Idiopathic Non-Caseating Granulomatous Lesion of the Pancreas Mimicking a Neuroendocrine Tumor: A Diagnostic Challenge

Abstract

Introduction

Pancreatic granulomas are uncommon and typically classified based on the presence or absence of caseation. Caseating granulomas are most often associated with tuberculosis, while non-caseating granulomas are usually secondary to systemic conditions such as sarcoidosis. Idiopathic cases are rare and can pose a significant diagnostic challenge, particularly when mimicking malignancy. We present a unique case initially suspected to be a neuroendocrine tumor, ultimately diagnosed as an idiopathic non-caseating pancreatic granuloma.

Case Presentation

A 75-year-old female was evaluated for left upper quadrant abdominal discomfort accompanied by chronic diarrhea and intermittent palpitations. Initial laboratory studies were notable for a markedly elevated chromogranin A level of 3123 ng/mL, with normal urinary metanephrine levels Cross-sectional imaging with magnetic resonance imaging demonstrated a 2.5-cm cystic lesion communicating with the main pancreatic duct and an additional hypointense lesion involving the pancreatic tail. Despite clinical concern for a neuroendocrine neoplasm, ^68Ga-DOTATATE PET/CT demonstrated no radiotracer uptake within the pancreatic lesion. Subsequent endoscopic ultrasound revealed a 2.7-cm well-defined, homogeneous hypoechoic pancreatic mass with multiple enlarged peripancreatic lymph nodes. Cytologic examination of fine-needle aspiration specimens showed non-caseating granulomatous inflammation in the setting of otherwise benign pancreatic and lymphoid tissue. Comprehensive evaluation failed to identify an underlying infectious, inflammatory, or systemic cause, supporting the diagnosis of an idiopathic non-caseating pancreatic granuloma.

Discussion

Non-caseating granulomas of the pancreas are rare, with sarcoidosis being the most frequently reported cause. Clinical presentation may include epigastric pain, weight loss, jaundice, fever, or nausea. Due to the potential overlap with malignancies, comprehensive diagnostic workup—including imaging, tissue sampling, and occasionally surgical intervention—is essential for accurate diagnosis and management.

Conclusion

Idiopathic non-caseating pancreatic granuloma is an exceptionally rare entity. A timely and thorough evaluation is critical to exclude malignancy and ensure appropriate patient management.

Introduction

Pancreatic granulomas are a rare disease. Idiopathic pancreatic granulomas are exceptionally rare, with only a limited number of cases reported in the literature, making their true incidence difficult to establish. Their clinical presentation and laboratory findings are often nonspecific and may overlap with pancreatic neoplasms, including neuroendocrine tumors, thereby creating substantial diagnostic uncertainty and necessitating comprehensive diagnostic evaluation.^1–11 The opposite of a caseating granuloma caused by tuberculosis, a non-caseating granuloma is secondary to systemic diseases such as sarcoidosis, rheumatoid arthritis, or Crohn’s.^1–11 Although most commonly it presents with chronic abdominal pain,^2–4 pancreatic granuloma can present with obstructive jaundice, acute pancreatitis, or pancreatic necrosis.^1–7 On imaging, it might be indistinguishable from cancer, requiring further workup.^2–8 When the underlying cause cannot be established, the pancreatic granuloma is labeled as idiopathic,¹² which may constitute a diagnostic dilemma requiring more investigation and possible intervention to distinguish it from the malignancy.⁴ Therefore, we present an interesting case of a patient who underwent extensive evaluation before reaching the diagnosis of idiopathic granuloma of the pancreas.

Case Presentation

A 75-year-old woman¹³ presented with several weeks of left upper quadrant abdominal pain. Her prior evaluation for palpitations and chronic diarrhea revealed a markedly elevated serum chromogranin A level of 3,123 ng/mL, with normal urinary metanephrine levels.

There was no weight loss, anorexia, flushing, cough, or night sweats. Physical exam was unremarkable, with no scleral icterus, lymphadenopathy, abdominal mass, or tenderness. The chest roentgenogram was normal. Magnetic resonance imaging (MRI) showed a 2.5 cm cystic lesion in the tail of the pancreas communicating with the main pancreatic duct (MPD) and a hypointense area in the distal pancreatic tail (Figure 1). Endoscopic ultrasound (EUS) was performed for further evaluation, which revealed a multi-cystic lesion in the tail of the pancreas, measuring 23×18 mm, with thick septations. There was no enhancing mural nodule, dilated MPD, or other worrisome features (Figure 2). A fine-needle aspiration (FNA) of the cystic lesion using a 22-gauge needle showed a carcinoembryonic antigen (CEA) level of 241 ng/mL, amylase of 49K U/L, positive GNAS and KRAS mutations, consistent with branch-duct intrapapillary mucinous neoplasm (BD-IPMN). In addition, there was a homogenous, well-defined, hypoechoic lesion measuring 11×27 mm in the distal tail of the pancreas (Figure 3) along with multiple enlarged peripancreatic lymph nodes (Figure 4). Fine needle biopsy (FNB) using a 22-gauge needle was obtained that showed multiple non-caseating granulomas and benign pancreatic and lymphoid tissue (Figures 5–7). There was no evidence of malignancy, and stains for acid-fast bacilli (AFB), FITE stain, and fungal stains were all negative. A follow-up gallium-68 DOTATATE positron emission tomography/computed tomography (^68Ga-DOTATATE PET/CT) demonstrated no radiotracer uptake within the pancreatic lesion, arguing against a somatostatin receptor–expressing neuroendocrine tumor. The proton pump inhibitor was stopped, a repeat serum chromogranin decreased to 1,696 ng/mL, and 5-hydroxy indole acetic acid (5-HIAA) was normal. At the 6-month follow-up, diarrhea and the LUQ pain were entirely resolved. An angiotensin-converting enzyme inhibitor was ordered, but the patient has never gotten that completed. However, there were no other clinical or radiologic manifestations to suggest sarcoidosis. A benign idiopathic etiology of the non-caseating pancreatic granuloma was concluded. The patient was doing clinically well with conservative management, and a repeat MRI was ordered for 1-year surveillance of the pancreatic tail BD-IPMN.

