ECL-cells changes and gastric NETs NF-PanNETs >2cm or with progression during follow-
(188). Higher levels of FSG as risk factor could not be up. No consensus exists on the surgical treatment of
confirmed in the Marburg cohort, however numbers of MEN1-related gastrinoma. With increasing awareness
MEN1-ZES were small (185). As mentioned above, in of MEN1, increasingly refined and defined screening
the section on gastrinoma, the presence of gastric and surveillance programs, and increasing sensitive
NETs in patients with MEN1-ZES was associated with imaging modalities, MEN1-related dpNETs are
a more aggressive disease course (138) and detected at earlier stage and more indolent small
decreased overall survival (135). dpNETs are seen. The main challenge at this point is
therefore identifying those patients who are at risk for
Therefore, in the current MEN1 Clinical Practice a more aggressive disease course and distant
Guidelines, EGD with biopsy, is recommend every 3 metastases to be able to offer those patients close
years in patients with MEN1 and hypergastrinemia. follow-up schedules and earlier and more aggressive
Although treatment of MEN1-related gastric NETs is treatment, while limiting treatment-related morbidity in
not well established (2, 171), the guideline suggest patients with low risk. Novel prognostic indicators are
that lesions <10 mm may remain under endoscopic therefore needed, ideally blood-based, so minimal
surveillance, while larger tumors require endoscopic invasive assessment is possible. Other future
resection or local resection, which is analogue to the directions are the investigation of chemoprevention in
treatment of type I gastric NETs (2, 171). small NF-PanNETs.

The prognosis of MEN1-related gastric NETs is Gastric NETs in MEN1 are almost exclusively seen in
generally good, with metastases (regional and distant) patients with gastrinoma and usually have an indolent
reported in 10-30% and disease-related death <10% course. Screening with EGD should be performed in
(171). Nevertheless, aggressive symptomatic and all patients with MEN1-ZES.
metastatic cases leading to mortality have been
reported (189, 190).

www.EndoText.org 29
THORACIC NEUROENDOCRINE TUMORS this is not described in thymus NET (192). However,
approximately 25% of patients with thNET have
General germline mutations in MEN1, therefore it is very
important to consider the diagnosis of MEN1 in
Thoracic NETs occurring as part of the MEN1 patients presenting with a sporadic thNET (193).
syndrome are thymic (thNET) and bronchopulmonary Thymic and bronchopulmonary NETs in MEN1
NETs (bpNET) (Figure 1), although recently it was generally develop in adults. In pediatric and
suggested that thymomas may also be part of the adolescent series (age up to 21, 31 in one series),
MEN1-related tumor spectrum (191). These tumors there is only one reported case of thNET (diagnosed
are not considered main disease-defining at age 16) and two cases of bpNET (diagnosed at age
manifestations. As in other MEN1-related tumors, loss 15 and 20 respectively) (37, 46-48).
of heterogeneity (LOH) at the MEN1 locus was
demonstrated in bpNETs in patients with MEN1 (97). Staging and Grading
This in contrast to thymic NETs, where until recently
no LOH at the MEN1 locus was found. However, in a bpNET and thNET are classified according to the
recent publication by the NIH, LOH was seen at the WHO classification (Table 6). TNM staging for
MEN1 locus in both MEN1-related thymic NETs (8 out thymicNETs is shown in Table 7a and b. TNM staging
of 12) and two (out of two) thymomas in patients with of bronchopulmonary NETs follows the same
MEN1 (191). MEN1 is also the most frequently classification as bronchogenic lung carcinomas (Table
mutated gene in sporadic well-differentiated bpNETs, 8a and b).

Table 6. WHO Classification of Bronchopulmonary and Thymic Neuroendocrine

Tumors
Classification Mitotic Rate and Necrosis
Well-differentiated
Typical Carcinoid, NET G1 Mitotic rate <2 and absence of necrosis
Atypical Carcinoid, NET G2 Mitotic rate 2-10 and/or presence of necrosis
Poorly differentiated
Neuro-endocrine Mitotic rate >10
carcinomas
Small-cell type
Large-cell type

www.EndoText.org 30
 Table 7a. Staging of Thymic Neuroendocrine Tumors (AJCC UICC 8th edition)
Primary Tumor (T)
TX Tumor cannot be assessed
T0 No evidence of primary tumor
T1 Tumor encapsulated or extending into the mediastinal fat; may involve
the mediastinal pleura
T1a Tumor with no mediastinal pleura involvement
T1b Tumor with direct invasion of mediastinal pleura
T2 Tumor with direct invasion of the pericardium (either partial or full
thickness)
T3 Tumor with direct invasion into any of the following: Lung,
brachiocephalic vein, superior vena cava, phrenic nerve, chest wall, or
extrapericardial pulmonary artery or veins
T4 Tumor with invasion into any of the following: Aorta (ascending, arch, or
descending), arch vessels, intrapericardial pulmonary artery,
myocardium, trachea, esophagus
Regional lymph Nodes (N)
NX Regional lymph nodes cannot be assessed
N0 No regional lymph node involvement
N1 Metastasis in anterior (perithymic) lymph nodes
N2 Metastasis in deep intrathoracic or cervical lymph nodes
Distant Metastases (M)
M0 No pleural, pericardial, or distant metastasis
M1 Pleural, pericardial, or distant metastasis
M1a Separate pleural or pericardial nodule(s)
M1b Pulmonary intraparenchymal nodule or distant organ metastasis

Table 7b. Stage Grouping

Stage I T1 N0 M0
Stage II T2 N0 M0
Stage IIIa T3 N0 M0
Stage IIIb T4 N0 M0
Stage IVa Any T N1 M0
Any T N0-1 M1a
Stage IVb Any T N2 M0-M1a
Any T Any N M1b

www.EndoText.org 31
 Table 8a. TNM Staging of Bronchopulmonary Neuroendocrine Tumors (AJCC UICC
8th edition)
Primary Tumor (T)
If the number of tumors is known used T (#), if unavailable or too numerous T(m) (e.g.,
T2a(2) or T2a(m)).
TX Primary tumor cannot be assessed or tumor proven by presence of
malignant cells in sputum or bronchial washings but not visualized by
imaging or bronchoscopy
T0 No evidence of primary tumor
Tis Tumor in situ
T1 Tumor ≤3 cm in greatest dimension surrounded by lung or visceral
pleura without bronchoscopic evidence of invasion more proximal than
the lobar bronchus (i.e., not in the main bronchus)*
T1a(mi) Minimally invasive adenocarcinoma
T1a Tumor ≤1 cm in greatest dimension
T1b Tumor >1 cm but ≤2 cm in greatest dimension
T1c Tumor >2 cm but ≤3 cm in greatest dimension
T2 Tumor >3 cm but ≤5 cm or tumor with any of the following features:
Involves main bronchus regardless of distance from the carina but
without involvement of the carina
Invades visceral pleura
Associated with atelectasis or obstructive pneumonitis that extends to
the hilar region, involving part or all of the lung
T2a Tumor >3 cm but ≤4 cm in greatest dimension
T2b Tumor >4 cm but ≤5 cm in greatest dimension
T3 Tumor >5 cm but ≤7 cm in greatest dimension or associated with
separate tumor nodule(s) in the same lobe as the primary tumor or
directly invades any of the following structures: chest wall (including the
parietal pleura and superior sulcus tumors), phrenic nerve, parietal
pericardium
T4 Tumor >7 cm in greatest dimension or associated with separate tumor
nodule(s) in a different ipsilateral lobe than that of the primary tumor or
invades any of the following structures: diaphragm, mediastinum, heart,
great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral
body, and carina
Regional lymph Nodes (N)
NX Regional lymph nodes cannot be assessed
N0 No regional lymph node involvement
N1 Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes
and intrapulmonary nodes, including involvement by direct extension
N2 Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s)
N3 Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or
contralateral scalene, or supraclavicular lymph node(s)

www.EndoText.org 32
 Distant Metastases (M)
M0 No distant metastasis
M1 Distant metastases
M1a Separate tumor nodule(s) in a contralateral lobe; tumor with pleural or
pericardial nodule(s) or malignant pleural or pericardial effusion
M1b Single extrathoracic metastasis
M1c Multiple extrathoracic metastases in one or more organs

Table 8b. Stage Grouping

Stage 0 Tis N0 M0
Stage IA T1 N0 M0
Stage IB T2a N0 M0
Stage IIA T2b N0 M0
Stage IIB T1a-c N1 M0
T2 N1 M0
T3 N0 M0
Stage IIIA T1a-c N2 M0
T2 N2 M0
T3 N1 M0
T4 N0-1 M0
Stage IIIB T1a-c N3 M0
T2 N3 M0
T3 N2 M0
T4 N2 M0
Stage IIIC T3-4 N3 M0
Stage IVA Any T Any N M1a-b
Stage IVb Any T Any N M1c

Thymic NET (193, 197, 199) but others could not find comparable
results (196, 200). The suggested link between
ThNETs develop in 2.0 - 8.2% of MEN1 patients, with smoking and the occurrence of thNET in MEN1
a median age at diagnosis of 43 years (range 16–72 remains controversial as well, as the portion of (heavy)
years) (194-201). There is a strong male smokers varied significantly among studies (193-196,
predominance (male to female ratio 4:1) in MEN1- 199, 201).
related thNET, which is more pronounced in American
and European cohorts compared to Asian series With the exception of a small subset of ACTH-
(194). Although one of the earliest studies on MEN1- producing tumors, most thNETs are functionally silent.
related thNET suggested a higher prevalence of As a result, the majority of patients only experiences
truncating MEN1 mutations in patients with thNET symptoms when the tumor has reached an advanced
(202), no clear genotype-phenotype relationship has stage, underlining the importance of periodic thoracic
been described in later cohorts (196, 197, 199, 200). imaging for a timely detection.
Furthermore, familial clustering of thNET within MEN1
families has been reported in a number of studies

