Pancreatic Neuroendocrine Tumor in Lynch Syndrome: Expanding the Tumor Spectrum of Mismatch Repair Deficiency

Abstract

Lynch syndrome is an autosomal dominant hereditary cancer syndrome caused by germline mutations in DNA mismatch repair genes. Currently, Lynch syndrome has well-established associations with colorectal and endometrial cancers. However, a definitive association between Lynch syndrome and pancreatic neuroendocrine tumors (P-NETs) remains unestablished. Herein, we report the case of a 38-year-old male with a maternal family history of Lynch syndrome who presented with hypoglycemia, abdominal pain, and diarrhea. Imaging revealed a 5.6 cm pancreatic tail mass with hepatic, lymph node, and osseous metastases. Synchronous sigmoid adenocarcinoma was identified during admission. Germline testing confirmed a pathogenic MLH1 mutation, and liver biopsy of the P-NET demonstrated loss of MLH1 and PMS2 expression. The patient was treated with capecitabine and temozolomide (CAPTEM) chemotherapy, pembrolizumab, long-acting repeatable octreotide (octreotide LAR), and diazoxide for hypoglycemia management. Disease progression with spinal epidural extension necessitated palliative radiation and intravenous immunoglobulin for severe thrombocytopenia. This case highlights the expanding phenotypic spectrum of Lynch syndrome and suggests that P-NETs may represent a rare but clinically significant manifestation. Early recognition of this association supports comprehensive genetic testing, enables the use of precision immunotherapy, and underscores the need for expanded surveillance strategies in patients with atypical tumor profiles.

Introduction

Lynch syndrome, formerly known as hereditary nonpolyposis colorectal cancer (HNPCC), is an autosomal dominant hereditary cancer syndrome caused by germline mutations in DNA mismatch repair (MMR) genes, including MLH1 on chromosome 3p22.2, MSH2 on 2p21-16, MSH6 on 2p16.3, and PMS2 on 7p22.1, or by deletions in EPCAM on 2p21 that lead to epigenetic silencing of MSH2 [1]. As a result, these genetic alterations produce defective MMR, giving rise to microsatellite instability (MSI) and increasing susceptibility to malignancies. Approximately 3-5% of all colorectal cancers are attributable to Lynch syndrome, and affected individuals typically develop malignancies at a significantly younger age than nonhereditary cases [2]. The cumulative risk of colorectal cancer by age 70 ranges from 30% to 74% and is higher in individuals with MLH1 and MSH2 mutations (54-60%). In addition to colorectal cancer, Lynch syndrome confers an increased lifetime risk of endometrial cancer (25-60%), gastric cancer (1-13%), and ovarian cancer (4-12%) [3]. Numerous other neoplasms are associated with an increased risk in individuals with Lynch syndrome, including cancers of the small intestine, urinary tract, biliary tract, pancreas, and prostate.

Within the pancreas, it is important to distinguish pancreatic ductal adenocarcinoma from pancreatic neuroendocrine tumors (P-NETs). Pancreatic ductal adenocarcinoma is an exocrine malignancy and represents the more commonly recognized pancreatic cancer associated with Lynch syndrome. Meanwhile, P-NETs arise from the endocrine/islet cell lineage and represent a distinct and much rarer pancreatic tumor subtype. This distinction is clinically important because the association between Lynch syndrome and P-NETs remains less clearly established.

P-NETs are a rare subset of pancreatic malignancies that account for 1-2% of all pancreatic tumors and about 7% of all neuroendocrine tumors, with reported incidences of under one per 100,000 population worldwide [4]. A definitive etiological association between Lynch syndrome and P-NETs remains unestablished; however, a growing number of rare cases describing their coexistence have been reported in the literature. The first molecularly confirmed case in 2017 demonstrated MMR deficiency in P-NET tissue from a Lynch syndrome patient, providing early plausibility for a shared mechanistic pathway [5]. Subsequent reports have described both functional and nonfunctional P-NETs arising in Lynch syndrome patients, including cases with pathogenic variants in MLH1 and MSH2. Functional P-NETs are characterized by ectopic hormone secretion that produces a distinct clinical syndrome, such as insulinoma-associated hypoglycemia or gastrinoma-associated peptic ulcer disease. In contrast, nonfunctional P-NETs do not produce a hormone-associated clinical syndrome and are typically associated with symptoms related to tumor growth or mass effect.

