Pancreatic Inflammation Induced by Immune Checkpoint Inhibitors in Melanoma Treatment: A Case Report

Introduction

Immune checkpoint inhibitors (ICI) have revolutionized cancer treatment, extending survival in several malignancies [1], including melanoma, non-small cell lung carcinoma, and head and neck squamous carcinomas [2].

These agents work by blocking inhibitory pathways, such as CTLA-4 and PD-1/PD-L1, thereby enhancing T-cell-mediated immune responses against tumors [3,4]. Commonly used ICIs include PD-1 inhibitors (eg, nivolumab, pembrolizumab), PD-L1 inhibitors (eg, atezolizumab, avelumab, durvalumab), and CTLA-4 inhibitors (eg, ipilimumab).

Although ICI therapy is generally well tolerated, it can cause adverse effects, such as dermatitis, endocrine disorders of the thyroid, pituitary, and adrenal glands, pneumonitis, colitis, and hepatitis [5]. However, pancreatic toxicity remains rare and under-recognized [6]. ICI-induced pancreatitis can range from asymptomatic hyperlipasemia to symptomatic acute pancreatitis [1,7,8]. Abu-Sbeih et al [9] reported in a study involving 2279 patients that 4% of them developed acute pancreatitis. Over half of patients with ICI-related pancreatic enzyme elevation were asymptomatic, making diagnosis particularly challenging [9].

The diagnostic criteria for ICI-related pancreatitis remain primarily clinical and radiological, supported by elevated pancreatic enzyme levels and the exclusion of other causes. Imaging can reveal diffuse or focal pancreatic enlargement, often indistinguishable from neoplastic processes [10]. While there are no standardized guidelines, current management is based on expert consensus and includes corticosteroid therapy in moderate to severe cases, with discontinuation or delay of immunotherapy depending on severity [11]

We present a case of a 41-old-man with immune-mediated pancreatitis mimicking a pancreatic neoplasm while receiving ipilimumab and nivolumab for metastatic melanoma, a particularly rare adverse effect. Notably, this case was managed successfully without the use of corticosteroids, which are typically considered the first-line treatment for moderate to severe adverse effects. The patient improved with temporary ICI discontinuation and close clinical monitoring, avoiding potential complications of immunosuppression.

Case Report

A previously healthy 41-year-old man received a diagnosis of melanoma in the left foot, wild-type BRAF, Breslow IV, with metastasis to the inguinal lymph nodes. Staging examinations using positron emission tomography-computed tomography (PET-CT) and brain magnetic resonance imaging (MRI) ruled out distant disease. The patient underwent surgery, followed by adjuvant treatment with nivolumab for 1 year, which was well tolerated.

Following a 1-year treatment hiatus, nodal and peritoneal recurrence occurred, leading to 4 cycles of combined ipilimumab and nivolumab, followed by maintenance nivolumab, with complete response. After 10 cycles of nivolumab, PET-CT revealed a focal area of increased fluorodeoxyglucose (FDG) uptake in the head of the pancreas, with a maximum standardized uptake value (SUVmax) of 5.5. The uptake pattern was well circumscribed and isolated, with no other hypermetabolic lesions detected throughout the body, reinforcing the localized nature of the finding (Figure 1). Findings raised concern for a metabolically active lesion, with imaging characteristics more suggestive of a primary neoplasm rather than metastatic melanoma.

Complementary evaluation with MRI identified a hypovascular, heterogeneous mass in the pancreatic head, measuring 40×32×20 mm, in close contact with the superior mesenteric vein. On coronal T1-weighted imaging, the lesion exhibited a cystic component with hypointense signal, while axial T2-weighted sequences showed hyperintensity, suggesting fluid content or necrotic areas. T1-weighted axial and T2-weighted coronal sections further confirmed the lesion’s contact with vascular structures, without clear evidence of vascular invasion. The imaging characteristics were also suggestive of a solid-cystic pancreatic mass, a potentially primary neoplasm (Figure 2).