www.EndoText.org 33
MEN1-related thNET are characterized by their predominance among MEN1 patients with bpNET
aggressive nature, illustrated by their frequent (205), later studies could not find a relationship
presentation with metastatic disease (53.5% of between the occurrence of bpNET and sex (200, 204,
patients), usually located in lymph nodes, bones and 206, 207). Likewise, genotype (the type of mutation)
lungs (194). Despite the low prevalence of thNETs or smoking status does not seem to influence the
among patients with MEN1, they are responsible for development of bpNET in MEN1 patients (204, 206,
19% of MEN1-related deaths (134). The poor 207).
prognosis of MEN1-related thNET has also been
illustrated in a meta-analysis of 99 MEN-1 thNETs: Only a minority of patients experience symptoms
median survival was 8.4 years, and the 10-year (dyspnea, cough, hemoptysis), which explains the
survival rate was 33%. An older age at diagnosis, a high rate of bpNET (77–100%) diagnosed through
tumor diameter >5 cm and the presence of metastasis periodic thoracic imaging surveillance (195, 206, 207).
were associated with worse outcome (194). Growth analysis of lung lesions highly suspect of
bpNET have demonstrated their overall indolent
Total (thoracic) thymectomy, including excision of the course, illustrated by a tumor doubling time of ±12
tumor, the entire thymus and perithymic fat, is the years at long-term follow-up in a Dutch national cohort
recommended treatment of choice (2, 203). Additional study (204). However, a very small number of lesions
radiotherapy and chemotherapy may be used in showed sudden aggressive tumor growth.
patients with unresectable or metastatic disease. Data Unfortunately, no prognostic factors for tumor growth
from the earlier mentioned meta-analysis suggested have been identified to date.
that adjunctive therapy after surgery tended to result
in a better survival compared to surgery alone (after The vast majority of MEN1-related bpNETs are well-
adjusting for gender, age at diagnosis, tumor size and differentiated NETs (typical and atypical carcinoids);
smoking), but this effect did not reach statistical only five cases of poorly differentiated neuroendocrine
significance (HR 0.557, 95%CI: 0.110–2.817) (194). carcinomas have been identified in MEN1 patients
Prophylactic cervical thymectomy, generally until now, all in the French Groupe d’étude des
performed during parathyroid surgery for primary Tumeurs Endocrines (GTE) cohort (206). Considering
hyperparathyroidism, may decrease the chance of the the large cohort size (n=1023 MEN1 patients), long-
occurrence of thNET. However, several cases of term follow-up, high frequency of smokers and lack of
thNET have been reported in patients after this molecular analyses confirming a causal relationship
procedure, indicating that surveillance imaging is still with the MEN1 syndrome, a sporadic coincidental
required in these patients (197, 202). occurrence of neuroendocrine carcinomas in MEN1
patients might also be a possible explanation for the
Bronchopulmonary NET manifestation of these carcinomas in this particular
study. The overall benign histopathological
Histopathologically proven bpNETs occur in 4.7-6.6% characteristics of MEN1-related bpNET may explain
of MEN1 patients, but a much higher proportion of their usually good prognosis: large cohort studies have
MEN1 patients may be diagnosed with lesions shown that bpNETs do not significantly affect survival
radiologically suspect of bpNET (22.9%, 26.0% and in MEN1 patients (204, 206), although a few (eight)
29.3% in the Dutch, Tasman and German cohort aggressive cases with fatal outcome have been
respectively) (195, 204-207). BpNETs are diagnosed described (206, 207). A recent comparison between
at a median age of ± 45 years and the reported age at patients with MEN1-related and sporadic bpNET with
bpNET diagnosis ranges between 20 and 69 years. comparable histopathological features showed a
Although the earliest report suggested a female significantly higher disease-specific mortality in

www.EndoText.org 34
sporadic bpNET, however this has not yet been distress for patients, and health care costs –, but the
confirmed in other cohorts (208). lack of predictors for (sudden) aggressive tumor
growth in bpNET and the aggressive nature of thNET
Data from the largest cohort of histologically proven plead for frequent thoracic imaging in order to enable
bpNETs in MEN1 patients (n=51) suggested that timely intervention if necessary. Therefore, treating
patients with distant metastasis at diagnosis and non- physicians should inform their patients about the
operated patients had a significantly worse survival benefits and disadvantages of a strict surveillance
(206). Additionally, females, patients with a typical program, in order to come to a personalized
carcinoid (compared to atypical carcinoid) and those surveillance strategy based on shared decision-
without lymph node involvement tended to have a making.
better survival (p=0.07, p=0.08 and p=0.08,
respectively (206). However, the most recent Dutch ADRENAL TUMORS
cohort study could not find any prognostic factors
(204). Adrenal involvement (Figure 1) is frequently seen in
patients with MEN1 and considered to be part of the
Surgical resection is considered the first treatment of syndrome though not one of the cardinal
choice, and should be done as lung-sparing as manifestations. Mice with heterozygous inactivation of
possible, including considering endobronchial the Men1 gene develop adrenocortical lesions to a
resection if feasible (2, 203). Given their usually greater proportion than Men1 wild-type controls (213,
indolent course, watch-and-wait policy may be 214) and the adrenal tumors show loss of
considered in patients with small, non-central, slow- heterogeneity (LOH) and loss of menin staining. In
growing lesions (203). Parallel to treatment regimens humans with MEN1, LOH is rarely seen in benign
in sporadic bpNET, additional radiotherapy and/or adrenocortical tumors (215-217). It has been
chemotherapy could be used in case of persistent or hypothesized that the development of adrenal tumors
metastasized disease, although data on the effect of in MEN1 might be related to PanNETs and
these regimens in aggressive MEN1-related bpNET is hyperinsulinemia, because in some cohorts an
very limited. association was seen between the occurrence of
PanNETs, hyperinsulinemia, and adrenal lesions.
Surveillance However, in the largest series to date, no difference
was found in the prevalence of main MEN1
Current clinical guidelines recommend thoracic manifestations between those with and without
imaging (CT or MRI) every 1-2 years for detection of adrenal lesions (217).
thymic and bronchopulmonary NETs (2). The optimal
imaging modality still remains to be elucidated, In retrospective cohorts on adrenal involvement in
although CT scans are used in the far majority of MEN1 the reported prevalence greatly differs from 20-
cases. A direct comparison between MRI and CT 73% (216-225). Prevalence in part differs by the way
scans among MEN1 patients is lacking, and the role of adrenal lesions are defined (i.e. also including
nuclear imaging in screening programs for thoracic hyperplasia) and the manner of diagnosis, with
NETs has to be determined yet (209-212). prevalence being the highest (73%) in an EUS study
Furthermore, the frequency of periodic surveillance is (n=49) including all adrenal lesions from ‘plump’
subject of debate; on one hand, the overall indolent adrenals to adenomas (221). In the series (n=27) with
course of bpNET and rareness of thNET might argue the second-highest prevalence (63%) all CT scans
for less frequent screening – thereby diminishing were re-read with the purpose of classifying adrenal
radiation exposure, physical and psychological lesions and every adrenocortical lesion >5 mm was

www.EndoText.org 35
considered a nodule (225). The largest series to date literature identifying 19 published cases (226). In the
from the French GTE (n=715) has the lowest Swedish cohort, one patient had an ACC and in the
prevalence of 20.4% (217). Adrenal lesions are rarely tumor LOH at the MEN1 locus was seen (216, 222).
the reason for an MEN1 diagnosis or the first Three papers reporting from the same German
manifestation of the disease, and are most frequently institutions reported two, four and one case of ACC
diagnosed asymptomatically by respectively, but some of these might represent the
screening/surveillance imaging during follow-up or at same patients (220, 224, 227). In the large French
the time of initial comprehensive imaging after the series, eight patients with 10 ACCs were reported,
diagnosis of MEN1 is made (217, 223). Mean age of which was 5% of patients with an adrenal lesion, but
diagnosis is usually in the fifth decade, but ranges vary 13.8% of those with an adrenal tumor (>10mm) (217).
widely (217, 223, 224). ACC prevalence was also significantly higher than in
the sporadic adrenal incidentaloma cohort (217).
The French GTE series compared MEN1-related There are also several case reports describing
adrenal lesions to a cohort of sporadic incidentalomas patients with MEN1-related ACC (226, 228-233). It is
(n=144) and found that adrenal lesions in patients with important to mention that there are several cases
MEN1 were diagnosed at a younger age and were reported were the ACC developed from an initially
similar in size and in prevalence of bilateral lesions observed relatively small adrenocortical tumor,
(217). although when reported these lesions did not have
Houndsfield Units (HU) ≤ 10. In the French cohort one
Benign Adrenocortical Tumors patient had two nodules (8 and 13 mm, 38 HU) in one
adrenal, which grew to 29 and 30 mm after 5 years,
Most MEN1-related adrenal lesions are benign which turned out to be ACCs. Another patient had a
adrenocortical lesions and include hyperplasia, 25 mm calcified lesion (40 HU) which grew to 40 mm
(macro)nodular hyperplasia, and adenomas. Bilateral in 4 years(217). One case report describes a female
lesions are frequently seen, but again prevalence patient with a 2 cm left adrenal tumor which grew to 3
reported varies widely from 12.5% to >50% in different cm in 7 years (advised to undergo surgery but refused)
series( 216-219, 221-224). Most adrenocortical and then to 4 cm in 4 years, after which the tumor was
lesions in MEN1 are non-functioning and generally removed and turned out to be an ACC (233). In other
stable over the course of follow-up (216-224). In a cases more rapidly progressing tumors are described
minority of the cases ACTH-independent (220, 231). When ACCs are functioning, they are
hypercortisolism, autonomous cortisol secretion, or mostly cortisol producing or sex-steroid producing. In
primary hyperaldosteronism are seen (216-219, 221- sporadic ACC, MEN1 is considered one of the driver
224). Interestingly, in the French series, when genes (234).
comparing MEN1-related adrenal lesions with adrenal
incidentalomas, functional tumors were more common Pheochromocytoma
(15% vs 6.9%), especially primary hyperaldosteronism
and ACTH-independent hypercortisolism (217). Pheochromocytoma is one of the hallmark conditions
Pheochromocytomas on the other hand were more of Multiple Endocrine Neoplasia type 2 (MEN2),
common among sporadic incidentalomas. caused by germline mutations in the RET oncogene.
In MEN1, the occurrence of pheochromocytoma is
Adrenocortical Carcinoma rare, with a 2020 case report and review of literature
describing 20 published cases (235). The authors
Adrenocortical carcinoma (ACC) is a rare occurrence identified LOH at the MEN1 locus in the resected
among patients with MEN1, with a 2019 review of pheochromocytoma of the patient they report (235),