A more recent Finnish registry study of Lynch syndrome-associated pancreatic and biliary tract cancers identified five neuroendocrine tumors among 28 pancreatic tumors in 26 patients, indicating this association may be more prevalent than previously anticipated [6]. Additionally, a 2025 literature review analyzing neuroendocrine neoplasms (NENs) in Lynch syndrome identified 13 reported cases encompassing well-differentiated NETs, neuroendocrine carcinomas, and mixed neuroendocrine non-neuroendocrine neoplasms (MiNENs) [7], proposing that NENs may represent an underrecognized component of the expanding tumor spectrum.

These findings raise important questions about shared molecular mechanisms, including MSI, impaired DNA damage repair, and tumor-specific alterations. This case report presents a patient with Lynch syndrome who developed a functional P-NET with hypoglycemia concurrent with sigmoid adenocarcinoma, adding to the limited literature on this rare association and highlighting the evolving role of precision medicine in hereditary cancer syndromes.

Case presentation

A 38-year-old Caucasian male with a significant family history of Lynch syndrome presented to the clinic with right upper quadrant and lower back pain and frequent diarrhea. His gas pains began earlier that morning, with intermittent symptoms over the preceding two days, accompanied by abnormal bowel movements with mucus and slight blood.

Initial differential diagnoses included pancreatic adenocarcinoma, other pancreatic carcinoma, P-NET, and insulinoma. His clinical course was notable for intermittent hypoglycemia, including an admission blood glucose level of 50 mg/dL. Initial imaging with CT of the abdomen and pelvis revealed a 2.9 × 3.3 × 3.3 cm mass in the tail of the pancreas with coarse calcifications, left upper quadrant varices suggestive of collateral formation, and a large heterogeneous lobular mass in segment 8 of the liver, measuring 8.8 × 11.4 × 9.5 cm, with a smaller hypodense lesion in segment 6.

Differential diagnosis, investigations, and treatment

This case highlights the rare diagnosis of metastatic insulinoma in a patient with Lynch syndrome, expanding the spectrum of Lynch syndrome-associated neoplasms and emphasizing the importance of considering functional P-NETs. At the time of presentation, the initial differential diagnosis included pancreatic adenocarcinoma, other pancreatic carcinomas, P-NET, and insulinoma. Pancreatic adenocarcinoma was considered, given the pancreatic tail mass with hepatic lesions concerning for metastasis; however, the patient’s recurrent hypoglycemia and somatostatin receptor-positive disease made a functional P-NET more likely. Insulinoma was also considered because of the patient’s hypoglycemia, although the presence of widespread metastatic findings and imaging supported a broader diagnosis of metastatic functional P-NET.

The patient was started on diazoxide for the management of his hypoglycemia. Later, he developed abdominal distention, with repeated imaging revealing moderate to severe colonic dilation consistent with ileus and a 5 × 3.5 cm mass along the posterior wall of the proximal sigmoid colon. Colonoscopy showed a 30 mm sessile polyp in the cecum and a 5 × 7 cm polyp in the sigmoid colon. Piecemeal polypectomy was performed, and pathology indicated an invasive adenocarcinoma arising in the setting of a large adenoma.

Immunohistochemistry (IHC) showed loss of nuclear staining for MLH1 and PMS2, raising clinical suspicion of Lynch syndrome. Notably, the patient’s mother had been diagnosed with Lynch syndrome, and he had previously been advised to pursue genetic testing at age 27 but did not undergo evaluation.

Positron emission tomography (PET) imaging confirmed widespread metastatic disease with somatostatin receptor type 2 expression, involving the primary tumor, likely located in the pancreatic tail, and metastases to the bilobar liver, left periaortic lymph node, and the axial and proximal appendicular skeleton (Figure 1).

Figure 1. Cross-sectional imaging of the pancreatic tail lesion.

(A, B) Axial MRI of the abdomen demonstrating a well-defined mass in the pancreatic tail (arrows). (C, D) Corresponding FDG PET/CT images show focally increased radiotracer uptake within the same region (arrows), concerning for a metabolically active malignancy in the pancreatic tail.

FDG PET, fluorodeoxyglucose positron emission tomography

Germline testing confirmed a pathogenic MLH1 mutation, consistent with Lynch syndrome. IHC of the liver biopsy demonstrated loss of MLH1 and PMS2 expression, supporting MMR deficiency in the metastatic tumor.

