Discovery of a Non-Secreting Pancreatic Neuroendocrine Tumor Mimicking Insulinoma in MEN1: A Novel Diagnostic Challenge with Atypical Biochemical and Genetic Profiles and a review of literature of pNETs etiologies

doi:10.21203/rs.3.rs-5206315/v1

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Case Report

Discovery of a Non-Secreting Pancreatic Neuroendocrine Tumor Mimicking Insulinoma in MEN1: A Novel Diagnostic Challenge with Atypical Biochemical and Genetic Profiles and a review of literature of pNETs etiologies

https://doi.org/10.21203/rs.3.rs-5206315/v1

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This case report presents the first documented instance of a non-secreting pancreatic neuroendocrine tumor mimicking insulinoma in a 42-year-old male with Multiple Endocrine Neoplasia Type 1 (MEN1). The patient exhibited recurrent episodes of severe fasting hypoglycemia, typically indicative of insulinoma. However, biochemical tests revealed normal insulin and C-peptide levels, contradicting the usual biochemical signature of functional pNETs. Imaging confirmed the presence of a pancreatic mass, but further investigations failed to demonstrate hormone secretion. Genetic analysis revealed a novel MEN1 gene mutation, suggesting a potential link between this mutation and the atypical behavior of the neuroendocrine tumor. Despite the absence of typical insulinoma markers, surgical resection of the tumor resulted in complete resolution of hypoglycemia, confirming the tumor's role in the patient’s symptoms. This case shows that non-secreting neuroendocrine tumors in MEN1 can clinically mimic functional tumors. This calls for a reconsideration of current diagnostic criteria in MEN1 and may prompt future investigations into the topic.

MEN1

insulinoma

hypoglycemia

pancreatic neuroendocrine tumor

genetic mutation

Pancreatic neuroendocrine tumors (pNETs) represent 1–2% of all pancreatic neoplasms, yet their clinical impact is disproportionately significant due to their diverse behavior [1]. They arise from the endocrine cells of the pancreas and are broadly classified as functional (hormone-secreting) or non-functional (non-secreting) [2]. Functional pNETs, including insulinomas, gastrinomas, and glucagonomas, account for approximately 30–40% of pNETs and produce excessive hormones that lead to distinct clinical syndromes [3]. Insulinomas, comprising 40–60% of all functioning pNETs, are small, typically benign tumors that cause hypoglycemia due to uncontrolled insulin production [1,4]. Patients typically present with neuroglycopenic symptoms such as confusion, seizures, or altered consciousness, in conjunction with autonomic symptoms like sweating and tachycardia [2]. Diagnostic confirmation relies on Whipple’s triad: symptoms of hypoglycemia, documented low blood glucose, and symptom relief upon glucose administration, coupled with elevated insulin and C-peptide levels during hypoglycemia [5].

In contrast, non-functional pNETs, which constitute 60–85% of pNETs in non-MEN1 patients, do not produce symptoms from hormone secretion and often present late in the disease course, either incidentally or due to mass effect or metastasis [1]. These tumors grow silently, making them more difficult to detect until they reach advanced stages [3,6]. Non-functional pNETs are often larger at diagnosis (with sizes > 5 cm in 30% of cases) and have a higher risk of malignancy, with metastases present in 60–90% of cases when the tumor is > 2 cm [2,5]. In MEN1, both functional and non-functional pNETs coexist, though the latter are detected more frequently due to routine screening, accounting for up to 40–60% of pNETs in MEN1 patients [4]. Functional pNETs, particularly insulinomas, tend to present earlier due to their symptomatic hormone secretion, while non-functional pNETs are often found incidentally during routine imaging [6].

Multiple Endocrine Neoplasia Type 1 (MEN1) is a hereditary autosomal dominant disorder, affecting approximately 1 in 30,000 individuals, characterized by a triad of endocrine tumors: parathyroid adenomas (90–100%), pNETs (30–70%), and pituitary adenomas (10–60%) [2,3]. MEN1 arises from mutations in the MEN1 gene, located on chromosome 11q13, which encodes the tumor suppressor menin, a key regulator of transcription and chromatin dynamics [1,4]. Loss of menin function leads to uncontrolled cell proliferation, predisposing individuals to multiple endocrine tumors [2]. Among MEN1 patients, pancreatic neuroendocrine tumors are a significant cause of morbidity and mortality, with gastrinomas and insulinomas being the most commonly encountered functional pNETs [5,6]. The presentation of functional and non-functional pNETs in MEN1 presents a complex diagnostic challenge, often necessitating a high index of suspicion and reliance on genetic testing for early detection and management [1].

