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Review Article
Pituitary Neuroendocrine Tumors in Multiple Endocrine Neoplasia
Sang Ouk Chin1orcid, Constance Chik2, Toru Tateno2orcid

DOI: https://doi.org/10.3803/EnM.2024.2074
Published online: August 30, 2024

1Department of Endocrinology and Metabolism, Kyung Hee University College of Medicine, Kyung Hee University Hospital, Seoul, Korea

2Division of Endocrinology and Metabolism, Department of Medicine, University of Alberta, Edmonton, AB, Canada

Corresponding author: Toru Tateno Division of Endocrinology and Metabolism, Department of Medicine, University of Alberta, Room 9-112J, Clinical Sciences Building, 11350-83 Avenue, Edmonton, AB, T6G 2G3, Canada Tel: +1-780-492-3626, Fax: +1-780-492-6444, E-mail: tateno@ualberta.ca
• Received: June 28, 2024   • Revised: July 23, 2024   • Accepted: August 2, 2024

Copyright © 2024 Korean Endocrine Society

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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  • Multiple endocrine neoplasia type 1 (MEN1) is an autosomal-dominant disorder characterized by tumors of the pituitary, parathyroid, and endocrine-gastrointestinal tract. Pituitary neuroendocrine tumors (PitNETs) occur in about 40% of MEN1 cases, with 10% being the first manifestation. Recent studies show a slight female predominance, with microPitNETs (<1 cm) being more common than macroPitNETs (>1 cm). Functional PitNETs (FPitNETs) are more frequent than non-functional ones (36% to 48%), with prolactinomas being the most common FPitNETs. MEN1-associated PitNETs are often plurihormonal, larger, and more invasive compared to sporadic types, though patient age and FPitNET proportions are similar. MEN1 mutation-negative patients tend to have larger, symptomatic PitNETs at diagnosis. Six patients with MEN1 have been reported to have pituitary carcinomas, including a mutation-negative patient. Treatment approach between PitNETs in MEN1 and sporadic types appears to be similar. PitNETs also occur in MEN4, but their epidemiology is less understood. In patients with a MEN1-like phenotype and negative genetic testing, MEN4 should be considered.
  • Keywords: Multiple endocrine neoplasia; Pituitary diseases; Neuroendocrine tumors
Multiple endocrine neoplasia (MEN) is an autosomal dominant disorder characterized by the occurrence of tumors involving two or more endocrine glands in a single patient. Two major forms of MEN are recognized and referred to as type 1 (MEN1) and type 2 (MEN2), and each type is characterized by the development of tumors within specific endocrine glands [1]. Patients with MEN1 or MEN2 carry mutations in the MEN1 (type 1) and RET (type 2) genes acting as a tumor suppressor gene and an oncogene, respectively. Mutations in MEN1 are identified in 85% to 90% of patients with MEN1 [1,2]. Approximately 5% to 25% of patients with a MEN1-like phenotype were found not to carry a mutation in MEN1 [3]. Instead, germline mutations in the cyclin-dependent kinase (CDK) inhibitor 1b gene (CDKN1B) have been identified in 3% of MEN1 mutation-negative patients presenting with a MEN1 phenotype [3], and these cases have been classified as MEN4 [4,5]. Twenty-three different mutations of CDKN1B associated with MEN4 and a total of 57 carriers have been reported in the literature [6].
MEN1 is diagnosed if one of three criteria is satisfied: a clinical criterion, if the patient has two or more MEN1 manifestations; a familial criterion, if the patient has one MEN1 manifestation and a first-degree relative with MEN1; and a genetic criterion, if the patient has a mutation in MEN1 [1]. MEN2 is characterized by medullary thyroid carcinoma (MTC) accompanied with pheochromocytoma, and three clinical variants, which are referred to as MEN2A, MEN2B, and MTC-only [1].
In patients with MEN1, pituitary neuroendocrine tumors (PitNETs; this review follows a major nomenclature change, in which pituitary adenomas are newly referred to as PitNETs according to the 2022 World Health Classification) [7] were reported to occur in approximately 40% of patients with MEN1 [8]. Only 22 cases of PitNETs in patients with MEN4 have been described in the literature (Table 1). Due to the small number of cases reported to date, assessment of the epidemiology and characteristics of PitNETs in patients with MEN4 is challenging, but the overall characteristics are assumed to be similar to those of PitNETs in MEN1 [5]. This article reviews the clinical features of PitNETs found in patients with MEN1 and MEN4. It is very serendipitous to note that there have been four reported cases of MEN2 with PitNETs, but all of them appear to be coincidental findings and independent of MEN2 [9-12].