The patient had no prior diagnosis of malignancy other than melanoma. He had no relevant comorbidities, such as hypertension or diabetes mellitus. He was a non-smoker and did not consume alcohol. The patient showed no clinical signs of jaundice, did not report any form of abdominal pain, and explicitly denied steatorrhea or unintentional weight loss. Laboratory test results revealed lipase and amylase levels of 1405 U/L and 422 U/L, respectively. The tumor markers CEA and CA 19-9 were within the reference range.

Given the high sensitivity and specificity of endoscopic ultrasound as a diagnostic tool, it was selected for the evaluation of this patient and showed a hypoechoic, poorly defined, non-vascularized lesion in the pancreatic head, measuring approximately 2.2 cm, without signs of infiltration of adjacent structures. Fine-needle aspiration was performed, and histological analysis revealed moderately active chronic inflammation, with prominent lymphoplasmacytic infiltrate, intense fibrosis, and focal acinar atrophy. No malignant cells were identified. Immunohistochemistry was negative for cytokeratin and S100 but positive for CD3 and CD8 T-cell markers, supporting a T-cell predominant inflammatory response consistent with immune-related chronic pancreatitis [9,12], as visualized in the endoscopic ultrasound-guided biopsy (Figures 3, 4).

Pancreatitis was classified as grade 2 according to the Common Terminology Criteria for Adverse Events, version 5.0 (CTCAE-5) [12]. Following the CTCAE-5 recommendations, nivolumab was temporarily withheld for 2 weeks. The patient remained asymptomatic during this period.

Corticosteroids were not initiated, owing to the patient’s mild clinical presentation. Notably, the pancreatic enzyme levels normalized spontaneously without further intervention, supporting the decision to resume immunotherapy. Given the patient’s history of metastatic melanoma and complete resolution of pancreatitis, nivolumab was safely restarted.

Follow-up PET-CT performed 3 months later demonstrated a significant reduction in metabolic activity in the pancreatic head lesion, with a decrease in SUVmax from 5.5 to 2.3. There was no FDG-avid lymphadenopathy or evidence of infiltrative disease. These findings were interpreted as a regression of inflammatory activity after transient suspension of immunotherapy (Figure 5).

Since then, there has been no recurrence of pancreatic inflammatory processes. The patient continued monthly administration of nivolumab, maintaining a complete response, with no changes in imaging or laboratory test results.

Another PET-CT scan conducted 3 months after reintroducing nivolumab showed complete resolution of FDG uptake in the pancreatic head. However, there was mild, diffuse, non-focal FDG uptake in the pancreatic tail, interpreted as physiological or subclinical inflammatory activity, without morphological changes on concurrent MRI (Figure 6).

The subsequent MRI confirmed complete resolution of the previously seen pancreatic head lesion. No residual masses or ductal abnormalities were observed. The pancreatic parenchyma demonstrated normal signal intensity and homogeneous post-contrast enhancement. There was no evidence of chronic pancreatitis, such as ductal irregularity, pseudocysts, or calcifications. The superior mesenteric vein and portal vein appeared normal, with no signs of thrombosis or invasion (Figure 7). These findings suggested a favorable response to immune checkpoint inhibition, with regression of tumor-associated inflammation and mass effect.

The patient remained asymptomatic, with pancreatic enzyme levels within normal limits. Similarly, no evidence of tumor recurrence originating from the melanoma was found.

Discussion

This case highlights a rare presentation of immune-related focal pancreatitis secondary to combined ICI therapy with ipilimumab and nivolumab for metastatic melanoma. The patient was asymptomatic, with an incidental finding of a pancreatic lesion on imaging, raising initial concern of pancreatic neoplasia. Histopathological evaluation confirmed immune-mediated pancreatitis. Notably, the patient experienced spontaneous resolution of imaging abnormalities without corticosteroid therapy, allowing for the safe resumption of nivolumab monotherapy.