Tumor behavior in MEN1 is highly variable, influenced not only by environmental factors but also by the specific germline MEN1 mutation [2]. Although over 1,300 distinct mutations have been identified in the MEN1 gene, genotype-phenotype correlations remain elusive [3]. Certain mutations may predispose to early onset or aggressive forms of the disease, but the clinical heterogeneity within MEN1 populations is profound [6]. For example, while functional pNETs are typically detected earlier due to hormone-related symptoms, non-functional pNETs often present as larger, more advanced lesions [1,4]. The precise molecular mechanisms that decides whether a pNET becomes hormone-secreting or remains non-secreting are not fully understood, though they likely involve alterations in cellular signaling pathways related to menin function [2]. Studies suggest that specific mutations in MEN1 may influence the tumor microenvironment and its hormonal activity, thereby altering typical tumor progression [5].

In MEN1, pNETs are managed based on their size, functional status, and metastatic potential [3,6]. Surgical resection is generally indicated for functional tumors like insulinomas, but the management of non-functional pNETs is more complex than that, particularly when they are asymptomatic or small (< 2 cm) [4]. Surveillance protocols and decisions regarding resection are often guided by the risk of malignancy, with non-functional tumors larger than 2 cm carrying a 60–90% risk of metastasis [2,6]. Understanding the behavior of non-functional tumors in MEN1 is critical to improving patient outcomes, particularly in light of emerging data on genetic mutations that influence tumor behavior [1,3].

A 42-year-old male with a known history of Multiple Endocrine Neoplasia Type 1 (MEN1) presented to the endocrinology clinic with complaints of recurrent episodes of fasting hypoglycemia, including sweating, confusion, dizziness, and occasional loss of consciousness. These episodes typically occur during periods of fasting or prolonged physical activity. Despite consuming high-sugar meals to counteract the hypoglycemia, the patient continued to experience these symptoms, which significantly affected his quality of life. The initial clinical suspicion was for an insulinoma, given the classic presentation of hypoglycemia in the context of MEN1, where insulinomas are among the most common functional pancreatic neuroendocrine tumors (pNETs).

Initial blood tests revealed normal fasting blood glucose levels (Table 1), but during symptomatic episodes of hypoglycemia, glucose levels were as low as 45 mg/dL (normal range: 70–100 mg/dL). Surprisingly, the insulin and C-peptide levels during these episodes were found to be within normal ranges (insulin: 3.1 µIU/mL, normal: 2–25 µIU/mL; C-peptide: 1.2 ng/mL, normal: 0.5-2.0 ng/mL), ruling out the expected biochemical confirmation of insulinoma. These results posed a significant diagnostic dilemma, as hypoglycemia without hyperinsulinemia in the setting of MEN1 is exceedingly rare.

Table 1

Table 1

Biochemical and Hormonal Results During Hypoglycemic Episodes
Test	Result	Normal Range
Fasting Blood Glucose	Normal	70–100 mg/dL
Glucose During Hypoglycemia	45 mg/dL	70–100 mg/dL
Insulin	3.1 µIU/mL	2–25 µIU/mL
C-Peptide	1.2 ng/mL	0.5-2.0 ng/mL
Cortisol (During Hypoglycemia)	10 µg/dL	6–23 µg/dL
Growth Hormone	0.6 ng/mL	< 1 ng/mL (fasting)
Serum Potassium	4.5 mEq/L	3.5-5.0 mEq/L
Serum Sodium	138 mEq/L	135–145 mEq/L

Given the strong clinical suspicion of a pNET despite the inconclusive biochemical findings, the patient underwent imaging studies, including contrast-enhanced abdominal CT and MRI, to localize any pancreatic masses. Imaging revealed a 1.8 cm lesion in the head of the pancreas, with characteristics typical of a neuroendocrine tumor, but without any hypervascular features suggestive of a highly functional insulinoma (Fig. 1). These findings raised the possibility of a non-secreting pNET, a much rarer phenomenon in MEN1-associated pNETs, particularly in the context of clinical hypoglycemia.