Epidemiology
Few studies have solely investigated the epidemiology of PitNETs in MEN1. According to literature published from the late 1980s to the early 2000s, the prevalence of PitNETs in MEN1 has been reported to be between 18% and 50% [13-16]. It is of note that limitations in these studies, such as different imaging modalities, retrospective data collection at single centers, and varying duration of follow-up, might have introduced some bias when analyzing the epidemiologic data and may not be generalizable to other populations. After the publication of the Endocrine Society Guideline in 2012 [17], there were four cohort studies (France, the Netherlands, the United States, and China) solely investigating PitNETs in MEN1. Two of these studies collected data from nationwide MEN1 databases [8,18], while the other two were based on single-center data [19,20].
In line with studies conducted between the late 1980s and 2010, the prevalence of PitNETs in MEN1, based on studies published after 2012 was reported to be between 31.5% and 52% [8,18-20]. According to a Dutch cohort study investigating the prevalence of PitNETs in MEN1 between 1990–2001 and 2001–2011, the incidence rates appeared to be similar between the two periods: 34.0 (95% confidence interval [CI], 20.5 to 53.1) and 34.6 (95% CI, 25.4 to 46.0) per 1,000 patient years [8]. A slight female predominance was also found, with the age of diagnosis of PitNETs in MEN1 typically occurring between the 30s and 50s [8,18-20]. It was interesting to note that approximately 10% of patients presented with a PitNET as the initial manifestation of MEN1 (Dutch study: 36/323, 11.1%; French study: 65/551, 11.8%) [8,18]. An earlier French-Belgium multicenter MEN1 study in 2002 similarly reported that 17% (56/136) of patients had PitNETs as their first manifestation of MEN1 [16].
Characteristics of PitNETs in MEN1
As for the functionality of PitNETs in MEN1, all four cohort studies published after 2012 showed that functional PitNETs (FPitNETs) were more frequent than non-functional PitNETs (NFPitNETs). Prolactinomas were the most common FPitNETs, followed by growth hormone-producing PitNETs (GHomas) and adrenocorticotropic hormone-producing PitNETs (ACTHomas) [8,18-20]. Some studies also reported the diagnosis of thyroid-stimulating hormone-producing PitNETs [18] and gonadotropin-producing PitNETs [8,18]. Interestingly, 5% to 10% of FPitNETs in MEN1 were co-secreting tumors [8,18-20]. There is some suggestion in the literature that pituitary-associated Cushing disease is more frequent than Cushing syndrome caused by adrenal lesions in pediatric MEN1 patients [21].
The analysis regarding the size of PitNETs in MEN1 demonstrates different results depending on the period of the analysis, possibly due to improvements in screening techniques and their availability. According to a study by Verges et al. [16] in 2002, there were more macroPitNETs than microPitNETs (n=19, 14% for microPitNETs; n=116, 85% for macroPitNETs). However, recent cohort studies commonly reported a higher prevalence of microPitNETs [8,18-20]. Improved imaging techniques, with improved magnetic resonance imaging resolution and performance, could account for the increasing prevalence of microPitNETs in MEN1 [18,20]. It should be noted that there was more macroPitNETs in MEN1 patients with GHomas [8]. A French cohort study in 2021 revealed that macroPitNETs were more likely to be FPitNETs than microPitNETs [18]. Interestingly, ACTHomas were mostly microPitNETs in most studies, but not in the French-Belgium study in 2002 [16]. All the cohort studies published after 2012 reported a higher proportion of patients with plurihormonal PitNETs (4% to 11%) [8,18-20], similar to those published before 2012 (10%) [16]. Most of them were found to produce prolactin and either growth hormone or adrenocorticotropic hormone. Interestingly, all these PitNETs were macroPitNETs. Plurihormonal PitNETs in MEN1 were more likely to be macroPitNETs than those producing a single hormone [20]. None of the cohort studies after 2012 reported cases of pituitary carcinoma in patients with MEN1. However, five such cases have been described [22-26], indicating that an appropriate evaluation is necessary when pituitary carcinoma is suspected.