The patient began first-line therapy with capecitabine and temozolomide (CAPTEM) along with octreotide and zoledronic acid. Given his microsatellite instability-high (MSI-H) P-NET status, pembrolizumab (200 mg IV every three weeks) was added to his CAPTEM regimen. Temozolomide was later dose-reduced to 300 mg during cycle 6 due to thrombocytopenia. Follow-up magnetic resonance cholangiopancreatography (MRCP), performed one year after diagnosis, demonstrated a marginal decrease in the dominant right hepatic lobe metastasis. Findings showed a slight increase in several smaller bilobar metastases, as well as a slower progression of the distal pancreatic mass compared with 2022.

In April 2024, imaging and colonoscopy showed no obvious mass at the prior descending colon site, aside from a scar and hyperplastic polyps in the rectum, demonstrating stable disease. Due to concerns regarding prolonged alkylator exposure, CAPTEM was discontinued in July 2024, but the patient remained on octreotide and pembrolizumab. He underwent bland embolization of the dominant liver lesion in August 2024.

November 2024 imaging demonstrated an increased size of the pancreatic tail neuroendocrine tumor (medial component 4 × 3 cm, previously 3.4 × 2.7 cm) and an increased size of multiple osseous metastases. The dominant right hepatic lobe metastasis showed a slight decrease in size with increased necrosis and cavitary collapse.

The patient was readmitted with a severe episode of uncontrollable cervical pain. The MRI report revealed scattered osseous metastases with tumor expansion into the epidural space, leading to mild spinal canal stenosis. During this episode, he developed progressive thrombocytopenia with multiple new pulmonary nodules, progression of hepatic metastases, and new splenic lesions, as shown on CT imaging. He received palliative radiation therapy to the cervical spine with improvement in pain and intravenous immunoglobulin for three days, with gradual platelet recovery. The outpatient oncologic plan included lutetium-177 DOTATATE therapy pending a DOTATATE PET scan and fluorodeoxyglucose positron emission tomography (FDG PET) due to concern for transformation to high-grade disease, with bridging CAPTEM chemotherapy. Despite these interventions, the patient had recurrent admissions for severe back pain with worsening physical decline. Given the nature of this progressive disease and repeated hospitalizations, he transitioned to hospice care with a focus on patient comfort and end-of-life care (Table 1).

Table 1. Timeline of diagnostic investigations, treatment, and clinical course.

IHC, immunohistochemistry; PET, positron emission tomography; CAPTEM, capecitabine and temozolomide; MSI-H, microsatellite instability-high; P-NET, pancreatic neuroendocrine tumor; MRCP, magnetic resonance cholangiopancreatography; IVIG, intravenous immunoglobulin; FDG PET, fluorodeoxyglucose positron emission tomography

Time point	Investigation/management	Key findings/outcome
Initial presentation	Blood glucose and abdominal imaging	Hypoglycemia; pancreatic tail mass with hepatic lesions concerning for metastatic disease
Initial hospitalization	Diazoxide	Started for hypoglycemia management
Initial hospitalization	Repeat imaging for abdominal distention	Moderate-to-severe colonic dilation/ileus; 5 × 3.5 cm proximal sigmoid colon mass
Initial hospitalization	Colonoscopy and polypectomy	Cecal and sigmoid polyps; pathology showed invasive adenocarcinoma arising in a large adenoma
Diagnostic workup	Colonic lesion IHC	Loss of MLH1 and PMS2, raising suspicion for Lynch syndrome
Staging	PET imaging	Somatostatin receptor-positive metastatic disease involving the pancreatic tail, liver, lymph node, and bone
Genetic/pathology confirmation	Germline testing and liver biopsy IHC	Pathogenic MLH1 mutation; liver biopsy with loss of MLH1/PMS2
First-line treatment	CAPTEM, octreotide, zoledronic acid	Systemic therapy initiated
During treatment	Pembrolizumab	Added due to MSI-H P-NET status
Cycle 6	Temozolomide dose reduction	Dose reduced due to thrombocytopenia
One year after diagnosis	Follow-up MRCP	Marginal decrease in the dominant hepatic lesion; slight increase in the smaller bilobar metastases
April 2024	Imaging and colonoscopy	No obvious recurrent colon mass; stable colonic disease
July 2024	Treatment adjustment	CAPTEM discontinued due to prolonged alkylator exposure; octreotide and pembrolizumab continued
August 2024	Bland embolization	Performed for the dominant liver lesion
November 2024	Follow-up imaging	Progression of pancreatic tail tumor and osseous metastases; treatment effect/necrosis in dominant liver lesion
Later admission	MRI/CT imaging	Epidural extension of osseous metastases, new pulmonary nodules, hepatic progression, new splenic lesions
Later admission	Palliative radiation and IVIG	Cervical spine radiation improved pain; IVIG given for thrombocytopenia
Final course	Planned Lu-177 DOTATATE/FDG PET and bridging chemotherapy	Disease continued to progress with recurrent admissions
End of care	Hospice transition	Focus shifted to comfort and end-of-life care