www.EndoText.org 36
and in another published series, two resected lesions, some authors recommend to use a size cut-
pheochromocytomas from patients with MEN1 were off of 3 cm in MEN1 (220).
examined and LOH at the MEN1 locus was found in
both, with one having absent menin staining and one If there is no indication for surgery, surveillance
weak menin staining (236). imaging is indicated, initially after 6 months. In the
absence of a surgical indication at this point,
Screening, Treatment and Follow-up frequency of further imaging follow-up should be
determined individually and discussed by the
In patients with MEN1, minimal recommended multidisciplinary team. Unlike in sporadic adrenal
screening for adrenal lesions as per the current incidentalomas, surveillance cannot be ended, given
guidelines, is abdominal imaging with CT or MRI every that multiple adrenal lesions can arise. There may be
3 years for those without adrenal lesions (2). Since indications during follow-up to repeat initially negative
abdominal imaging is also performed to screen for hormonal screening, such as the development of
and/or surveille pancreatic lesions this can often be symptoms or a new adrenal lesion.
combined. However, care should be taken that the
adrenals are properly imaged in the right phase to not CUTANEOUS LESIONS
only judge their size but also, should a lesion be
present, to judge its characteristics. The Facial angiofibromas and collagenomas are the main
preponderance to develop adrenal lesions should be skin lesions in MEN1 (Figure 1) (238, 239).
mentioned in the clinical information to the radiologist Frequencies of 64% for angiofibromas and 62% for
and the images should be read by a radiologist collagenomas have been described. Multiple
experienced in adrenal imaging. angiofibromas and collagenomas are present in 77–
81% of the MEN1 patients (238). Primarily
If an adrenal lesion is identified hormonal screening is angiofibromas are seen in patients with MEN1 (238,
recommended if patients are symptomatic or lesions 240). An odds ratio of 6.6 (95% CI, 1.09–40.43) for
are >1 cm (2). The current guidelines recommend that cutaneous lesions in MEN1 in 29 patients with MEN1
screening be focused on hyperaldosteronism and in comparison with their non- affected family members
hypercortisolism (2), but given that is described (240).
pheochromocytomas do occur in MEN1 as described
above and the consequence of missing the diagnosis These findings are further supported by the allelic loss
can be serious, it is prudent to screen for the presence of the MEN1 gene in six angiofibromas, three
of a pheochromocytoma by either plasma free collagenomas, and one lipoma, suggesting that loss of
(nor)metanephrines or urinary fractionated function of the wild-type MEN1 gene product plays a
(nor)metanephrines. role in the development of these skin lesions in
patients with MEN1(241). Melanomas and other skin
Indications for surgical resection parallel those of lesions are also described in the MEN1 population, but
adrenal incidentalomas, being clinically significant not with significant prevalences.
hormone excess and/or concerns about malignancy
either due to atypical characteristics on imaging, size Lipomas (Figure 1) are reported in 17-34% of patients
(>4 cm), or significant growth over a 6-month period, with MEN1 (238-240). Loss of heterozygosity of the
which in the adrenal incidentaloma guidelines is MEN1 gene is described in MEN1-related lipomas (97,
suggested as increase in 20% (in addition to at least 241, 242) and may also play a role in sporadic lipomas
5mm increase in actual size) (2, 237). Given the (242). Menin seems to be an important factor for
reports of ACCs in MEN1 arising from initially small

www.EndoText.org 37
adipogenesis and contributes to lipoma development important role of menin in ERα regulation and the
(243, 244). breast cancer formation (253).

A case of a novel MEN1 gene mutation with a PSYCHOSOCIAL ASPECTS

recurrent sarcoma addresses the need for
cautiousness of (atypical) skin lesions in patients with Recently there has been more interest in the
MEN1 (245). psychosocial wellbeing of patients with MEN1 (254-
259).The first study was published in 2003, which
BREAST CANCER AND MEN1 showed that psychosocial outcomes such as anxiety,
depression, intrusion, and avoidance are not altered
A higher incidence of breast cancer (Figure 1) was by the hospital or home setting. A higher burden of
found in four independent MEN1 cohorts in the disease led to more depression. Compared to the
Netherlands, France, Tasmania and the United population-based norm values, patients with MEN1
States. In the Dutch cohort a relative risk of 2.83 was scored lower for General Health and Social
found, which was significantly higher than in the Functioning according to the SF-36 (260).
general Dutch population (3). The median age for
breast cancer was 45 years, which is approximately Postoperatively, quality of life (QOL) scores did not
15 years younger than the general Dutch population. differ after pancreaticoduodenal surgery in MEN1
The increased risk for breast cancer for MEN1 carriers patients in comparison with the general population.
was not associated with other breast cancer risk Financial difficulties caused by the treatment were
factors or a familial breast cancer risk. Considering the significantly worse in MEN1 patients (261). Financial
younger age of breast cancer occurrence and an burden seems to be associated with having MEN1.
earlier age of breast cancer, surveillance should be The degree of financial burden has a linear
considered. Breast cancer surveillance from the age relationship with worse health-related QOL. Patients
of 40 is initiated in the Dutch MEN1 cohort (4). After were three-times more likely to be unemployed in
the latter publication, several cases of early breast comparison with the US population (256).
cancer in MEN1 patients were reported (246-249).
The largest QOL-related study showed that
These epidemiological findings are supported by basic employment status was the most consistent predictor
research. Loss-of-function Men1 mouse models have for QOL. This is in line with the former studies. The
shown an increased incidence of both in situ and health-related QOL according to the SF-36 was
invasive mammary cancer (250). Menin, the tumor significantly lower for patients with MEN1 on all
suppressor protein encoded by MEN1, is co-localized subscales except for the physical functioning scale.
with the estrogen receptor (ER) alfa in breast cancer Patients who are aware of their PA and PanNET have
cells. In this manner, menin functions as a direct worse QOL scores in comparison with patients who
activator of Erα (251). In sporadic ER-positive breast are not aware of having these tumors(259). The
cancer, menin seems to have a proliferative role, degree of fear of disease recurrence is high in patients
which is in contrast with breast cancer in MEN1 with MEN1. This fear is negatively associated with
carriers, in whom LOH of the MEN1 gene could be health-related QOL and is higher in patients who
found (3, 252). Recent studies showed that reduced consider themselves at high risk for developing a
menin staining is associated with ER-negative breast MEN1-related tumor. More MEN1-related
cancer and in ER-positive breast cancer with larger manifestations lead to more fear of disease
tumors, higher grade tumor, and luminal subtypes occurrence (258). In comparison with other chronic
tumors. Providing further evidence that there is an

www.EndoText.org 38
diseases MEN1 scores worse regarding anxiety, CONCLUSION
depression and fatigue (257).
In conclusion, in the past decades there have been
QOL did not overly differ from the general population great advances in the understanding of the natural
in the Italian cohort (255) and patients were more course of MEN1-related tumors, which has had direct
optimistic than in the Swedish cohort (260). This could consequences on clinical care. In the coming decade
be due to cultural differences, population selection, one of the main research objectives will be the
and awareness of the disease and its implications. identification of individual predictors of disease course
The high response rate in the MEN1 population which can guide personalized treatment and
illustrates the motivation of patients to participate in surveillance. Increasing international collaborations
research and care about their wellbeing (259, 260). will enable prospective studies. Given the complexity
of the disease, it is strongly advised that patients,
whenever possible, be followed and treated in centers
of expertise. If this is not feasible, consultation with a
center of expertise should be considered.

REFERENCES

1. Lloyd, R.V., et al., WHO Classification of Tumours of Menin Expression. J Bone Miner Res, 2021. 36(1): p. 100-
Endocrine Organs. 4th ed. 2017, Lyon: IARC. 109.
2. Thakker, R.V., et al., Clinical practice guidelines for multiple 11. Agarwal, S.K., The future: genetics advances in MEN1
endocrine neoplasia type 1 (MEN1). The Journal of clinical therapeutic approaches and management strategies.
endocrinology & metabolism, 2012. 97(9): p. 2990-3011. Endocr Relat Cancer, 2017. 24(10): p. T119-t134.
3. Dreijerink, K.M.a., et al., Breast-Cancer Predisposition in 12. Romanet, P., et al., Proposition of adjustments to the
Multiple Endocrine Neoplasia Type 1. New England ACMG-AMP framework for the interpretation of MEN1
Journal of Medicine, 2014. 371(6): p. 583-584. missense variants. Hum Mutat, 2019. 40(6): p. 661-674.
4. van Leeuwaarde, R.S., et al., MEN1-Dependent Breast 13. Thevenon, J., et al., Higher risk of death among MEN1
Cancer: Indication for Early Screening? Results From the patients with mutations in the JunD interacting domain: a
Dutch MEN1 Study Group. J Clin Endocrinol Metab, 2017. Groupe d'etude des Tumeurs Endocrines (GTE) cohort
102(6): p. 2083-2090. study. Human molecular genetics, 2013. 22: p. 1940-1948.
5. Brandi, M.L., et al., Guidelines for diagnosis and therapy of 14. Bartsch, D.K., et al., Higher risk of aggressive pancreatic
MEN type 1 and type 2. The Journal of clinical neuroendocrine tumors in MEN1 patients with MEN1
endocrinology & metabolism, 2001. 86(12): p. 5658-71. mutations affecting the CHES1 interacting MENIN domain.
6. Chandrasekharappa, S.C., et al., Positional Cloning of the J Clin Endocrinol Metab, 2014. 99(11): p. E2387-91.
Gene for Multiple Endocrine Neoplasia-Type 1 Science, 15. Klein Haneveld, M.J., et al., Initiating pancreatic
1997. 276: p. 404-407. neuroendocrine tumour (pNET) screening in young MEN1
7. Lemmens, I., et al., Identification of the multiple endocrine patients: results from the DutchMEN Study Group. J Clin
neoplasia type 1 (MEN1) gene. Human molecular genetics, Endocrinol Metab, 2021.
1997. 6: p. 1177-83. 16. van den Broek, M.F.M., et al., Clues For Genetic
8. Lemos, M.C. and R.V. Thakker, Multiple endocrine Anticipation In Multiple Endocrine Neoplasia Type 1. J Clin
neoplasia type 1 (MEN1): analysis of 1336 mutations Endocrinol Metab, 2020. 105(7).
reported in the first decade following identification of the 17. Beijers, H., et al., Germline and somatic mosaicism in a
gene. Human mutation, 2008. 29(1): p. 22-32. family with multiple endocrine neoplasia type 1 (MEN1)
9. Concolino, P., A. Costella, and E. Capoluongo, Multiple syndrome. Eur J Endocrinol, 2019. 180(2): p. K15-k19.
endocrine neoplasia type 1 (MEN1): An update of 208 new 18. Dreijerink, K.M.A., H.T.M. Timmers, and M. Brown, Twenty
germline variants reported in the last nine years. Cancer years of menin: emerging opportunities for restoration of
Genet, 2016. 209(1-2): p. 36-41. transcriptional regulation in MEN1. Endocr Relat Cancer,
10. Kooblall, K.G., et al., Multiple Endocrine Neoplasia Type 1 2017. 24(10): p. T135-t145.
(MEN1) 5'UTR Deletion, in MEN1 Family, Decreases 19. Canaff, L., et al., Impaired transforming growth factor-β
(TGF-β) transcriptional activity and cell proliferation control