The prevalence of NFPitNETs in MEN1 was found to be between 36% and 48% in recent studies [8,18-20], exceeding the rate of 15% reported in a study published by Verges et al. [16]. MicroPitNETs were reported to be more common than macroadenomas [8,18-20]. Intriguingly, the change in size of NFPitNETs in MEN1 was not evident: More than 90% of these patients exhibited no significant size change even without treatment after a median follow-up of 6 years [8]. According to Wu et al. [19], there was no progression to macroPitNETs among 19 patients with asymptomatic microPitNETs during a median follow-up of 35 months. Based on these data, it seems appropriate to observe NFPitNETs in MEN1 in the majority of patients, considering their indolent natural history [18,20]. Nonetheless, it should be noted that 10% of patients with NFPitNETs in MEN1 underwent surgical removal due to symptoms associated with growth [20]. Therefore, additional long-term studies are necessary to confirm the characteristics of NFPitNETs in MEN1.
A comparison of PitNETs between MEN1 and non-MEN1 patients by Trouillas et al. [27] in 2008 revealed that the patient age and the proportion of FPitNETs between the two groups were similar. However, there were more plurihormonal PitNETs, which were larger and more histologically invasive, in MEN1 patients than in non-MEN1 patients [27]. Unfortunately, there are not many studies analyzing the differences in characteristics of PitNETs in MEN1 according to the presence or absence of MEN1 mutation. No specific types or locations of mutations have been reported to significantly correlate with the risk of PitNETs in MEN1 [16]. Interestingly, MEN1 mutation-negative patients were shown to be more likely to have a PitNET (17.0% with PitNETs vs. 4.5% without PitNETs) and to be more symptomatic with larger tumor sizes at the time of diagnosis, requiring direct treatment [8]. This difference might be explained by the higher likelihood of these patients undergoing follow-up and screening programs for MEN1 after being diagnosed with a PitNET. This result also emphasizes that MEN1 mutations are not associated with the aggressiveness or progression of PitNETs in MEN1 when compared with the sporadic type [8]. MEN1 mosaicism could be another possible explanation for the higher prevalence of PitNETs in MEN1 mutation-negative patients [28]. In addition, it is worthwhile to note that the prevalence of MEN1 mutations was reported to be slightly higher in young adults (<30 years) with macroPitNETs and in children with FPitNETs such as prolactinomas or GHomas than in those with sporadic PitNETs [29-31]. Indeed, according to a recent prolactinoma consensus statement, MEN1 germline mutation screening could be considered in patients with a family history of PitNETs and in patients aged <30 years old with macroPitNETs; however, the grading of the recommendation was weak based on the quality of evidence [32]. Together, a more comprehensive screening in patients with PitNETs at these age groups seems warranted [33].
Treatment
There appears to be no significant difference in the treatment approaches needed between PitNETs in MEN1 and sporadic types [33]. The current practice guideline also recommends that the treatment of PitNETs in MEN1 is similar to that in nonMEN1 cases and consists of appropriate medical therapy (e.g., dopamine agonists for two prolactinomas; somatostatin analogues for GHomas) or surgical removal with radiotherapy in cases of residual unresectable tumor [1]. An earlier study reported a poorer response to treatment compared with a control group: normalization of hypersecreting pituitary hormones occurred in only 42% of cases after treatment which included medical, surgical, and radiotherapy interventions [16]. Additionally, successful treatment outcomes were much less frequent in MEN1 than in non-MEN1 cases (42% vs. 90%, P<0.001) [16].
However, recent studies have shown more promising treatment outcomes. Data from the Dutch MEN1 database revealed that 91.2% (31/34) of patients with prolactinomas who underwent the treatment immediately after diagnosis achieved hormonal control during follow-up (median, 13.8 years; range, 2.5 to 32). Additionally, all patients with GHomas (n=8) also reached hormonal control after multimodal treatment [8]. A single-center study in China reported that approximately 50% of patients with prolactinomas experienced either symptomatic improvement or a decrease in prolactin levels after medical treatment with bromocriptine [19]. The relapse rate after surgical removal of GHomas was 14.3% [19]. Furthermore, among the 36 patients with FPitNETs who underwent transsphenoidal resection, 29 patients (81%) achieved remission [20]. This improvement in treatment outcomes may be due to newly extended therapeutic options for prolactinomas and GHomas [18]. Interestingly, the treatment response was similar regardless of the presence of MEN1 mutation. [8].