Discussion

Lynch syndrome is one of the most common hereditary cancer syndromes, with an estimated prevalence of approximately one in 279 individuals in the general population. It results from germline pathogenic variants in DNA MMR genes, including MLH1, MSH2, MSH6, and PMS2. Currently, colorectal cancer remains the most recognized manifestation. Contemporary data show that the tumor spectrum associated with Lynch syndrome has expanded substantially [8].

Lynch syndrome includes extracolonic tumors such as endometrial, gastric, small intestine, hepatobiliary, urinary tract, ovarian, pancreatic, and brain cancers [9]. This expanding spectrum of cancers has informed current management strategies, encouraging surveillance, preventive colonoscopies, and individualized genetic screening based on the patient's presentation and history.

P-NETs​​​​ and Lynch syndrome

P-NETs are not classically considered part of the Lynch syndrome spectrum, and the presence of MSI or MMR deficiency is rare in P-NETs. In the current literature, MMR deficiency in well-differentiated P-NETs is reported in less than 1% of cases [10] when assessed by IHC, with only one study demonstrating preserved expression of all four MMR proteins in 100% of 35 P-NETs examined [11].

Additionally, polymerase chain reaction (PCR)-based studies have not been consistently replicated, and the only other associations between P-NETs and Lynch syndrome are currently limited to case reports and series. There is biological plausibility for an association between Lynch syndrome and P-NETs. Lynch-associated tumors arise when DNA repair mechanisms are impaired, leading to an accumulation of mutations, and may be linked to defective MMR pathways.

Furthermore, the established association between Lynch syndrome and pancreatic ductal adenocarcinoma provides additional support for a potential association between P-NETs and Lynch syndrome-related mechanisms. Identification of MSI or MMR deficiency in P-NETs would further support this mechanistic link.

Tumor phenotype versus germline diagnosis

Lynch syndrome represents a germline diagnosis, whereas MSI and IHC findings reflect tumor phenotype. Importantly, Lynch syndrome can be present even when tumor testing demonstrates preserved MLH1 expression and microsatellite stability. Missense mutations can produce structurally intact but functionally impaired MMR proteins that evade IHC detection. Immunohistochemical technique limitations, tumor heterogeneity, and low tumor antigen expression may further contribute to false-negative MSI or IHC results.

Distinguishing sporadic MLH1 loss from Lynch syndrome

Distinguishing sporadic from hereditary etiologies is critical. Sporadic MLH1 deficiency is most commonly caused by MLH1 promoter hypermethylation, frequently in conjunction with a BRAF V600E mutation [12]. BRAF V600E has been identified in up to 75% of colorectal cancers with epigenetic silencing of MLH1, making it unlikely that a MSI-H patient with a BRAF V600E mutation carries a germline MMR mutation [13]. The absence of a BRAF mutation and MLH1 promoter methylation should prompt germline MMR testing to evaluate for Lynch syndrome.

Screening guidelines and universal tumor testing

The Amsterdam II criteria and Bethesda guidelines have historically guided the identification of high-risk cancer patients [14]. The Amsterdam II criteria require at least three relatives with Lynch syndrome-associated cancers across two generations, with at least one individual diagnosed before the age of 50 [14]. Meanwhile, the Bethesda guidelines were developed to identify individuals who should undergo MSI testing. However, both of these clinical criteria have limited sensitivity and can overlook approximately 25-50% of Lynch syndrome cases [14]. Current practice has shifted toward universal tumor testing, with routine IHC for MLH1, MSH2, MSH6, and PMS2, and/or MSI testing recommended for all colorectal and endometrial cancers.

