Intraductal oncocytic papillary neoplasm (IOPN), a rare precancerous pancreatic ductal tumor, remains limited and poorly characterized in imaging literature globally (1). Adsay et al. first outlined it in 1996 as a distinct clinicopathological entity (2). In 2010, WHO guidelines initially classified it as part of intraductal papillary mucinous neoplasms (IPMN), marking a significant evolution in its classification (3). IOPN was formally reclassified as a separated tumor category in the 2019 WHO digestive system tumor classification due to its unique molecular and histological profile (4). Histopathological hallmarks include arborizing papillae lined by mitochondria-rich oncocytes cells. Genetically, IOPNs generally lack the activating mutations in KRAS and GNAS that are commonly seen in other IPMN subtypes. And molecular profiling reveals characteristic PRKACA/PRKACB fusions (3, 5). Due to the rarity of IOPN, relevant literature, particularly radiologic characterization, remains sparse. In order to address this knowledge gap, we present a retrospective analysis of three surgically confirmed IOPN cases in our hospital, integrating clinicopathological data with imaging findings and relevant literature review.

Pancreatic IOPN is a rare digestive system tumor, accounting for 4.5% of pancreatic intraductal neoplasms‌ (6). It was regarded as a pathological subtype of intraductal papillary mucinous neoplasm (IPMN) and has been recognized as a distinct tumor entity in the 2019 WHO classification of digestive system tumors owing to its distinct pathological morphology and genetic mutation (4). To date, fewer than 100 cases of pancreatic IOPN have been reported globally. Wang et al. subsequently published the first systematic review on IOPN, summarizing its comprehensive clinicopathological features (7).

Epidemiological analysis from a systematic review (8) shows a male predominance in IOPNs (male-to-female ratio 1.5:1), with a mean diagnostic age of 58.2 years. Clinically, IOPNs lack pathognomonic manifestations, primarily presenting with nonspecific symptoms, including abdominal pain and jaundice‌. Approximately 34.2% of cases were incidentally detected during routine examinations without overt symptoms, highlighting their indolent biological behavior‌. Importantly, unlike conventional IPMN, serum biomarkers including CEA and CA19-9 show no diagnostic correlation with IOPN progression (normal ranges: CEA < 5 ng/mL, CA19-9 < 37 U/mL) (9).

In our case series, the clinical presentations aligned with established characteristics. The characteristics of these cases are summarized in Table 1. All three patients underwent standardized tumor marker profiling. However, Case 1 exhibited elevated CA19-9 levels (204.91 U/mL), potentially attributed to concurrent biliary obstruction, whereas Case 2 and 3 maintained values within normal limits.

Paolino et al. (8) reported the average diameter of IOPNs was 45.5 mm in a comprehensive analysis of 289 cases. These tumors are pathologically characterized by confinement within dilated pancreatic ducts and present with arborizing papillary architectures composed of mitochondria-rich oncocytic cells with large, distinct nucleoli, without obvious mucin production (3). Histopathological evaluation revealed that almost all cases (96.6%) demonstrated high-grade dysplasia, and half of the cases showed invasive carcinoma ‌‌ (8). Moreover, Hirabayashi et al. explained that the presence of hyalinised fibrovascular cores is more commonly described in IOPNs than in IPMNs (10). Molecular profiling further differentiates IOPNs through their unique genetic signature: IOPNs lack certain gene mutations found in IPMN or pancreatic ductal adenocarcinoma, such as KRAS, GNAS, TP53, SMAD4 and CDKN2A (11). Instead, they demonstrate recurrent kinase fusion events, with PRKACB: ATP1B1 being the predominant genetic alteration, followed by PRKACA-related fusions (5, 8). Some scholars regard these gene fusions as driving factors for oncocytic differentiation (12).

As for IHC, almost all IOPNs express MUC5AC, similar to IPMN. MUC1 (EMA) expression is diffusely positive in IOPNs, overlapping with features of ITPNs and pancreatobiliary-type IPMNs (9). Additionally, MUC6 also exhibits diffuse and strong expression, showing tumor pyloric lineage differentiation, although its expression intensity is characteristically weaker than that in ITPNs (8). MUC2‌/CDX2 expression is limited to ‌focal goblet cell components‌, contrasting sharply with the diffuse positivity pattern in intestinal-type IPMNs (3, 8). Moreover, Oncocytic elements exhibit a characteristic granular positivity for HepPar1 (9). Compared with other subtypes of IPMN, CD117 expression is significantly more common in IOPN (13). Research regarding the immune microenvironment has found that IOPNs are enriched in immune cells, with the most notable finding being an increased proportion of CD8 + cells within the infiltrating component. This finding may explain the occurrence of active autoimmune surveillance in invasive IOPNs, which could be associated with the favorable prognosis of IOPN patients (14).