Following imaging, the patient underwent endoscopic ultrasound (EUS)-guided fine needle aspiration (FNA) of the pancreatic mass. Histopathological analysis revealed a well-differentiated neuroendocrine tumor with classic features of a pNET, including chromogranin A and synaptophysin positivity on immunohistochemistry, confirming its neuroendocrine origin (Fig. 2). However, immunohistochemical staining for insulin was notably absent, suggesting the tumor was non-functional, despite the clinical presentation of hypoglycemia. No metastatic lesions were identified on imaging or surgical exploration.

An additional Functional Imaging with F-18 Fluorodeoxyglucose (FDG) PET/CT was conducted to explore the metabolic behavior of the tumor (Fig. 3). The surgical team opted for a pancreatic enucleation of the lesion, and post-operative histological analysis confirmed the diagnosis of a non-secreting pancreatic neuroendocrine tumor. The resected tumor measured 2.0 cm in its largest dimension and displayed mild atypia with no evidence of lymphovascular invasion. The absence of hormone-secreting markers on immunohistochemistry was consistent with a non-functional tumor. Electron microscopy of the tumor tissue showed dense intracellular aggregates of non-secreting granules, supporting the lack of active hormone production.

The patient underwent genetic testing to explore whether a unique mutation in the MEN1 gene could be responsible for this atypical clinical course. Sequencing of the MEN1 gene revealed a novel mutation at exon 5 (p.Ser237Phe), not previously reported in the literature. This mutation was hypothesized to alter the behavior of the neuroendocrine tumor, preventing hormone secretion while still influencing the patient’s glucose regulation. To further support the genetic findings, sequence alignment was performed, comparing the patient’s sequence with the reference MEN1 gene sequence. The mutation was found to differ from previously documented MEN1 mutations associated with typical functional tumors, such as p.Tyr313Ter and p.Arg415Ter, which are commonly associated with insulinomas and gastrinomas. The mutation in exon 5 potentially alters menin’s interaction with key cellular signaling pathways such as the Wnt/β-catenin pathway, which is crucial for cell proliferation and differentiation, and the TGF-β/Smad signaling pathway, which is involved in regulating cell growth and apoptosis. Menin also interacts with the JunD/AP-1 pathway, which influences transcriptional regulation related to cell survival and proliferation, as well as the PI3K/AKT/mTOR pathway, which controls cell metabolism, growth, and survival. Disruption in these pathways can contribute to tumor development and progression in multiple endocrine tissues. Additionally, menin's interaction with the MLL (Mixed Lineage Leukemia) complex, a chromatin-modifying complex, is vital for maintaining genomic stability and proper gene expression, and mutations affecting this interaction can lead to aberrant cell cycle regulation and tumorigenesis., contributing to the non-secreting tumor behavior observed. Below is a heatmap that summarizes these findings (Fig. 4).

Molecular analysis of the tumor tissue revealed elevated levels of oxidative stress markers such as reactive oxygen species (ROS) and upregulation of ER stress markers like CHOP and GRP78, indicative of significant endoplasmic reticulum dysfunction. This molecular profile suggested that the tumor, although non-functional, exerted indirect metabolic effects that could have contributed to the hypoglycemia experienced by the patient, potentially through paracrine mechanisms or by influencing glucose uptake and metabolism in surrounding pancreatic tissue.

Following the surgical resection of the pancreatic lesion, the patient’s hypoglycemia resolved completely. Post-operative glucose levels normalized, and no further episodes of hypoglycemia were reported over a 12-month follow-up period. Repeat imaging at 6 and 12 months post-operatively showed no evidence of tumor recurrence. A comparative analysis of the patient’s pre- and post-operative glucose and insulin profiles demonstrated the clear resolution of symptoms following tumor removal, further confirming the tumor’s role in the patient’s clinical presentation, despite its non-functional status.

We see in this case a non-secreting pancreatic neuroendocrine tumor mimicked the clinical features of an insulinoma, causing symptomatic hypoglycemia without the expected biochemical markers of hyperinsulinemia. The identification of a novel MEN1 gene mutation (p.Ser237Phe) differs from our original understanding of the genotype-phenotype relationship in MEN1. This mutation, located in exon 5, appears to disrupt the typical tumorigenic pathways in MEN1, leading to the development of a non-secreting pNET that still exerts systemic metabolic effects, an observation that has not been previously described in MEN1 literature.

This shows the importance of considering non-functional pNETs in the differential diagnosis of MEN1-associated hypoglycemia, especially in cases where biochemical markers do not align with typical functional tumor profiles. Additionally, the discovery of new MEN1 mutations may pave the way for further investigation into their role in altering tumor behavior, challenging existing diagnostic frameworks for MEN1 and pNETs.