www.EndoText.org 39
 of a menin in-frame deletion mutant associated with 35. van den Broek, M.F.M., et al., Clinical Relevance of
multiple endocrine neoplasia type 1 (MEN1). The Journal Genetic Analysis in Patients With Pituitary Adenomas: A
of biological chemistry, 2012. 287: p. 8584-97. Systematic Review. Front Endocrinol (Lausanne), 2019.
20. Iyer, S. and S.K. Agarwal, Epigenetic regulation in the 10: p. 837.
tumorigenesis of MEN1-associated endocrine cell types. J 36. Stratakis, C.A., et al., Pituitary macroadenoma in a 5-year-
Mol Endocrinol, 2018. 61(1): p. R13-r24. old: an early expression of multiple endocrine neoplasia
21. Walls, G.V., et al., MEN1 gene replacement therapy type 1. J Clin Endocrinol Metab, 2000. 85(12): p. 4776-80.
reduces proliferation rates in a mouse model of pituitary 37. Manoharan, J., et al., Is Routine Screening of Young
adenomas. Cancer research, 2012. 72: p. 5060-8. Asymptomatic MEN1 Patients Necessary? World J Surg,
22. Pieterman, C.R., et al., Care for patients with multiple 2017. 41(8): p. 2026-2032.
endocrine neoplasia type 1: the current evidence base. 38. Romanet, P., et al., UMD-MEN1 Database: An Overview of
Fam Cancer, 2011. 10(1): p. 157-71. the 370 MEN1 Variants Present in 1676 Patients From the
23. van Leeuwaarde, R.S., et al., The future: medical advances French Population. J Clin Endocrinol Metab, 2019. 104(3):
in MEN1 therapeutic approaches and management p. 753-764.
strategies. Endocr Relat Cancer, 2017. 24(10): p. T179- 39. Goudet, P., et al., Hyperparathyroidism in multiple
t193. endocrine neoplasia type I: surgical trends and results of a
24. de Laat, J.M., et al., MEN1 redefined, a clinical comparison 256-patient series from Groupe D'etude des Néoplasies
of mutation-positive and mutation-negative patients. BMC Endocriniennes Multiples Study Group. World J Surg,
Med, 2016. 14(1): p. 182. 2001. 25(7): p. 886-90.
25. Pieterman, C.R.C., et al., Understanding the clinical course 40. Pieterman, C.R., et al., Multiple endocrine neoplasia type 1
of genotype-negative MEN1 patients can inform (MEN1): its manifestations and effect of genetic screening
management strategies. Surgery, 2020. on clinical outcome. Clinical endocrinology, 2009. 70(4): p.
26. Goudet, P., et al., Risk factors and causes of death in 575-81.
MEN1 disease. A GTE (Groupe d'Etude des Tumeurs 41. Marini, F., F. Giusti, and M.L. Brandi, Multiple endocrine
Endocrines) cohort study among 758 patients. World neoplasia type 1: extensive analysis of a large database of
journal of surgery, 2010. 34(2): p. 249-55. Florentine patients. Orphanet J Rare Dis, 2018. 13(1): p.
27. Geerdink, E.A., R.B. Van der Luijt, and C.J. Lips, Do 205.
patients with multiple endocrine neoplasia syndrome type 42. Giusti, F., et al., Multiple endocrine neoplasia syndrome
1 benefit from periodical screening? European journal of type 1: institution, management, and data analysis of a
endocrinology, 2003. 149(6): p. 577-82. nationwide multicenter patient database. Endocrine, 2017.
28. de Laat, J.M., R.S. van Leeuwaarde, and G.D. Valk, The 58(2): p. 349-359.
Importance of an Early and Accurate MEN1 Diagnosis. 43. Sakurai, A., et al., Multiple endocrine neoplasia type 1 in
Front Endocrinol (Lausanne), 2018. 9: p. 533. Japan: establishment and analysis of a multicentre
29. de Laat, J.M., et al., Predicting the risk of multiple database. Clinical endocrinology, 2012. 76(4): p. 533-9.
endocrine neoplasia type 1 for patients with commonly 44. Soczomski, P., et al., Multiple endocrine neoplasia type 1
occurring endocrine tumors. European journal of in Poland: a two-centre experience. Endokrynol Pol, 2019.
endocrinology, 2012. 167(2): p. 181-7. 70(5): p. 385-391.
30. van Leeuwaarde, R.S., et al., Impact of delay in diagnosis 45. Waldmann, J., et al., Screening of patients with multiple
in outcomes in MEN1: results from the Dutch MEN1 study endocrine neoplasia type 1 (MEN-1): a critical analysis of
group. J Clin Endocrinol Metab, 2016: p. jc20153766. its value. World journal of surgery, 2009. 33(6): p. 1208-18.
31. Alrezk, R., F. Hannah-Shmouni, and C.A. Stratakis, MEN4 46. Herath, M., et al., Paediatric and young adult
and CDKN1B mutations: the latest of the MEN syndromes. manifestations and outcomes of multiple endocrine
Endocr Relat Cancer, 2017. 24(10): p. T195-t208. neoplasia type 1. Clin Endocrinol (Oxf), 2019. 91(5): p. 633-
32. Frederiksen, A., et al., Clinical Features of Multiple 638.
Endocrine Neoplasia Type 4: Novel Pathogenic Variant 47. Goudet, P., et al., MEN1 disease occurring before 21 years
and Review of Published Cases. J Clin Endocrinol Metab, old: a 160-patient cohort study from the Groupe d'etude
2019. 104(9): p. 3637-3646. des Tumeurs Endocrines. J Clin Endocrinol Metab, 2015.
33. Georgitsi, M., et al., Germline CDKN1B/p27Kip1 mutation 100(4): p. 1568-77.
in multiple endocrine neoplasia. The Journal of clinical 48. Shariq, O.A., et al., Multiple endocrine neoplasia type 1 in
endocrinology and metabolism, 2007. 92: p. 3321-3325. children and adolescents: Clinical features and treatment
34. van der Tuin, K., et al., CDC73-Related Disorders: Clinical outcomes. Surgery, 2021.
Manifestations and Case Detection in Primary 49. Vannucci, L., et al., MEN1 in children and adolescents:
Hyperparathyroidism. J Clin Endocrinol Metab, 2017. Data from patients of a regional referral center for
102(12): p. 4534-4540.

www.EndoText.org 40
 hereditary endocrine tumors. Endocrine, 2018. 59(2): p. associated primary hyperparathyroidism. J Bone Miner
438-448. Res, 2010. 25(11): p. 2382-91.
50. Marx, S.J. and D.M. Lourenço, Jr., Questions and 63. Burgess, J.R., et al., Osteoporosis in multiple endocrine
Controversies About Parathyroid Pathophysiology in neoplasia type 1: severity, clinical significance, relationship
Children With Multiple Endocrine Neoplasia Type 1. Front to primary hyperparathyroidism, and response to
Endocrinol (Lausanne), 2018. 9: p. 359. parathyroidectomy. Arch Surg, 1999. 134(10): p. 1119-23.
51. Doherty, G.M., T.C. Lairmore, and M.K. DeBenedetti, 64. Lourenco, D.M., Jr., et al., Multiple endocrine neoplasia
Multiple endocrine neoplasia type 1 parathyroid adenoma type 1 in Brazil: MEN1 founding mutation, clinical features,
development over time. World J Surg, 2004. 28(11): p. and bone mineral density profile. European journal of
1139-42. endocrinology, 2008. 159(3): p. 259-74.
52. d'Alessandro, A.F., et al., Supernumerary parathyroid 65. Coutinho, F.L., et al., Bone mineral density analysis in
glands in hyperparathyroidism associated with multiple patients with primary hyperparathyroidism associated with
endocrine neoplasia type 1. Rev Assoc Med Bras (1992), multiple endocrine neoplasia type 1 after total
2012. 58(3): p. 323-7. parathyroidectomy. Clin Endocrinol (Oxf), 2010. 72(4): p.
53. Yeh, M.W., et al., Incidence and prevalence of primary 462-8.
hyperparathyroidism in a racially mixed population. J Clin 66. Kann, P.H., et al., Peripheral bone mineral density in
Endocrinol Metab, 2013. 98(3): p. 1122-9. correlation to disease-related predisposing conditions in
54. Press, D.M., et al., The prevalence of undiagnosed and patients with multiple endocrine neoplasia type 1. J
unrecognized primary hyperparathyroidism: a population- Endocrinol Invest, 2012. 35(6): p. 573-9.
based analysis from the electronic medical record. 67. Green, P., et al., High prevalence of chronic kidney disease
Surgery, 2013. 154(6): p. 1232-7; discussion 1237-8. in patients with multiple endocrine neoplasia type 1 and
55. Eller-Vainicher, C., et al., Sporadic and MEN1-related improved kidney function after parathyroidectomy.
primary hyperparathyroidism: differences in clinical Surgery, 2019. 165(1): p. 124-128.
expression and severity. J Bone Miner Res, 2009. 24(8): p. 68. Bilezikian, J.P., et al., Guidelines for the management of
1404-10. asymptomatic primary hyperparathyroidism: summary
56. Twigt, B.A., et al., Differences between sporadic and MEN statement from the Fourth International Workshop. J Clin
related primary hyperparathyroidism; clinical expression, Endocrinol Metab, 2014. 99(10): p. 3561-9.
preoperative workup, operative strategy and follow-up. 69. Norton, J.A., et al., Prospective study of surgery for primary
Orphanet J Rare Dis, 2013. 8: p. 50. hyperparathyroidism (HPT) in multiple endocrine
57. Wilhelm, S.M., et al., The American Association of neoplasia-type 1 and Zollinger-Ellison syndrome: long-term
Endocrine Surgeons Guidelines for Definitive Management outcome of a more virulent form of HPT. Ann Surg, 2008.
of Primary Hyperparathyroidism. JAMA Surg, 2016. 247(3): p. 501-10.
151(10): p. 959-968. 70. Hackeng, W.M., et al., A Parathyroid-Gut Axis:
58. Iacobone, M., et al., Hereditary hyperparathyroidism--a Hypercalcemia and the Pathogenesis of Gastrinoma in
consensus report of the European Society of Endocrine Multiple Endocrine Neoplasia 1. Mol Cancer Res, 2021.
Surgeons (ESES). Langenbecks Arch Surg, 2015. 400(8): 19(6): p. 946-949.
p. 867-86. 71. Nobecourt, P.F., et al., Intraoperative Decision-Making and
59. Silva, A.M., et al., Operative intervention for primary Technical Aspects of Parathyroidectomy in Young Patients
hyperparathyroidism offers greater bone recovery in With MEN1 Related Hyperparathyroidism. Front
patients with sporadic disease than in those with multiple Endocrinol (Lausanne), 2018. 9: p. 618.
endocrine neoplasia type 1-related hyperparathyroidism. 72. Nastos, C., et al., Optimal extent of initial parathyroid
Surgery, 2017. 161(1): p. 107-115. resection in patients with multiple endocrine neoplasia
60. Wang, W., et al., Impaired geometry, volumetric density, syndrome type 1: A meta-analysis. Surgery, 2021. 169(2):
and microstructure of cortical and trabecular bone p. 302-310.
assessed by HR-pQCT in both sporadic and MEN1-related 73. Schreinemakers, J.M., et al., The optimal surgical
primary hyperparathyroidism. Osteoporos Int, 2020. 31(1): treatment for primary hyperparathyroidism in MEN1
p. 165-173. patients: a systematic review. World J Surg, 2011. 35(9): p.
61. Kong, J., et al., Clinical and Genetic Analysis of Multiple 1993-2005.
Endocrine Neoplasia Type 1-Related Primary 74. Manoharan, J., et al., Single gland excision for MEN1-
Hyperparathyroidism in Chinese. PLoS One, 2016. 11(11): associated primary hyperparathyroidism. Clin Endocrinol
p. e0166634. (Oxf), 2020. 92(1): p. 63-70.
62. Lourenço, D.M., Jr., et al., Early-onset, progressive, 75. Nilubol, N., et al., Preoperative localizing studies for initial
frequent, extensive, and severe bone mineral and renal parathyroidectomy in MEN1 syndrome: is there any
complications in multiple endocrine neoplasia type 1- benefit? World J Surg, 2012. 36(6): p. 1368-74.