In summary, our findings align with prior reports demonstrating that IOPN exhibits ‌distinctive clinical and pathological characteristics‌. The IHC characteristics of these cases are summarized in Table 2.

In the largest multicenter cohort study to date (n = 414), Paolino et al. (8) systematically described the clinical, pathological and radiological features of IOPNs. The pancreatic head (131/237; 55.3%) was the most common site for IOPNs, followed by the tail (33/237; 13.9%) and body (24/237; 10.1%)‌. Main duct and branch duct involvement were equal, at about 38.2%, and the involvement of both the main and branch ducts was 23.6%. In terms of imaging presentation, cystic morphology constituted the majority (24/38; 63.2%), followed by solid lesions (7/38; 18.4%) and mixed cystic-solid architecture (5/38; 13.2%)‌. In our case series, two cases were located in the pancreatic head, one in the body/tail region; two cases were classified as branch-duct type, and one as main-duct type. One solid tumor was localized within the main pancreatic duct of the pancreatic head while the others were cystic-solid tumors with well-defined peripheral encapsulation.

In previous reports (6, 7), large multilocular cystic architecture with MPD dilatation and predominant solid components occupying the majority of the cyst‌ volume were the main characteristics of the imaging of IOPNs. The nodules, thickened septa, or cyst walls were contrast-enhanced because the solid components of the tumor were highly vascularized. According to MRI findings, IOPNs were reported to exhibit predominantly ‌hypointense signals on T1WI and hyperintense signals on T2WI. What is more (9), the characteristic of ‌complex and arborizing papillae‌ suggested a possible diagnosis of IOPN. Additionally, bile duct obstruction and dilatation of the downstream MPD could also be observed (15).

In this case series, the imaging characteristics of the lesions demonstrated consistent patterns across multiple modalities. The lesions predominantly exhibited hypointense signals on T1WI and hyperintense signals on T2WI, which agreed with established radiographic descriptions in the literature. The solid components of the tumors demonstrated moderately progressive enhancement on contrast-enhanced dynamic imaging, with enhancement intensity measuring slightly lower than or comparable to that of the adjacent pancreatic parenchyma. DWI further characterized these solid portions as exhibiting mild diffusion restriction.

Notably, all tumors were radiologically identified within either the MPD or branch pancreatic ducts. Therefore, this anatomical characteristic underscores the critical importance of meticulously evaluating the spatial relationship between the lesions and the pancreatic ductal system was critical for accurate diagnosis. In contrast to extraductal neoplasms, which typically demonstrate mass effect manifesting as ductal displacement or compression, the branch duct-type intraductal tumors presented as cystic-solid lesions that maintained intimate anatomical continuity with the involved duct. These intraductal masses were consistently associated with mild dilation of the affected branch pancreatic duct, which maintained patency at its junction with the MPD.

Studies (16, 17) have shown that an increase in mitochondrial number within oncocytic cells leads to heightened metabolic activity in oncocytic tumors. This pathophysiological mechanism explains the significant 18F-fluorodeoxyglucose (FDG) avidity observed in IOPNs, which demonstrated through positron emission tomography (PET) imaging. What’s more, this metabolic profile frequently results in diagnostic confusion with malignant processes. The current diagnosis relies on fine-needle aspiration (FNA) (18), allowing for histological evaluation of the characteristic oncocytic cells with eosinophilic granular cytoplasm and nuclear features.

Regarding the clinical malignancy of IOPN, firstly, the study by Paolino et al. (8) found that it universally exhibited high-grade dysplasia. In our cases, two cases showed high-grade dysplasia, one of which was accompanied by focal microinvasion. Additionally, perineural and vascular invasion were infrequently reported, with over 90% of patients achieving excellent long-term survival after the operation (8). Although the risk is low, IOPN does have the potential for metastasis and recurrence. The patients who relapsed did not suffer further relapses after complete pancreatectomy (15). In our case series, all patients showed no signs of recurrence on postoperative imaging or in laboratory tests.