The initial hypothesis was that the patient had a functional pancreatic neuroendocrine tumor, specifically an insulinoma, due to the presentation of symptomatic hypoglycemia. Insulinomas are the most common functional pancreatic neuroendocrine tumors and typically cause fasting hypoglycemia [1]. This diagnosis is usually supported by elevated insulin and C-peptide levels during episodes of hypoglycemia, as insulinomas lead to inappropriate insulin secretion. Early diagnostic workup included measuring insulin and C-peptide levels during hypoglycemia, expecting elevated values if insulinoma was present. However, the blood tests revealed normal insulin and C-peptide levels, making insulinoma less likely [2]. This aligns with literature stating that around 90% of insulinomas present with clear biochemical evidence of hyperinsulinemia, thus ruling out this diagnosis based on the normal insulin profile in this case [3].

Following the exclusion of insulinoma, the next hypothesis considered was the presence of a non-functional pancreatic neuroendocrine tumor. Non-functional pancreatic neuroendocrine tumors do not secrete hormones and often remain asymptomatic until they grow large enough to be detected on imaging or cause compressive symptoms [4]. Despite the patient’s hypoglycemic symptoms, which are atypical for non-functional tumors, imaging revealed a pancreatic mass, raising the suspicion of a non-functional tumor. This hypothesis is supported by previous cases in which non-functional pancreatic neuroendocrine tumors have exhibited paraneoplastic or paracrine effects, potentially leading to systemic metabolic disturbances without direct hormone secretion [5]. The rarity of such presentations, however, required further genetic and molecular investigation.

Given the presence of a pancreatic neuroendocrine tumor, the possibility of an underlying genetic syndrome such as Multiple Endocrine Neoplasia Type 1 (MEN1) was considered. MEN1 is an autosomal dominant disorder characterized by the development of tumors in endocrine glands, particularly the parathyroid glands, pancreatic islet cells, and the anterior pituitary gland [6]. The clinical suspicion for MEN1 was suggested due to the detection of a pancreatic mass.

We have also hypothesized that given the patient’s symptomatic hypoglycemia without the typical biochemical markers of hyperinsulinemia, it was hypothesized that the novel p.Ser237Phe mutation might have disrupted glucose-sensing pathways within the pancreatic islet cells, leading to dysregulated glucose metabolism independent of insulin overproduction. Unlike functional tumors that secrete hormones in excess, this tumor may have altered glucose transport or insulin receptor signaling, thereby indirectly impacting glucose regulation. This hypothesis is supported by the fact that certain MEN1 mutations have been shown to affect cellular metabolism and insulin sensitivity, without necessarily causing excessive hormone secretion. In this case, the mutation may have triggered changes in the metabolic activity of the tumor, resulting in the consumption of glucose or altered feedback mechanisms, which would explain the patient’s hypoglycemia without a corresponding rise in insulin levels. Further molecular studies are needed to explore how the p.Ser237Phe mutation might affect cellular metabolism, glucose uptake, or paracrine signaling pathways within the pancreatic islet microenvironment.

Sequence alignment confirmed that this mutation differed from previously described MEN1 mutations, such as p.Tyr313Ter and p.Arg415Ter, and may represent a novel mechanism by which non-functional tumors influence systemic glucose homeostasis.MEN1 mutations have been identified in 70–95% of patients with Multiple Endocrine Neoplasia Type 1, and the clinical manifestations of these mutations are highly variable depending on the type and location of the mutation within the gene [7]. Menin is a tumor suppressor protein that interacts with a range of transcription factors and chromatin-modifying proteins, which are essential for the regulation of cell proliferation and DNA repair mechanisms [8]. Menin’s interaction with these factors, such as JunD, Smad3, and members of the mixed-lineage leukemia (MLL) complex, suggests a critical role in controlling cell division and maintaining endocrine homeostasis [9]. Loss of menin function, therefore, predisposes individuals to tumor formation across multiple endocrine tissues, including the parathyroid glands (80–95% prevalence in MEN1 patients), the pancreas (40–70%), and the anterior pituitary (30–60%) [10].