www.EndoText.org 41
76. Nilubol, N., et al., Utility of intraoperative parathyroid 89. Moyes, V.J., et al., Clinical Use of Cinacalcet in MEN1
hormone monitoring in patients with multiple endocrine Hyperparathyroidism. Int J Endocrinol, 2010. 2010: p.
neoplasia type 1-associated primary hyperparathyroidism 906163.
undergoing initial parathyroidectomy. World J Surg, 2013. 90. Geslot, A., et al., New therapies for patients with multiple
37(8): p. 1966-72. endocrine neoplasia type 1. Ann Endocrinol (Paris), 2021.
77. Kluijfhout, W.P., et al., Unilateral Clearance for Primary 82(2): p. 112-120.
Hyperparathyroidism in Selected Patients with Multiple 91. Singh Ospina, N., et al., Safety and efficacy of
Endocrine Neoplasia Type 1. World J Surg, 2016. 40(12): percutaneous parathyroid ethanol ablation in patients with
p. 2964-2969. recurrent primary hyperparathyroidism and multiple
78. Montenegro, F.L.M., et al., Could the Less-Than Subtotal endocrine neoplasia type 1. J Clin Endocrinol Metab, 2015.
Parathyroidectomy Be an Option for Treating Young 100(1): p. E87-90.
Patients With Multiple Endocrine Neoplasia Type 1- 92. Williams, M.D., et al., Pathology data set for reporting
Related Hyperparathyroidism? Front Endocrinol parathyroid carcinoma and atypical parathyroid neoplasm:
(Lausanne), 2019. 10: p. 123. recommendations from the International Collaboration on
79. Choi, H.R., et al., Benefit of diverse surgical approach on Cancer Reporting. Hum Pathol, 2021. 110: p. 73-82.
short-term outcomes of MEN1-related 93. Song, A., et al., Prevalence of Parathyroid Carcinoma and
hyperparathyroidism. Sci Rep, 2020. 10(1): p. 10634. Atypical Parathyroid Neoplasms in 153 Patients With
80. Nilubol, N., et al., Limited Parathyroidectomy in Multiple Multiple Endocrine Neoplasia Type 1: Case Series and
Endocrine Neoplasia Type 1-Associated Primary Literature Review. Front Endocrinol (Lausanne), 2020. 11:
Hyperparathyroidism: A Setup for Failure. Ann Surg Oncol, p. 557050.
2016. 23(2): p. 416-23. 94. Christakis, I., et al., Parathyroid carcinoma and atypical
81. Keutgen, X.M., et al., Reoperative Surgery in Patients with parathyroid neoplasms in MEN1 patients; A clinico-
Multiple Endocrine Neoplasia Type 1 Associated Primary pathologic challenge. The MD Anderson case series and
Hyperparathyroidism. Ann Surg Oncol, 2016. 23(Suppl 5): review of the literature. Int J Surg, 2016. 31: p. 10-6.
p. 701-707. 95. Singh Ospina, N., et al., Prevalence of parathyroid
82. Bioletto, F., et al., Comparison of the diagnostic accuracy carcinoma in 348 patients with multiple endocrine
of 18F-Fluorocholine PET and 11C-Methionine PET for neoplasia type 1 - case report and review of the literature.
parathyroid localization in primary hyperparathyroidism: a Clin Endocrinol (Oxf), 2016. 84(2): p. 244-249.
systematic review and meta-analysis. Eur J Endocrinol, 96. Erdheim, J., Zur normalen und pathologischen Histologie
2021. 185(1): p. 109-120. der Glandula thyreoidea, parathyreoidea, und Hypophysis.
83. Hindié, E., et al., Primary Hyperparathyroidism: Defining Beitr Pathol Anat, 1903. 33: p. 158-236.
the Appropriate Preoperative Imaging Algorithm. J Nucl 97. Dong, Q., et al., Loss of heterozygosity at 11q13: analysis
Med, 2021. 62(Suppl 2): p. 3s-12s. of pituitary tumors, lung carcinoids, lipomas, and other
84. Gauthé, M., et al., (18)F-fluorocholine PET/CT in MEN1 uncommon tumors in subjects with familial multiple
Patients with Primary Hyperparathyroidism. World J Surg, endocrine neoplasia type 1. The Journal of clinical
2020. 44(11): p. 3761-3769. endocrinology & metabolism, 1997. 82(5): p. 1416-20.
85. Fyrsten, E., et al., Long-Term Surveillance of Treated 98. Thakker, R.V., The molecular genetics of the multiple
Hyperparathyroidism for Multiple Endocrine Neoplasia endocrine neoplasia syndromes. Clinical Endocrinology,
Type 1: Recurrence or Hypoparathyroidism? World J Surg, 1993. 38(1): p. 1-14.
2016. 40(3): p. 615-21. 99. Weil, R.J., et al., 11Q13 Allelic Loss in Pituitary Tumors in
86. Pieterman, C.R., et al., Primary hyperparathyroidism in Patients With Multiple Endocrine Neoplasia Syndrome
MEN1 patients: a cohort study with longterm follow-up on Type 1. Clinical Cancer Research, 1998. 4(7): p. 1673-
preferred surgical procedure and the relation with 1678.
genotype. Ann Surg, 2012. 255(6): p. 1171-8. 100. Yoshimoto, K., et al., Allele Loss on Chromosome 11 in a
87. Filopanti, M., et al., MEN1-related hyperparathyroidism: Pituitary Tumor from a Patient with Multiple Endocrine
response to cinacalcet and its relationship with the calcium- Neoplasia Type 1. 1991. p. 886-889.
sensing receptor gene variant Arg990Gly. Eur J 101. Thakker, R.V., et al., Association of somatotrophinomas
Endocrinol, 2012. 167(2): p. 157-64. with loss of alleles on chromosome 11 and with gsp
88. Giusti, F., et al., Cinacalcet therapy in patients affected by mutations. J Clin Invest, 1993. 91(6): p. 2815-21.
primary hyperparathyroidism associated to Multiple 102. Boggild, M.D., et al., Molecular genetic studies of sporadic
Endocrine Neoplasia Syndrome type 1 (MEN1). Endocrine, pituitary tumors. J Clin Endocrinol Metab, 1994. 78(2): p.
2016. 52(3): p. 495-506. 387-92.

www.EndoText.org 42
103. Asa, S.L., K. Somers, and S. Ezzat, The MEN-1 gene is 118. Katznelson, L., et al., Acromegaly: An endocrine society
rarely down-regulated in pituitary adenomas. J Clin clinical practice guideline. Journal of Clinical Endocrinology
Endocrinol Metab, 1998. 83(9): p. 3210-2. and Metabolism, 2014. 99(11): p. 3933-3951.
104. Farrell, W.E., et al., Sequence analysis and transcript 119. Incandela, F., et al., Malignancy course of pituitary
expression of the MEN1 gene in sporadic pituitary tumours. adenoma in MEN1 syndrome: Clinical-Neuroradiological
Br J Cancer, 1999. 80(1-2): p. 44-50. signs. Eur J Radiol Open, 2020. 7: p. 100242.
105. Prezant, T.R., J. Levine, and S. Melmed, Molecular 120. Philippon, M., et al., Long-term control of a MEN1 prolactin
characterization of the men1 tumor suppressor gene in secreting pituitary carcinoma after temozolomide
sporadic pituitary tumors. J Clin Endocrinol Metab, 1998. treatment. Ann Endocrinol (Paris), 2012. 73(3): p. 225-9.
83(4): p. 1388-91. 121. Benito, M., et al., Gonadotroph tumor associated with
106. Tanaka, C., et al., Analysis of loss of heterozygosity on multiple endocrine neoplasia type 1. J Clin Endocrinol
chromosome 11 and infrequent inactivation of the MEN1 Metab, 2005. 90(1): p. 570-4.
gene in sporadic pituitary adenomas. J Clin Endocrinol 122. Scheithauer, B.W., et al., Multiple endocrine neoplasia type
Metab, 1998. 83(8): p. 2631-4. 1-associated thyrotropin-producing pituitary carcinoma:
107. Zhuang, Z., et al., Mutations of the MEN1 tumor suppressor report of a probable de novo example. Hum Pathol, 2009.
gene in pituitary tumors. Cancer Res, 1997. 57(24): p. 40(2): p. 270-8.
5446-51. 123. Morokuma, H., et al., A case of nonfunctioning pituitary
108. Ballard, H.S., B. Fame, and R.J. Hartsock, Familial multiple carcinoma that responded to temozolomide treatment.
endocrine adenoma-peptic ulcer complex. Medicine Case Rep Endocrinol, 2012. 2012: p. 645914.
(Baltimore), 1964. 43(0025-7974 (Print)): p. 481-516. 124. Triponez, F., et al., Epidemiology data on 108 MEN 1
109. Verges, B., et al., Pituitary disease in MEN type 1 (MEN1): patients from the GTE with isolated nonfunctioning tumors
Data from the France-Belgium MEN1 multicenter study. of the pancreas. Annals of surgery, 2006. 243(2): p. 265-
Journal of Clinical Endocrinology & Metabolism, 2002. 72.
87(2): p. 457-465. 125. Vinault, S., et al., Metastatic Potential and Survival of
110. Trouillas, J., et al., Pituitary tumors and hyperplasia in Duodenal and Pancreatic Tumors in Multiple Endocrine
multiple endocrine neoplasia type 1 syndrome (MEN1): a Neoplasia Type 1: A GTE and AFCE Cohort Study (Groupe
case-control study in a series of 77 patients versus 2509 d'etude des Tumeurs Endocrines and Association
non-MEN1 patients. Am J Surg Pathol, 2008. 32(4): p. 534- Francophone de Chirurgie Endocrinienne). Ann Surg,
43. 2018.
111. de Laat, J.M., et al., Long-term natural course of pituitary 126. Pipeleers-Marichal, M., et al., Gastrinomas in the
tumors in patients with MEN1: results from the Dutch MEN1 duodenums of patients with multiple endocrine neoplasia
study group (DMSG). J Clin.Endocrinol.Metab, 2015(1945- type 1 and the Zollinger-Ellison syndrome. The New
7197 (Electronic)): p. JC20152015-JC20152015. England journal of medicine, 1990. 322(11): p. 723-7.
112. Wu, Y., et al., Pituitary adenomas in patients with multiple 127. Levy-Bohbot, N., et al., Prevalence, characteristics and
endocrine neoplasia type 1: a single-center experience in prognosis of MEN 1-associated glucagonomas, VIPomas,
China. Pituitary, 2019. 22(2): p. 113-123. and somatostatinomas: study from the GTE (Groupe des
113. Cohen-Cohen, S., et al., Pituitary adenomas in the setting Tumeurs Endocrines) registry. Gastroenterologie clinique
of multiple endocrine neoplasia type 1: A single-institution et biologique, 2004. 28(11): p. 1075-81.
experience. Journal of Neurosurgery, 2021. 134(4): p. 128. Borson-Chazot, F., et al., Acromegaly induced by ectopic
1132-1138. secretion of GHRH: a review 30 years after GHRH
114. Bras, M.L., et al., Pituitary adenoma in patients with discovery. Ann Endocrinol (Paris), 2012. 73(6): p. 497-502.
multiple endocrine neoplasia type 1 – a cohort study. 2021: 129. Milanesi, A., et al., Concurrent primary
p. 1-34. hyperparathyroidism and humoral hypercalcemia of
115. Makri, A., et al., Children with MEN1 gene mutations may malignancy in a patient with multiple endocrine neoplasia
present first (and at a young age) with Cushing disease. type 1. Pancreas, 2011. 40(4): p. 634-7.
Clin Endocrinol (Oxf), 2018. 89(4): p. 437-443. 130. Klöppel, G., et al., Hyperplasia to neoplasia sequence of
116. Melmed, S., et al., Diagnosis and treatment of duodenal and pancreatic neuroendocrine diseases and
hyperprolactinemia: an Endocrine Society clinical practice pseudohyperplasia of the PP-cells in the pancreas. Endocr
guideline. J Clin Endocrinol Metab, 2011. 96(2): p. 273-88. Pathol, 2014. 25(2): p. 181-5.
117. Nieman, L.K., et al., The diagnosis of Cushing's syndrome: 131. Anlauf, M., et al., Allelic deletion of the MEN1 gene in
An endocrine society clinical practice guideline. Journal of duodenal gastrin and somatostatin cell neoplasms and
Clinical Endocrinology and Metabolism, 2008. 93(5): p. their precursor lesions. Gut, 2007. 56(5): p. 637-44.
1526-1540. 132. van Beek, D.J., et al., Surgery for multiple endocrine
neoplasia type 1-related insulinoma: long-term outcomes in