Per National Comprehensive Cancer Network (NCCN) Guidelines, P-NETs are staged based on primary tumor size, lymph node involvement, and distant metastasis. T1 tumors are ≤2 cm (limited to the pancreas), T2 tumors are >2 cm but ≤4 cm (limited to the pancreas), T3 tumors are >4 cm (limited to the pancreas or invading the duodenum, ampulla of Vater, or common bile duct), and T4 tumors invade adjacent organs or the walls of large vessels [15].

Lymph node status is classified as N0 (no regional lymph node involvement) or N1 (regional lymph node involvement). Distant metastasis is categorized as M0 (no distant metastasis), M1a (metastasis confined to the liver), M1b (extrahepatic metastasis), or M1c (both hepatic and extrahepatic metastases). Stage I is classified as T1N0M0, Stage II is T2-T3N0M0, Stage III is T4N0M0 or any T with N1M0, and Stage IV is any T, any N, with M1 [15].

Despite a known maternal history of Lynch syndrome, this patient did not undergo germline genetic testing. According to the Amsterdam II criteria and Bethesda criteria, individuals with a first-degree relative diagnosed with Lynch syndrome should undergo genetic evaluation and initiate surveillance. Failure to pursue timely genetic testing and surveillance may delay the diagnosis of both colorectal and extracolonic malignancies.

Management of P-NETs and the role of targeted imaging

According to NCCN guidelines, management of P-NETs is guided by tumor grade, stage, functional status, and disease burden. CAPTEM is an established systemic therapy for high-burden P-NETs, demonstrating objective response rates of 39.7% and a median progression-free survival of 22.7 months in P-NETs [16]. Temozolomide induces DNA damage, and tumors with impaired DNA repair mechanisms may exhibit increased sensitivity. For insulinomas, diazoxide is commonly used for symptomatic control of hypoglycemia by suppressing insulin secretion through activation of pancreatic beta-cell potassium channels. Somatostatin analogs, including octreotide and lanreotide, may also be employed for hormonal control. The ECOG-2211 trial demonstrated that CAPTEM significantly improved progression-free survival (PFS) compared with temozolomide monotherapy in advanced P-NETs [16].

DOTATATE PET/CT plays a critical role in evaluating somatostatin receptor expression in neuroendocrine tumors and determining eligibility for peptide receptor radionuclide therapy (PRRT) [17]. When PRRT is planned, long-acting somatostatin analogs are typically withheld for four to six weeks before treatment to optimize receptor targeting [18].

Immunotherapy implications of MSI-H status

Pembrolizumab is FDA-approved for the treatment of any unresectable or metastatic MSI-H or deficient mismatch repair (dMMR) solid tumor, regardless of tissue of origin, based on durable responses observed across 15 different tumor types with a response rate of 39.6% [19]. In 2023, this indication received full approval based on data from over 500 patients across more than 30 cancer types [20].

Immunotherapy may be appropriately applied to MSI-H P-NETs when unresectable or metastatic, highlighting the need for tumor-specific treatment strategies. For example, stage I colorectal cancer with MSI-H status is typically managed with surgical resection alone, as these patients have an excellent prognosis. This distinction is important because it highlights the role of immunotherapy in various stages of tumor progression.

Clinical implications

This case underscores the expanding tumor spectrum of Lynch syndrome and the importance of comprehensive molecular evaluation in patients with atypical tumor profiles.

Conclusions

Lynch syndrome manifests with early-onset malignancies originating from rapidly proliferating tissues such as the colorectum, endometrium, and other organs. In addition to its well-established cancer risks, Lynch syndrome may be associated with P-NETs, rare neoplasms that can present with functional hormonal excess syndromes. Here, we present a unique case of a 38-year-old male with known Lynch syndrome who presented to the clinic with metastatic insulinoma, causing severe hypoglycemia, other associated symptoms, and complex management challenges. Further evaluation revealed osseous involvement with epidural extension. The patient is receiving multimodal therapy, including palliative radiation, systemic chemotherapy with CAPTEM, and planned PRRT. His clinical course was complicated by severe thrombocytopenia requiring supportive care and palliative management. Although the patient had been previously advised to undergo genetic testing because of his family history, he had not pursued formal Lynch syndrome surveillance prior to presentation. Following diagnosis, evaluation for additional neoplasms included colonoscopy, PET imaging, and serial abdominal imaging, with continued follow-up coordinated through oncology and gastroenterology. This case highlights the potential for aggressive P-NETs associated with Lynch syndrome and underscores the need for enhanced surveillance protocols to detect atypical manifestations of hereditary cancer syndromes.