Figure 1.

Magnetic resonance cholangiopancreatography (MRCP) showing a 2.5 cm cystic lesion in the tail of the pancreas communicating with the main pancreatic duct, consistent with a branch-ductal intrapapillary mucinous neoplasm (BD-IPMN).

Figure 2.

Endoscopic ultrasound (EUS) showing a multi-cystic lesion in the tail of the pancreas measuring 23×18 mm with thick septations, with no enhancing mural nodule or other worrisome features.

Figure 3.

Endoscopic ultrasound (EUS) showing a homogenous well-defined hypoechoic lesion in the tail of the pancreas measuring 11×27 mm.

Figure 4.

Endoscopic ultrasound (EUS) showing two hypoechoic and irregular-shaped enlarged peri-pancreatic lymph nodes.

Figure 5.

Hematoxylin & eosin stain (40X) showing non-caseating epithelioid granuloma represented by tightly packed epithelioid cells, Langhans giant cells, and lymphocytes, with the adjacent normal lymphoid tissue.

Figure 6.

Hematoxylin & eosin stain (40X) showing hyalinized non-caseating granulomas with benign pancreatic tissue.

Figure 7.

Hematoxylin & eosin stain (40X) showing lymphoid tissue surrounded by red blood cells with scattered lymphocytes.

Discussion

Activated macrophages aggregate to form granuloma by acquiring an epithelial-like morphology.² Pancreatic granuloma can be subdivided histologically as caseating and non-caseating. The former is well known to be caused by tuberculosis, whereas the latter is the subject of a few case reports. Sarcoidosis was the most common cause of non-caseating pancreatic granuloma,^{1,7,8,10,11,14–20} followed by rheumatoid arthritis,^2–4 and Crohn’s disease.^5,20 Other cases were associated with granulomatosis with polyangiitis (formerly Wegener’s granulomatosis),²¹ xanthogranulomatous disease,²² insulin-dependent diabetes mellitus,⁹ or foreign body.⁶ Even though it is most likely related to chronic inflammatory conditions, pancreatic granuloma can sometimes lead to a serious clinical presentation, such as severe acute pancreatitis.

On computed tomography (CT) scan, the pancreatic head is the most common location for pancreatic granuloma, followed by the tail.¹⁰ The radiologic findings may occasionally resemble pancreatic malignancy and lead to further intervention or even surgery such as the Whipple procedure.^10,17 Previous systematic reviews have demonstrated that ^68Ga-DOTATATE PET/CT has high diagnostic accuracy with low false-positive rates for somatostatin receptor–expressing neuroendocrine neoplasms, supporting its reliability as an imaging biomarker. Therefore, the absence of radiotracer uptake within the pancreatic lesion in our patient significantly reduced the likelihood of a neuroendocrine tumor and supported consideration of alternative diagnoses.^23,24

In a few case reports, some criteria suggested the diagnosis of systemic sarcoidosis with pancreatic involvement and excluded pancreatic malignancy.^12,19 Those criteria included elevated angiotensin-converting enzyme (ACE) level, clinical responsiveness to corticosteroids, histology of non-caseating granuloma, and mediastinal or hilar lymphadenopathy on CT scan. However, sarcoidosis could be associated with an increased risk for cancer development in several solid organs like the lungs, liver, or stomach, and, in some cases, melanoma or lymphoma,¹⁵ leading to a diagnostic dilemma. Hence, there is a need to aggressively treat a new pancreatic mass in the sarcoidosis.¹⁷ In 90% of cases, sarcoidosis involves the pulmonary system. However, extrapulmonary manifestations are also common, among which the gastrointestinal system can be involved.¹⁶ However, granuloma involving the pancreas is rare in sarcoidosis, accounting for only 1–5% of cases. In addition, retroperitoneal or peri-pancreatic lymphadenopathy occurs in two-thirds of these cases. In some cases, pancreatic involvement of sarcoidosis can present with elevated serum lipase and mimic acute pancreatitis.¹⁹ Therefore, pancreatic involvement in sarcoidosis should be suspected whenever symptoms such as weight loss, weakness, and liver mass accompany abdominal pain.⁸