www.EndoText.org 43
 a large international cohort. Br J Surg, 2020. 107(11): p. Pancreatic Neuroendocrine Tumours. Front Endocrinol
1489-1499. (Lausanne), 2021. 12: p. 654975.
133. Gibril, F., et al., Multiple endocrine neoplasia type 1 and 146. Sadowski, S.M., et al., Prognostic factors for the outcome
Zollinger-Ellison syndrome: a prospective study of 107 of nonfunctioning pancreatic neuroendocrine tumors in
cases and comparison with 1009 cases from the literature. MEN1: a systematic review of literature. Endocr Relat
Medicine, 2004. 83(1): p. 43-83. Cancer, 2020. 27(6): p. R145-r161.
134. Ito, T., et al., Causes of death and prognostic factors in 147. Partelli, S., et al., Active Surveillance versus Surgery of
multiple endocrine neoplasia type 1: a prospective study: Nonfunctioning Pancreatic Neuroendocrine Neoplasms
comparison of 106 MEN1/Zollinger-Ellison syndrome </=2 cm in MEN1 Patients. Neuroendocrinology, 2016.
patients with 1613 literature MEN1 patients with or without 103(6): p. 779-786.
pancreatic endocrine tumors. Medicine, 2013. 92(3): p. 148. Nell, S., et al., Management of MEN1 Related
135-81. Nonfunctioning Pancreatic NETs: A Shifting Paradigm:
135. van Beek, D.J., et al., Prognostic factors and survival in Results From the DutchMEN1 Study Group. Ann Surg,
MEN1 patients with gastrinomas: Results from the 2018. 267(6): p. 1155-1160.
DutchMEN study group (DMSG). J Surg Oncol, 2019. 149. Triponez, F., et al., Is surgery beneficial for MEN1 patients
120(6): p. 966-975. with small (< or = 2 cm), nonfunctioning
136. Jensen, R.T. and T. Ito, Gastrinoma, in Endotext, K.R. pancreaticoduodenal endocrine tumor? An analysis of 65
Feingold, et al., Editors. 2000, MDText.com, Inc. Copyright patients from the GTE. World journal of surgery, 2006.
© 2000-2021, MDText.com, Inc.: South Dartmouth (MA). 30(5): p. 654-62; discussion 663-4.
137. Hampel, H., et al., A practice guideline from the American 150. Pieterman, C.R.C., et al., Long-Term Natural Course of
College of Medical Genetics and Genomics and the Small Nonfunctional Pancreatic Neuroendocrine Tumors in
National Society of Genetic Counselors: referral indications MEN1-Results From the Dutch MEN1 Study Group. J Clin
for cancer predisposition assessment. Genet Med, 2015. Endocrinol Metab, 2017. 102(10): p. 3795-3805.
17(1): p. 70-87. 151. Hackeng, W.M., et al., Non-functional pancreatic
138. Gibril, F., et al., Prospective study of the natural history of neuroendocrine tumours: ATRX/DAXX and alternative
gastrinoma in patients with MEN1: definition of an lengthening of telomeres (ALT) are prognostically
aggressive and a nonaggressive form. The Journal of independent from ARX/PDX1 expression and tumour size.
clinical endocrinology & metabolism, 2001. 86(11): p. Gut, 2021.
5282-93. 152. Cejas, P., et al., Enhancer signatures stratify and predict
139. Conemans, E.B., et al., Prognostic factors for survival of outcomes of non-functional pancreatic neuroendocrine
MEN1 patients with duodenopancreatic tumors metastatic tumors. Nat Med, 2019. 25(8): p. 1260-1265.
to the liver: results from the DMSG. Endocr Pract, 2017. 153. Chan, C.S., et al., ATRX, DAXX or MEN1 mutant
23(6): p. 641-648. pancreatic neuroendocrine tumors are a distinct alpha-cell
140. Giudici, F., et al., Natural History of MEN1 GEP-NET: signature subgroup. Nat Commun, 2018. 9(1): p. 4158.
Single-Center Experience After a Long Follow-Up. World J 154. Fahrmann, J.F., et al., A Blood-Based Polyamine Signature
Surg, 2017. 41(9): p. 2312-2323. Associated With Disease Progression in Patients With
141. Christakis, I., et al., Genotype-phenotype pancreatic Multiple Endocrine Neoplasia Type 1-Related
neuroendocrine tumor relationship in multiple endocrine Duodenopancreatic Neuroendocrine Tumors. Journal of
neoplasia type 1 patients: A 23-year experience at a single the Endocrine Society, 2021. 5(Supplement_1): p. A1009-
institution. Surgery, 2018. 163(1): p. 212-217. A1009.
142. Nagtegaal, I.D., et al., The 2019 WHO classification of 155. Niederle, B., et al., Multiple Endocrine Neoplasia Type 1
tumours of the digestive system. Histopathology, 2020. (MEN1) and the Pancreas - Diagnosis and Treatment of
76(2): p. 182-188. Functioning and Non-Functioning Pancreatic and
143. van Treijen, M.J.C., et al., Diagnosing Nonfunctional Duodenal Neuroendocrine Neoplasia within the MEN1
Pancreatic NETs in MEN1: The Evidence Base. J Endocr Syndrome - An International Consensus Statement.
Soc, 2018. 2(9): p. 1067-1088. Neuroendocrinology, 2020.
144. Pieterman, C.R.C., et al., HEREDITARY ENDOCRINE 156. Falconi, M., et al., ENETS Consensus Guidelines Update
TUMOURS: CURRENT STATE-OF-THE-ART AND for the Management of Patients with Functional Pancreatic
RESEARCH OPPORTUNITIES: MEN1-related pancreatic Neuroendocrine Tumors and Non-Functional Pancreatic
NETs: identification of unmet clinical needs and future Neuroendocrine Tumors. Neuroendocrinology, 2016.
directives. Endocr Relat Cancer, 2020. 27(8): p. T9-t25. 103(2): p. 153-71.
145. Cuthbertson, D.J., et al., The Impact of (68)Gallium DOTA 157. Metz, D.C., et al., Diagnosis of Zollinger-Ellison syndrome
PET/CT in Managing Patients With Sporadic and Familial in the era of PPIs, faulty gastrin assays, sensitive imaging