Furthermore, CD117 demonstrated a relatively high positivity rate in IOPN and was highly correlated with the PRKACA fusion gene (13). The loss of CD117 expression was often observed in invasive carcinoma components, suggesting its potential role as a marker for malignant transformation. Significant CD117 expression was noted in our Case 2, indicating possible malignant potential. Additionally, Ki-67 demonstrated a significant correlation with the malignancy of pancreatic neoplasms (19). A higher Ki-67 index was associated with greater tumor aggressiveness. In our cases, the Ki-67 index was consistently low, supporting the classification of pancreatic IOPN as a low-grade malignant tumor. Given its malignant potential, surgical resection is the preferred and highly curative treatment. This underscores the importance of accurate preoperative diagnosis to avoid both overtreatment and undertreatment.

The differential diagnosis of IOPNs mainly includes IPMNs, ITPNs, pancreatic neuroendocrine tumor (PanNET), pancreatic ductal adenocarcinoma (PDAC), and mucinous cystic neoplasm. Table 3 summarized the comparative features of IOPN and other cystic-solid lesions of the pancreas.

Similar to IOPN, IPMN is classified into main duct type, branch duct type, and mixed type based on the extent of lesion involvement (15). IPMN secretes abundant mucin with minimal solid components, whereas IOPN typically demonstrates a low degree of mucin production (20). Additionally, IPMN cases exhibit higher frequency of peripheral invasion and worse prognosis than IOPN, reflecting IPMN’s propensity for progression to invasion carcinoma (15).

Both ITPNs and IOPNs typically present as solid or solid-cystic intraductal masses accompanied by upstream pancreatic duct dilation. Distinctively, ITPN classically demonstrates the “two-tone duct sign” and “cork-of-wine-bottle sign.” Histologically, features of ITPN include the absence of eosinophilic cytoplasm and virtually no mucin production (21, 22). And on IHC, MUC5AC is typically negative (23). Compared to IOPNs, previous studies have shown that aggressie tendencies, such as vascular invasion, are more frequently observed in ITPN (21).

Oncocytic PanNETs originate from the pancreatic islet cells and are classified as functional or non-functional based on their ability to produce metabolically active hormones such as insulin, glucagon, vasoactive intestinal peptide, and so on (24, 25). Functional tumors are mostly hypervascular small tumors, with insulinomas and gastrinomas demonstrating marked enhancement in the arterial phase of contrast-enhanced imaging; non-functional tumors are typically larger and often accompanied by necrosis or calcification (25). The enhancement patterns of both entities aid in differential diagnosis.

On cross-sectional imaging, pancreatic ductal adenocarcinoma (PDAC) typically manifests as an irregular, hypovascular mass demonstrating characteristic imaging biomarkers, including pancreatic duct dilatation and parenchymal atrophy, with a demonstrated predilection for perivascular invasion (26)‌. The tumor marker CA19-9 levels are significantly elevated‌ in most cases, serving as a diagnostic adjunct. Current management paradigms emphasize multidisciplinary approaches incorporating neoadjuvant therapy, surgical resection when anatomically feasible,and adjuvant chemotherapy. Despite therapeutic advances, the 5-year survival rate remains dismally low at under 10%, and the disease is prone to locoregional recurrence or distant metastasis ‌ (27).

Mucinous cystic neoplasm (MCNs) predominantly affect postmenopausal women and are commonly located in the body and tail of the pancreas (28). Approximately 4–12% of cases progress to invasive carcinoma. Imaging reveals well-circumscribed multilocular cystic lesions, linear septations, and thickened cyst walls enhancing on contrast phases. High-risk stigmata for malignant transformation include a maximum lesion diameter greater than 4 cm and the presence of mural nodules, solid components, or upstream pancreatic duct dilation (29).

In conclusion, IOPN represents a rare pancreatic entity characterized by distinctive clinicopathological hallmarks. Definitive diagnosis necessitates mulimodal integration of MRI findings, molecular profiling, and immunohistochemical signatures. Accurate identification is critical for guiding surgical planning and predicting favorable prognosis. While this series contributes to the existing literature, the limited cohort underscores the imperative for multicenter registry studies to enhance doctors’ understanding of IOPNs.