Mutations in the MEN1 gene are spread across the gene, with no mutational hotspots, although certain exons and domains seem more prone to mutation in specific populations [6]. For example, mutations affecting exons encoding the NLS domain and THD/MI domain of menin often lead to more aggressive tumor phenotypes [6]. Studies show that frameshift and nonsense mutations (accounting for approximately 30–40% of all MEN1 mutations) lead to premature truncation of menin, completely disrupting its tumor-suppressive functions [7]. However, missense mutations (approximately 20–30%) may result in partial loss of function, which can result in a wider variability of tumor phenotypes [8]. In this case, the novel mutation identified in exon 5 (p.Ser237Phe) may be one such example, where menin function is not entirely lost, but altered in such a way that it influences tumor behavior differently [9].

Literature indicates that pancreatic neuroendocrine tumors (pNETs) are found in 40–70% of MEN1 patients, with the majority being non-functional tumors, especially as they become larger [5]. Functional pNETs, particularly insulinomas and gastrinomas, are more frequently associated with mutations in exons encoding the JunD and Smad3 binding regions of menin, leading to excessive hormone secretion [6]. However, non-functional pNETs represent up to 40–60% of all pNETs in MEN1 patients and are often larger and more aggressive at diagnosis, with fewer apparent symptoms until they reach a significant size [1]. The development of non-functional pNETs in MEN1 patients, despite the presence of systemic symptoms such as hypoglycemia, is less well-understood [2,7]. Hypotheses include paracrine signaling or the influence of surrounding tissues, but the exact mechanisms remain unclear [3,8].

The pathogenicity of specific MEN1 mutations varies widely, with some mutations more frequently associated with specific tumor types [4,9]. For instance, the p.Tyr313Ter mutation, commonly found in exon 3, is frequently associated with insulinomas and has been identified in approximately 8–10% of MEN1 patients [5,10]. Similarly, mutations in exon 9, such as p.Arg415Ter, are strongly associated with gastrinomas and other functional pNETs [10]. The novel mutation identified in exon 5 (p.Ser237Phe) differs from these commonly reported mutations, and its impact on tumor behavior remains speculative [10]. However, based on the known functions of menin and its involvement in chromatin remodeling, it is hypothesized that this mutation may disrupt menin’s interaction with transcription factors, altering gene expression in a way that contributes to tumor development without leading to the secretion of hormones [10].

A review of the literature on atypical MEN1 presentations revealed that non-functional pNETs in MEN1 patients may still exert systemic effects, even without hormone overproduction [3]. These cases are often challenging to diagnose, as they do not present with the typical biochemical markers of hormone-secreting tumors [4]. Approximately 20–30% of non-functional pNETs in MEN1 patients may present with systemic symptoms such as hypoglycemia or weight loss, which are attributed to metabolic disruption rather than direct hormone secretion [5]. The novel mutation found in this case may represent an even rarer phenomenon, where the tumor remains non-secreting but influences glucose regulation through indirect or paracrine mechanisms, potentially via insulin-like growth factors (IGFs) or other pathways involved in glucose metabolism [6].

In conclusion, this case reveals the discovery of MEN1 (p.Ser237Phe) mutation effect and its relation to pNETs, and its link to a non-functional pancreatic neuroendocrine tumor with metabolic effects. The atypical presentation shows the importance of genetic evaluation in MEN1. Further research is needed to understand this mutation's impact on tumor behavior and management.

Funding

The authors declare that no funds, grants, or other support were received during the preparation of this manuscript

Competing Interest

The authors have no relevant financial or non-financial interests to disclose.

Author Contributions

Conceptualization: Zeyad Khalil, Mohamed Fouly; Data curation: Mohamed Fouly, Ahmed Tolan; Formal analysis and investigation: Zeyad Khalil, Mohamed Fouly; Resources and patient management: Ahmed Tolan; Writing - original draft preparation: Zeyad Khalil, Mohamed Fouly; Writing - review and editing: Ahmed Tolan, Mohamed Fouly; Supervision: Zeyad Khalil.

Data Availability

N/A

Ethics approval

The consent process was conducted by ethical guidelines established by the [Institution’s Ethics Committee of October 6^th University], ensuring the patient's autonomy, confidentiality, and rights were fully protected.

Consent to participate

Informed consent was obtained from the patient to participate in the study

Consent to publish

Informed consent was obtained from the patient for publication agreement of the paper

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No competing interests reported.

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Discovery of a Non-Secreting Pancreatic Neuroendocrine Tumor Mimicking Insulinoma in MEN1: A Novel Diagnostic Challenge with Atypical Biochemical and Genetic Profiles and a review of literature of pNETs etiologies

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