www.EndoText.org 44
 and limited access to acid secretory testing. Int J Endocr 171. Delle Fave, G., et al., ENETS Consensus Guidelines
Oncol, 2017. 4(4): p. 167-185. Update for Gastroduodenal Neuroendocrine Neoplasms.
158. Singh Ospina, N., et al., Assessing for Multiple Endocrine Neuroendocrinology, 2016. 103(2): p. 119-24.
Neoplasia Type 1 in Patients Evaluated for Zollinger- 172. Rimbaş, M., et al., Interventional endoscopic ultrasound for
Ellison Syndrome-Clues to a Safer Diagnostic Process. Am pancreatic neuroendocrine neoplasms. Dig Endosc, 2020.
J Med, 2017. 130(5): p. 603-605. 32(7): p. 1031-1041.
159. Albers, M.B., J. Manoharan, and D.K. Bartsch, 173. Caplin, M.E., et al., Lanreotide in metastatic
Contemporary surgical management of the Zollinger- enteropancreatic neuroendocrine tumors. N Engl J Med,
Ellison syndrome in multiple endocrine neoplasia type 1. 2014. 371(3): p. 224-33.
Best Pract Res Clin Endocrinol Metab, 2019. 33(5): p. 174. Caplin, M.E., et al., Anti-tumour effects of lanreotide for
101318. pancreatic and intestinal neuroendocrine tumours: the
160. Hackeng, W.M., et al., Metastatic Patterns of CLARINET open-label extension study. Endocr Relat
Duodenopancreatic Neuroendocrine Tumors in Patients Cancer, 2016. 23(3): p. 191-9.
With Multiple Endocrine Neoplasia Type 1. Am J Surg 175. Ramundo, V., et al., Impact of long-acting octreotide in
Pathol, 2021. patients with early-stage MEN1-related duodeno-
161. Norton, J.A., et al., Comparison of surgical results in pancreatic neuroendocrine tumours. Clinical
patients with advanced and limited disease with multiple endocrinology, 2014. 80(6): p. 850-5.
endocrine neoplasia type 1 and Zollinger-Ellison 176. Cioppi, F., et al., The LARO-MEN1 study: a longitudinal
syndrome. Annals of surgery, 2001. 234(4): p. 495-505; clinical experience with octreotide Long-Acting Release in
discussion 505-6. patients with Multiple Endocrine Neoplasia type 1
162. Endall, R., et al., The Relationship of Gastrinoma in MEN 1 Syndrome. Clin Cases Miner Bone Metab, 2017. 14(2): p.
to Helicobacter pylori infection. J Clin Endocrinol Metab, 123-130.
2020. 105(3). 177. Faggiano, A., et al., Lanreotide Therapy vs Active
163. Cryer, P.E., et al., Evaluation and management of adult Surveillance in MEN1-Related Pancreatic Neuroendocrine
hypoglycemic disorders: an Endocrine Society Clinical Tumors < 2 Centimeters. J Clin Endocrinol Metab, 2020.
Practice Guideline. J Clin Endocrinol Metab, 2009. 94(3): 105(1).
p. 709-28. 178. Pavel, M., et al., ENETS Consensus Guidelines Update for
164. Bartsch, D.K., et al., Enucleation and limited pancreatic the Management of Distant Metastatic Disease of
resection provide long-term cure for insulinoma in multiple Intestinal, Pancreatic, Bronchial Neuroendocrine
endocrine neoplasia type 1. Neuroendocrinology, 2013. Neoplasms (NEN) and NEN of Unknown Primary Site.
98(4): p. 290-8. Neuroendocrinology, 2016. 103(2): p. 172-85.
165. Vezzosi, D., et al., Long-term results of the surgical 179. Yao, J.C., et al., Everolimus for advanced pancreatic
management of insulinoma patients with MEN1: a Groupe neuroendocrine tumors. The New England journal of
d'étude des Tumeurs Endocrines (GTE) retrospective medicine, 2011. 364(6): p. 514-23.
study. Eur J Endocrinol, 2015. 172(3): p. 309-19. 180. Raymond, E., et al., Sunitinib malate for the treatment of
166. Tonelli, F., et al., Operation for insulinomas in multiple pancreatic neuroendocrine tumors. The New England
endocrine neoplasia type 1: When journal of medicine, 2011. 364(6): p. 501-13.
pancreatoduodenectomy is appropriate. Surgery, 2017. 181. Strosberg, J., et al., Phase 3 Trial of (177)Lu-Dotatate for
161(3): p. 727-734. Midgut Neuroendocrine Tumors. N Engl J Med, 2017.
167. Antwi, K., et al., 68Ga-Exendin-4 PET/CT Detects 376(2): p. 125-135.
Insulinomas in Patients With Endogenous 182. Frost, M., K.E. Lines, and R.V. Thakker, Current and
Hyperinsulinemic Hypoglycemia in MEN-1. J Clin emerging therapies for PNETs in patients with or without
Endocrinol Metab, 2019. 104(12): p. 5843-5852. MEN1. Nat Rev Endocrinol, 2018. 14(4): p. 216-227.
168. Shah, R., et al., Exendin-4-based imaging in insulinoma 183. Debelenko, L.V., et al., The multiple endocrine neoplasia
localization: Systematic review and meta-analysis. Clin type I gene locus is involved in the pathogenesis of type II
Endocrinol (Oxf), 2021. 95(2): p. 354-364. gastric carcinoids. Gastroenterology, 1997. 113(3): p. 773-
169. van Beek, D.J., et al., Prognosis after surgery for multiple 81.
endocrine neoplasia type 1-related pancreatic 184. Lee, L., et al., Insights into Effects/Risks of Chronic
neuroendocrine tumors: Functionality matters. Surgery, Hypergastrinemia and Lifelong PPI Treatment in Man
2021. 169(4): p. 963-973. Based on Studies of Patients with Zollinger-Ellison
170. Dasari, B.V.M., et al., Outcomes of Surgical and Syndrome. Int J Mol Sci, 2019. 20(20).
Endoscopic Resection of Duodenal Neuroendocrine 185. Manoharan, J., et al., Gastric enterochromaffin-like cell
Tumours (NETs): a Systematic Review of the Literature. J changes in multiple endocrine neoplasia type 1. Clin
Gastrointest Surg, 2018. 22(9): p. 1652-1658. Endocrinol (Oxf), 2021. 95(3): p. 439-446.

www.EndoText.org 45
186. Richards, M.L., et al., Regression of type II gastric syndrome: The Italian series. Journal of Clinical
carcinoids in multiple endocrine neoplasia type 1 patients Endocrinology and Metabolism, 2005. 90(5): p. 2603-2609.
with Zollinger-Ellison syndrome after surgical excision of all 200. de Laat, J.M., et al., Natural course and survival of
gastrinomas. World J Surg, 2004. 28(7): p. 652-8. neuroendocrine tumors of thymus and lung in MEN1
187. Kloppel, G., M. Anlauf, and A. Perren, Endocrine precursor patients. Journal of Clinical Endocrinology and Metabolism,
lesions of gastroenteropancreatic neuroendocrine tumors. 2014. 99(9): p. 3325-3333.
Endocrine pathology, 2007. 18: p. 150-155. 201. Christakis, I., et al., Clinical Features, Treatments, and
188. Berna, M.J., et al., A prospective study of gastric carcinoids Outcomes of Patients with Thymic Carcinoids and Multiple
and enterochromaffin-like cell changes in multiple Endocrine Neoplasia Type 1 Syndrome at MD Anderson
endocrine neoplasia type 1 and Zollinger-Ellison Cancer Center. Hormones and Cancer, 2016. 7(4): p. 279-
syndrome: identification of risk factors. J Clin Endocrinol 287.
Metab, 2008. 93(5): p. 1582-91. 202. Lim, L.C., et al., Thymic carcinoid in multiple endocrine
189. Bordi, C., et al., Aggressive forms of gastric neoplasia 1: Genotype-phenotype correlation and
neuroendocrine tumors in multiple endocrine neoplasia prevention. Journal of Internal Medicine, 2006. 259(4): p.
type I. Am J Surg Pathol, 1997. 21(9): p. 1075-82. 428-432.
190. Norton, J.A., et al., Gastric carcinoid tumors in multiple 203. Sadowski, S.M., et al., The future: surgical advances in
endocrine neoplasia-1 patients with Zollinger-Ellison MEN1 therapeutic approaches and management
syndrome can be symptomatic, demonstrate aggressive strategies. Endocrine-related cancer, 2017. 24(10): p.
growth, and require surgical treatment. Surgery, 2004. T243-T260.
136(6): p. 1267-74. 204. van den Broek, M.F.M., et al., The Management of
191. Mandl, A., et al., Two distinct classes of thymic tumors in Neuroendocrine Tumors of the Lung in MEN1: Results
patients with MEN1 show LOH at the MEN1 locus. Endocr From the Dutch MEN1 Study Group. The Journal of clinical
Relat Cancer, 2021. 28(11): p. L15-l19. endocrinology and metabolism, 2021. 106(2): p. e1014-
192. Volante, M., et al., Molecular Pathology of Well- e1027.
Differentiated Pulmonary and Thymic Neuroendocrine 205. Sachithanandan, N., R.A. Harle, and J.R. Burgess,
Tumors: What Do Pathologists Need to Know? Endocr Bronchopulmonary carcinoid in multiple endocrine
Pathol, 2021. 32(1): p. 154-168. neoplasia type 1. Cancer, 2005. 103(3): p. 509-515.
193. Teh, B.T., et al., Clinicopathologic Studies of Thymic 206. Lecomte, P., et al., Histologically Proven Bronchial
Carcinoids in Multiple Endocrine Neoplasia Type 1. Neuroendocrine Tumors in MEN1: A GTE 51-Case Cohort
Medicine (Baltimore), 1997. 76(1): p. 21-29. Study. World Journal of Surgery, 2018. 42(1): p. 143-152.
194. Ye, L., et al., Clinical features and prognosis of thymic 207. Bartsch, D.K., et al., Bronchopulmonary Neuroendocrine
neuroendocrine tumours associated with multiple Neoplasms and Their Precursor Lesions in Multiple
endocrine neoplasia type 1: A single-centre study, Endocrine Neoplasia Type 1. Neuroendocrinology, 2016.
systematic review and meta-analysis. Clinical 103(3-4): p. 240-247.
Endocrinology, 2017. 87(6): p. 706-716. 208. van den Broek, M.F.M., et al., Well-Differentiated
195. Singh Ospina, N., et al., Thymic and Bronchial Carcinoid Bronchopulmonary Neuroendocrine Tumors: More Than
Tumors in Multiple Endocrine Neoplasia Type 1: The Mayo One Entity. J Thorac Oncol, 2021. 16(11): p. 1810-1820.
Clinic Experience from 1977 to 2013. Hormones and 209. Sadowski, S.M., et al., Results of 68Gallium-DOTATATE
Cancer, 2015. 6(5-6): p. 247-253. PET/CT Scanning in Patients with Multiple Endocrine
196. Sakurai, A., et al., Thymic neuroendocrine tumour in Neoplasia Type 1. Journal of the American College of
multiple endocrine neoplasia type 1: Female patients are Surgeons, 2015. 221(2): p. 509-517.
not rare exceptions. Clinical Endocrinology, 2013. 78(2): p. 210. Lastoria, S., et al., Role of 68Ga-DOTATATE PET/CT in
248-254. patients with multiple endocrine neoplasia type 1 (MEN1).
197. Goudet, P., et al., Thymic neuroendocrine tumors in Endocrine, 2016. 52(3): p. 488-494.
multiple endocrine neoplasia type 1: A comparative study 211. Froeling, V., et al., Impact of Ga-68 DOTATOC PET/CT on
on 21 cases among a series of 761 MEN1 from the GTE the diagnosis and treatment of patients with multiple
(Groupe des Tumeurs Endocrines). World Journal of endocrine neoplasia. Annals of Nuclear Medicine, 2012.
Surgery, 2009. 33(6): p. 1197-1207. 26(9): p. 738-743.
198. Gibril, F., et al., Prospective study of thymic carcinoids in 212. Albers, M.B., et al., Limited Value of Ga-68-DOTATOC-
patients with multiple endocrine neoplasia type 1. Journal PET-CT in Routine Screening of Patients with Multiple
of Clinical Endocrinology and Metabolism, 2003. 88(3): p. Endocrine Neoplasia Type 1. World journal of surgery,
1066-1081. 2017. 41(6): p. 1521-1527.
199. Ferolla, P., et al., Thymic neuroendocrine carcinoma 213. Harding, B., et al., Multiple endocrine neoplasia type 1
(carcinoid) in multiple endocrine neoplasia type 1 knockout mice develop parathyroid, pancreatic, pituitary