PitNETs in MEN4
There is no epidemiologic data regarding the prevalence of PitNETs in MEN4. A Danish study by Frederiksen et al. [5], which investigated 13 family members with a pathogenic variant in the CDKN1B gene, reported four cases of PitNETs: three were NFPitNETs, and one was an ACTHoma. To date, 22 cases of PitNETs with MEN4 have been described in the literature (Table 1): six NFPitNETs [5,34-36], four GHomas [4,37-39], seven ACTHomas [5,40,41], and five prolactinomas [39,42,43]. Unlike the high prevalence of prolactinomas in MEN1 and nonMEN1 sporadic types, only 23% of FPitNETs in MEN4 (n=5) were prolactinomas [39,42,43]. It is not possible to determine whether this difference is due to the small number of cases or a specific effect of CDKN1B mutation on lactotroph cells in the pituitary gland, different from the impact of MEN1 mutation [5,6]. A MEN1 mutation-negative patient presenting with a MEN1-like phenotype, who had pituitary carcinoma, was reported [44]. However, a further analysis for a diagnosis of MEN4 was not completed [44]. The small number of cases and consequent lack of sufficient studies limits confidence in recommending different treatment modalities for PitNETs in patients with MEN4.
Surveillance in patients with MEN1 or MEN4
Most cohort studies published after 2000 reported the age of diagnosis for PitNETs in MEN1 to be between the 30s and 50s [8,18-20], with the earliest diagnosis in one patient at 5 years [20]. Based on these findings, it is recommended that genetically confirmed individuals with MEN1 or MEN4 begin biochemical screening and radiological screening for PitNETs at age 5, with these screenings conducted annually and every 3 years, respectively [1,33]. For those without a MEN1 pathogenic variant but with evident clinical features of MEN1, next-generation screening should be used to determine whether a germline mutation is present in CDKN1B to explore the possibility of MEN4 [45].
Screening in patients with PitNETs
Since fewer than 3% of patients with PitNETs are expected to have MEN1 [1], it may not be necessary to screen all patients with PitNETs for MEN1. Nevertheless, genetic assessment is recommended to all children and young patients with a PitNET to inform management and family surveillance [46].
The prevalence of PitNETs in MEN1 syndrome is approximately 40%, with 10% of patients showing PitNET as the initial manifestation of MEN1, and there is a slight female predominance (Fig. 1). Most recent cohort studies published after 2012 reported that microPitNETs are more frequently found than macroPitNETs. Interestingly, plurihormonal PitNETs occur more frequently than monohormonal PitNETs in MEN1. FPitNETs are more common than NFPitNETs, and prolactinomas are the most common FPitNETs in patients with MEN1 [8,18-20].
Most of the recently published cohort studies reported the age at diagnosis of PitNETs in MEN1 to be between the 30s and 50s [8,18-20], with the earliest age being 5 years [20]. Unlike previous reports, recent cohort studies commonly indicate that PitNETs in MEN1 are typically microPitNETs, respond well to conventional treatments used for non-MEN1 patients, and exhibit an indolent nature particularly in case of NFPitNETs [8,18-20]. There appears to be no specific difference in the treatment approaches needed between PitNETs in MEN1 and non-MEN1 patients. Despite insufficient data, a comparison of PitNETs between MEN1 and non-MEN1 patients revealed no significant difference in patient age or the proportion of FPitNETs between the two groups [27]. Interestingly, MEN1 mutation-negative patients were shown to be more likely to have PitNETs, and those with mutation-negative status were more likely to be symptomatic and to have larger tumors at the time of diagnosis, requiring direct treatment. Nonetheless, the treatment response was similar regardless of the presence of a mutation [8].
Due to the small number of cases of PitNETs in patients with MEN4, it is challenging to describe the epidemiology or to suggest specific treatment strategies for PitNETs in these cases (Fig. 1). As for PitNETs in MEN2, it is rare and expected to be mostly coincidental, but could be possibly meaningful findings, and thus clinicians should be cautious about the possibility of accompanying pituitary lesions in such patients. More updated and larger studies regarding this issue are necessary.