Immune-related pancreatitis is an uncommon toxicity of ICIs, occurring in approximately 2% of patients, particularly those receiving combination regimens [9,13]. Most reported cases involve asymptomatic elevations of pancreatic enzymes, without radiological or histological confirmation [12,13]. Focal mass-forming pancreatitis is exceptionally rare and can mimic pancreatic cancer clinically and radiologically, posing a significant diagnostic challenge [14,15].

The Brazilian Society of Clinical Oncology recommends suspending ICI treatment in cases of grade 2 immune-related toxicities and, at the physician’s discretion, initiating corticosteroid therapy [16]. Reintroduction of ICI treatment is advised once the toxicity has improved [16]. In the present case, rapid spontaneous improvement without the need for intervention supported the decision to continue immunotherapy.

The decision to resume nivolumab monotherapy without corticosteroid intervention was based on a risk-benefit assessment prioritizing oncologic control. Given the normal pancreatic enzyme levels, resolving imaging findings, and absence of clinical pancreatitis symptoms, the potential risks of corticosteroid-induced immunosuppression, such as infection or diminished anti-tumor response, outweighed the benefits. Alternative strategies, such as prolonged ICI discontinuation or empiric steroid therapy, were considered but ultimately deemed unnecessary.

A unique aspect of this case is the lesion’s radiological appearance, which initially suggested pancreatic malignancy. This underscores a critical diagnostic pitfall in patients with cancer receiving ICIs, in which immune-mediated inflammatory processes can mimic tumor progression or metastasis [14,15]. In particular, the possibility of pancreatic metastasis should be considered in melanoma. When melanoma metastasizes to the pancreas, it typically presents as multiple hypervascular lesions, although hypovascular patterns can also occur. These lesions are usually hypoechoic on ultrasound, hypodense on CT, and hyperintense on T1-weighted MRI with gadolinium contrast [17,18]. In the present case, the absence of typical imaging features of melanoma metastases – such as multiplicity and hypervascularity – reduced the suspicion for secondary involvement. Instead, the presence of a solitary, hypovascular pancreatic mass closely mimicked a primary pancreatic neoplasm, particularly pancreatic adenocarcinoma. This highlights a critical diagnostic pitfall in patients undergoing immunotherapy, in whom immune-mediated pancreatitis can radiologically simulate primary pancreatic cancer, rather than metastatic disease.

This case also reinforces the importance of a multidisciplinary approach, involving oncology, radiology, gastroenterology, pathology, and surgery teams, to establish the complex differential diagnosis between immune-related pancreatitis and pancreatic neoplasms. It also emphasizes the need for heightened clinical suspicion of immune-mediated toxicities in patients receiving ICIs, especially when faced with atypical radiologic findings.

Conclusions

ICI-related focal pancreatitis is a rare and diagnostically challenging adverse event, particularly when it mimics primary pancreatic neoplasms. This case highlights the importance of considering immune-related pancreatitis in the differential diagnosis of new pancreatic masses in patients undergoing immunotherapy.

The patient’s history of metastatic melanoma increased the difficulty of differential diagnosis, in which pancreatic lesions can represent either metastatic disease or a primary pancreatic malignancy. This underscores the crucial role of endoscopic ultrasound-guided biopsy in avoiding misdiagnosis and preventing unnecessary surgical interventions. Multidisciplinary collaboration is essential for the accurate diagnosis and management of immune-related adverse events. Additionally, in patients with mild or asymptomatic presentations, conservative management, with temporary suspension of ICI treatment – without the use of corticosteroids – can lead to resolution of pancreatic inflammation.

Further research is needed to clarify the phenotype of immune-related pancreatitis and develop evidence-based guidelines distinguishing cases that require immunosuppression from those suitable for conservative management, while balancing toxicity and oncologic control.