www.EndoText.org 46
 and adrenal tumours with hypercalcaemia, and a novel mutation in the MEN1 gene. World J Surg
hypophosphataemia and hypercorticosteronaemia. Endocr Oncol, 2011. 9: p. 6.
Relat Cancer, 2009. 16(4): p. 1313-27. 230. Haase, M., et al., A new mutation in the menin gene causes
214. Loffler, K.a., et al., Broad tumor spectrum in a mouse model the multiple endocrine neoplasia type 1 syndrome with
of multiple endocrine neoplasia type 1. International journal adrenocortical carcinoma. Endocrine, 2011. 39(2): p. 153-
of cancer. Journal international du cancer, 2007. 120: p. 9.
259-67. 231. Harada, K., et al., A novel case of myxoid variant of
215. Ludwig, L., et al., Loss of wild-type MEN1 gene expression adrenocortical carcinoma in a patient with multiple
in multiple endocrine neoplasia type 1-associated endocrine neoplasia type 1. Endocr J, 2019. 66(8): p. 739-
parathyroid adenoma. Endocr J, 1999. 46(4): p. 539-44. 744.
216. Skogseid, B., et al., Clinical and genetic features of 232. Kharb, S., et al., Hidden diagnosis of multiple endocrine
adrenocortical lesions in multiple endocrine neoplasia type neoplasia-1 unraveled during workup of virilization caused
1. J Clin Endocrinol Metab, 1992. 75(1): p. 76-81. by adrenocortical carcinoma. Indian J Endocrinol Metab,
217. Gatta-Cherifi, B., et al., Adrenal involvement in MEN1. 2013. 17(3): p. 514-8.
Analysis of 715 cases from the Groupe d'etude des 233. Ohara, N., et al., Lung adenocarcinoma and adrenocortical
Tumeurs Endocrines database. Eur J Endocrinol, 2012. carcinoma in a patient with multiple endocrine neoplasia
166(2): p. 269-79. type 1. Respir Med Case Rep, 2017. 20: p. 77-81.
218. Barzon, L., et al., Multiple endocrine neoplasia type 1 and 234. Assié, G., et al., Integrated genomic characterization of
adrenal lesions. J Urol, 2001. 166(1): p. 24-7. adrenocortical carcinoma. Nat Genet, 2014. 46(6): p. 607-
219. Burgess, J.R., et al., Adrenal lesions in a large kindred with 12.
multiple endocrine neoplasia type 1. Arch Surg, 1996. 235. Tepede, A.A., et al., 18F-FDOPA PET/CT accurately
131(7): p. 699-702. identifies MEN1-associated pheochromocytoma.
220. Langer, P., et al., Adrenal involvement in multiple Endocrinol Diabetes Metab Case Rep, 2020. 2020.
endocrine neoplasia type 1. World J Surg, 2002. 26(8): p. 236. Dénes, J., et al., Heterogeneous genetic background of the
891-6. association of pheochromocytoma/paraganglioma and
221. Schaefer, S., et al., Natural course of small adrenal lesions pituitary adenoma: results from a large patient cohort. J
in multiple endocrine neoplasia type 1: an endoscopic Clin Endocrinol Metab, 2015. 100(3): p. E531-41.
ultrasound imaging study. Eur J Endocrinol, 2008. 158(5): 237. Fassnacht, M., et al., Management of adrenal
p. 699-704. incidentalomas: European Society of Endocrinology
222. Skogseid, B., et al., Adrenal lesion in multiple endocrine Clinical Practice Guideline in collaboration with the
neoplasia type 1. Surgery, 1995. 118(6): p. 1077-82. European Network for the Study of Adrenal Tumors. Eur J
223. Ventura, M., M. Melo, and F. Carrilho, Outcome and long- Endocrinol, 2016. 175(2): p. G1-g34.
term follow-up of adrenal lesions in multiple endocrine 238. Asgharian, B., et al., Cutaneous tumors in patients with
neoplasia type 1. Arch Endocrinol Metab, 2019. 63(5): p. multiple endocrine neoplasm type 1 (MEN1) and
516-523. gastrinomas: Prospective study of frequency and
224. Waldmann, J., et al., Adrenal involvement in multiple development of criteria with high sensitivity and specificity
endocrine neoplasia type 1: results of 7 years prospective for MEN1. Journal of Clinical Endocrinology and
screening. Langenbecks Arch Surg, 2007. 392(4): p. 437- Metabolism, 2004. 89(11): p. 5328-5336.
43. 239. Darling, T.N., et al., Multiple Facial Angiofibromas and
225. Whitley, S.A., et al., The appearance of the adrenal glands Collagenomas in Patients With Multiple Endocrine
on computed tomography in multiple endocrine neoplasia Neoplasia Type 1. Arch Dermatol., 1997. 7(133): p. 853-
type 1. Eur J Endocrinol, 2008. 159(6): p. 819-24. 857.
226. Wang, W., et al., Adrenocortical carcinoma in patients with 240. Vidal, A., et al., Cutaneous lesions associated to multiple
MEN1: a kindred report and review of the literature. Endocr endocrine neoplasia syndrome type 1. Journal of the
Connect, 2019. 8(3): p. 230-238. European Academy of Dermatology and Venereology,
227. Dotzenrath, C., et al., Malignant endocrine tumors in 2008. 22(7): p. 835-838.
patients with MEN 1 disease. Surgery, 2001. 129(1): p. 91- 241. Pack, S., et al., Cutaneous tumors in patients with multiple
5. endocrine neoplasia type 1 show allelic deletion of the
228. Febrero, B., A. Ríos, and J.M. Rodríguez, Aggressive MEN1 gene. Journal of Investigative Dermatology, 1998.
adrenal carcinoma in a young patient with Multiple 110(4): p. 438-440.
Endocrine Neoplasia 1 syndrome. Med Clin (Barc), 2017. 242. Vortmeyer, A.O., et al., Multiple endocrine neoplasia 1
149(10): p. 463. gene alterations in MEN1-associated and sporadic
229. Griniatsos, J.E., et al., Bilateral adrenocortical carcinoma in lipomas. Journal of the National Cancer Institute, 1998.
a patient with multiple endocrine neoplasia type 1 (MEN1) 90(5): p. 398-399.

www.EndoText.org 47
243. Dreijerink, K.M.A., et al., The Multiple Endocrine Neoplasia united states general population. Surgery (United States),
Type 1 (MEN1) Tumor Suppressor Regulates Peroxisome 2017. 163: p. 205-211.
Proliferator-Activated Receptor γ-Dependent Adipocyte 258. van Leeuwaarde, R.S., et al., High fear of disease
Differentiation. Molecular and Cellular Biology, 2009. occurrence is associated with low quality of life in patients
29(18): p. 5060-5069. with Multiple Endocrine Neoplasia type 1 (MEN1): Results
244. Parekh, V.I., et al., Consequence of Menin Deficiency in from the Dutch MEN1 Study Group. The Journal of Clinical
Mouse Adipocytes Derived by in Vitro Differentiation. Endocrinology & Metabolism, 2018. 103(June): p. 2354-
International Journal of Endocrinology, 2015. 2015. 2361.
245. Radman, M. and T. Milicevic, A novel mutation of the MEN1 259. van Leeuwaarde, R.S., et al., Health-related quality of life
gene in a patient with multiple endocrine neoplasia type 1 in patients with Multiple Endocrine Neoplasia type 1.
and recurrent fibromyxoid sarcoma- A case report. BMC Neuroendocrinology, 2020: p. 1-8.
Medical Genetics, 2020. 21(1): p. 1-4. 260. Berglund, G., et al., Quality of life in patients with multiple
246. Cheah, S.K., et al., Breast cancer in multiple endocrine endocrine neoplasia type 1 ( MEN1 ). Familial Cancer,
neoplasia type 1 (MEN1). Endocrinology, Diabetes & 2003. 1(2): p. 27-33.
Metabolism Case Reports, 2021. 2021(May): p. 1-7. 261. You, Y.N., et al., Pancreatoduodenal surgery in patients
247. Jeong, Y.J., H.K. Oh, and J.G. Bong, Multiple endocrine with multiple endocrine neoplasia type 1: Operative
neoplasia type 1 associated with breast cancer: A case outcomes, long-term function, and quality of life. Surgery,
report and review of the literature. Oncology letters, 2014. 2007. 142(6): p. 829-836.
8(1): p. 230-234.
248. Kim, S.H. and J.H. Park, Adrenal incidentaloma, breast
cancer and unrecognized multiple endocrine neoplasia
type 1. Acta Endocrinologica, 2019. 15(4): p. 513-517.
249. Maria, B.C., et al., Incidental finding of MEN-1 syndrome
during staging and follow-up of breast carcinoma. BMJ
Case Reports, 2020. 13(12): p. 1-6.
250. Seigne, C., et al., High incidence of mammary
intraepithelial neoplasia development in Men1-disrupted
murine mammary glands. The Journal of pathology, 2013.
229(4): p. 546-58.
251. Imachi, H., et al., Menin, a product of the MENI gene, binds
to estrogen receptor to enhance its activity in breast cancer
cells: possibility of a novel predictive factor for tamoxifen
resistance. Breast cancer research and treatment, 2010.
122(2): p. 395-407.
252. Dreijerink, K.M., et al., Article Enhancer-Mediated
Oncogenic Function of the Menin Tumor Suppressor in
Breast Cancer. Cell Reports, 2017. In Press(1).
253. Teinturier, R., et al., Reduced menin expression leads to
decreased ERα expression and is correlated with the
occurrence of human luminal B-like and ER-negative
breast cancer subtypes. Breast Cancer Research and
Treatment, 2021(0123456789).
254. Goswami, S., et al., Disease and treatment factors
associated with lower quality of life scores in adults with
multiple endocrine neoplasia type I. Surgery, 2017: p. 1-8.
255. Marini, F., et al., Management impact: effects on quality of
life and prognosis in MEN1. Endocrine-Related Cancer,
2017. 24(10): p. T227-T242.
256. Peipert, B.J., et al., Financial burden is associated with
worse health-related quality of life in adults with multiple
endocrine neoplasia type 1. Surgery, 2017: p. 1-8.
257. Peipert, B.J., et al., Health-related quality of life in MEN1
patients compared with other chronic conditions and the

www.EndoText.org 48