CONFLICTS OF INTEREST

No potential conflict of interest relevant to this article was reported.

Fig. 1.
Clinical features and management of pituitary neuroendocrine tumors (PitNETs) in multiple endocrine neoplasia type 1 (MEN1) and multiple endocrine neoplasia type 4 (MEN4).
enm-2024-2074f1.jpg
Table 1.
Previously Reported Cases of PitNETs in MEN4
Study Sex Age, yra PitNET Tumor size
Frederiksen et al. (2019) [5] Female NA NF Micro
Frederiksen et al. (2019) [5] Male NA NF Macro
Frederiksen et al. (2019) [5] Male NA NF Micro
Molatore et al. (2010) [34] Female 79 NF Micro
Chevalier et al. (2020) [35] Female 66 NF Macro
Mazarico-Altisent et al. (2023) [36] Female 44 NF Micro
Occhi et al. (2013) [4] Female 62 GHoma NA
Pellegata et al. (2006) [37] Female 48 GHoma Macro
Sambugaro et al. (2015) [38] Female 5 GHoma Macro
Tichomirowa et al. (2012) [39] Male NA GHoma NA
Frederiksen et al. (2019) [5] Female 37 ACTHoma Micro
Georgitsi et al. (2007) [40] Female 46 ACTHoma NA
Chasseloup et al. (2020) [41] Male 13 ACTHoma Micro
Chasseloup et al. (2020) [41] Male 15 ACTHoma Micro
Chasseloup et al. (2020) [41] Female 13 ACTHoma Micro
Chasseloup et al. (2020) [41] Female 12 ACTHoma Micro
Chasseloup et al. (2020) [41] Male 15 ACTHoma Micro
Seabrook et al. (2022) [42] Female 39 Prolactinoma Micro
Tichomirowa et al. (2012) [39] Male NA Prolactinoma NA
Tichomirowa et al. (2012) [39] Female NA Prolactinoma NA
Tichomirowa et al. (2012) [39] Female NA Prolactinoma NA
Singeisen et al. (2023) [43] Female 54 Prolactinoma Macro

PitNET, pituitary neuroendocrine tumor; MEN4, multiple endocrine neoplasia type 4; NA, not available; NF, non-functional; GHoma, growth hormoneproducing PitNET; ACTHoma, adrenocorticotropic hormone-producing PitNET.

a Age at diagnosis of PitNET.

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      Pituitary Neuroendocrine Tumors in Multiple Endocrine Neoplasia
      Image
      Fig. 1. Clinical features and management of pituitary neuroendocrine tumors (PitNETs) in multiple endocrine neoplasia type 1 (MEN1) and multiple endocrine neoplasia type 4 (MEN4).

      Fig. 1.

      Pituitary Neuroendocrine Tumors in Multiple Endocrine Neoplasia
      Study Sex Age, yra PitNET Tumor size
      Frederiksen et al. (2019) [5] Female NA NF Micro
      Frederiksen et al. (2019) [5] Male NA NF Macro
      Frederiksen et al. (2019) [5] Male NA NF Micro
      Molatore et al. (2010) [34] Female 79 NF Micro
      Chevalier et al. (2020) [35] Female 66 NF Macro
      Mazarico-Altisent et al. (2023) [36] Female 44 NF Micro
      Occhi et al. (2013) [4] Female 62 GHoma NA
      Pellegata et al. (2006) [37] Female 48 GHoma Macro
      Sambugaro et al. (2015) [38] Female 5 GHoma Macro
      Tichomirowa et al. (2012) [39] Male NA GHoma NA
      Frederiksen et al. (2019) [5] Female 37 ACTHoma Micro
      Georgitsi et al. (2007) [40] Female 46 ACTHoma NA
      Chasseloup et al. (2020) [41] Male 13 ACTHoma Micro
      Chasseloup et al. (2020) [41] Male 15 ACTHoma Micro
      Chasseloup et al. (2020) [41] Female 13 ACTHoma Micro
      Chasseloup et al. (2020) [41] Female 12 ACTHoma Micro
      Chasseloup et al. (2020) [41] Male 15 ACTHoma Micro
      Seabrook et al. (2022) [42] Female 39 Prolactinoma Micro
      Tichomirowa et al. (2012) [39] Male NA Prolactinoma NA
      Tichomirowa et al. (2012) [39] Female NA Prolactinoma NA
      Tichomirowa et al. (2012) [39] Female NA Prolactinoma NA
      Singeisen et al. (2023) [43] Female 54 Prolactinoma Macro
      Table 1. Previously Reported Cases of PitNETs in MEN4

      PitNET, pituitary neuroendocrine tumor; MEN4, multiple endocrine neoplasia type 4; NA, not available; NF, non-functional; GHoma, growth hormoneproducing PitNET; ACTHoma, adrenocorticotropic hormone-producing PitNET.

      Age at diagnosis of PitNET.

      Table 1.

      Endocrinol Metab : Endocrinology and Metabolism
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