Nevertheless, the literature has also described pancreatic involvement in other autoimmune diseases. Among the long-term complications of rheumatoid arthritis, visceral involvement is rare. Pancreatic involvement in this disease was described only in four case reports.^2–4 Like sarcoidosis, it can also mimic pancreatic malignancy by either involving the pancreatic head² or the tail,^3,4 leading to unnecessary intervention or surgery. Extra-articular involvement is essential to reach a correct diagnosis and exclude malignant or infectious processes.² Elevation of rheumatoid factor, cyclic citrullinated peptide, and active disease are clues that help lead to a successful diagnosis. Therefore, awareness of possible pancreatic involvement among rheumatologists, gastroenterologists, and surgeons is necessary for proper diagnosis.

The first case of pancreatic involvement in Crohn’s disease was described in 1995.⁵ A patient presented with cholestasis and a mass in the head of the pancreas with duodenal and gastric mucosal changes consistent with Crohn’s disease. However, the differentiation between Crohn’s disease and tuberculosis can sometimes be challenging since caseation can be absent in extrapulmonary manifestation of the latter, and acid-fast bacilli (AFB) is shown only in one-third of the patients.²⁵

Granulomatosis with polyangiitis (formerly Wegener’s granulomatosis) is a rare autoimmune disease characterized by necrotizing or granulomatous vasculitis of small to medium-sized vessels.²¹ Acute pancreatitis can sometimes be the first presentation of the disease with vasculitis involvement.^26,27 Not only inflammation of the pancreas can occur, but also a mass can be present on imaging.^21,28 In three case reports, patients improved with corticosteroids or other immunosuppressive therapy, favoring the diagnosis of autoimmune disease.^21,26,28 Kontis et al and two other reports described 50% positivity for anti-neutrophil cytoplasmic antibody (ANCA).^21,26,28 Even though positive serology can help make the diagnosis, pancreatic involvement in granulomatosis with polyangiitis should be suspected even when ANCA is negative.

Non-caseating granuloma can also involve the pancreas in non-immune-mediated diseases. For example, a case report of granulomatous pancreatitis in an insulin-dependent diabetic patient was discovered in the postmortem exam.⁹ Therefore, the author suggested that granulomatous pancreatitis could be a possible underlying cause of diabetes mellitus. However, more work on the subject is necessary to develop such a conclusion.

Xanthogranulomatous pancreatitis, another rare and misdiagnosed lesion of the pancreas, was also described in the literature.²² The pathophysiology is not clear but is believed to result from a combination of duct obstruction, infection, and repeated hemorrhage. Because the disease was misdiagnosed as a primary pancreatic cystic neoplasm, distal pancreatectomy and splenectomy were performed due to worrisome features.

The etiology of non-caseating granuloma involving the pancreas cannot be established in one sporadic case involving a 56-year-old woman with clinical and radiologic findings of a pancreatic mass that was described as “idiopathic” pancreatic granuloma.¹²

Most cases of pancreatic granuloma can have a relatively similar presentation with epigastric pain, sometimes associated with weight loss,^1,2,4,17,27 jaundice,⁹ or fever and nausea.^9,26,27 Consequently, extensive workup and further intervention (EUS with FNA) or even surgery, including the Whipple procedure^2–8 and chemotherapy⁴ might be needed for evaluation and definitive management. Some patients may significantly improve with steroid therapy.¹⁰ Therefore, it is essential to rule out other etiologies before confirming the diagnosis as “idiopathic” non-caseating pancreatic granuloma.¹²

Conclusion

Non-caseating pancreatic granuloma is uncommon. Multiple etiologies include mycobacterial infection, sarcoidosis, Crohn’s disease, fungal infection, and autoimmune disease, including rheumatoid arthritis or vasculitis (eg., granulomatosis with polyangiitis), or foreign body (eg., Talc) can be encountered. Malignancy has to be ruled out whenever there is evidence of a pancreatic mass. Idiopathic etiology of pancreatic granuloma is rare but has been described in very few cases in the literature. Careful evaluation and prompt diagnosis are essential for proper management.

Funding Statement

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Abbreviations

ANCA, Anti-Neutrophilic Cytoplasmic Antibody; GNAS, Guanine Nucleotide Binding Protein.

Data Sharing Statement

All data generated or analyzed during this study are included in this published article.

Ethics Approval and Consent to Participate

According to the policies of the Institutional Review Board (IRB) at MetroHealth Medical Center/Case Western Reserve University, institutional approval was not required for the publication of this single-patient case report. Written informed consent was obtained from the patient for publication of this case report and any accompanying images.

Consent for Publication

Written informed consent for publication of the patient’s clinical details and any accompanying clinical images was obtained from the patient.

Disclosure

The authors report no conflicts of interest in this work.