IPNB is a grossly visible neoplastic lesion characterized by papillary proliferation of the biliary lining within the duct lumen itself. It can arise anywhere along the intrahepatic and extrahepatic biliary tree and is widely regarded as a premalignant condition that progresses to invasive cholangiocarcinoma through a stepwise dysplasia-carcinoma sequence. Hepatolithiasis, the formation of stones within the intrahepatic bile ducts, is an established predisposing factor for chronic cholangitis and biliary carcinogenesis, with a particularly high prevalence in East Asian populations. When patients with hepatolithiasis undergo biliary-enteric drainage, incomplete separation of the bile duct from the intestinal tract can permit persistent enterobiliary reflux and bacterial colonization of the bile, processes that may drive repeated injury and aberrant repair of the biliary epithelium.

The first patient was a 66-year-old man with a 19-year history of recurrent right upper quadrant pain who presented with four days of chills, fever, and jaundice consistent with acute cholangitis. His surgical history was extensive: cholecystectomy with partial left hepatectomy in 2007, followed by two afferent-loop biliary-enteric drainage procedures in 2010 and 2014 for recurrent stones. In both reconstructions the common bile duct was left intact, creating a persistent blind pouch and long-term enterobiliary reflux. The original operative records were unavailable, so the exact rationale for preserving the duct could not be determined, although the authors note that non-standardized afferent-loop jejunohilar anastomosis without duct transection was performed at some centers for complex recurrent hepatolithiasis when hilar inflammation and adhesions made formal dissection technically difficult.

Laboratory testing confirmed acute cholangitis, with leukocytosis, an elevated neutrophil ratio, and thrombocytopenia, alongside hypoalbuminemia and raised direct bilirubin, alkaline phosphatase, and gamma-glutamyl transpeptidase levels suggesting chronic biliary injury and obstructive jaundice. His serum CA19-9 tumor marker was markedly elevated at 170.92 U/mL. Magnetic resonance imaging revealed cystic and irregular tubular dilatation of the bile ducts in the residual left hepatic lobe, with intraluminal filling defects that proved intraoperatively to be a mixture of stones, gelatinous mucin, and diffuse papillary mucinous tumor. MRCP further showed dendritic, beaded intrahepatic dilatation, anastomotic stricture at the hepatic hilum, and alternating strictures and dilatations compatible with persistent reflux and chronic cholangitis.

At revision surgery, the team found an afferent-loop jejunohilar anastomosis with an untransected common bile duct and residual blind pouch. Opening the anastomosis released a large volume of gelatinous mucin, and extensive papillary tumor lined the residual left intrahepatic ducts. Surgeons performed completion residual left hemihepatectomy and hilar bile duct excision, removed the previous anastomotic segment, completely transected the common bile duct, and re-established bile flow through a Roux-en-Y hepaticojejunostomy, the approach favored in current practice. Pathology revealed intestinal-type IPNB with high-grade intraepithelial neoplasia and focal invasive mucinous adenocarcinoma. The resection margin was microscopically positive for non-invasive papillary tumor at the ductal stump, an R1 resection, although the invasive component itself was fully removed. Immunohistochemistry showed positivity for CK7, MUC5AC, MUC2, CDX2, CK20, and CEA, with a Ki-67 labeling index of 60 to 70 percent and wild-type p53. At 12 months of follow-up the patient remained alive, recurrence-free, and asymptomatic with normalized imaging and tumor markers.

The second patient, a 69-year-old woman, presented with two months of dull, distending upper abdominal pain. She had undergone cholecystectomy for gallstones roughly 30 years earlier and a biliary-jejunostomy for hepatolithiasis 12 years before admission. Her laboratory results showed hypoalbuminemia, markedly elevated cholestatic enzymes including alkaline phosphatase at 567.8 U/L, and sharply raised tumor markers: CEA at 225.96 U/mL, CA19-9 at 53.52 U/mL, and CA125 at 66.47 U/mL. Contrast-enhanced CT demonstrated a large heterogeneous mass in the right hepatic lobe with capsular invasion and progressive enhancement, together with diffuse intrahepatic biliary dilatation from an intraductal mass-forming lesion. Intraoperatively, her pre-colic afferent-loop jejunohilar anastomosis again lacked common bile duct transection, and the blind afferent limb was dilated to approximately 20 centimeters with torsion, distal stricture, and severe adhesions.

She underwent right hemihepatectomy with regional lymphadenectomy. The resected specimen contained dilated right intrahepatic bile ducts filled with a gray-white tumor measuring 12 by 8 by 6.5 centimeters, extending partially into the hilar bile duct and containing abundant mucinous material. Pathology identified pancreatobiliary-type IPNB complicated by moderately to poorly differentiated invasive adenocarcinoma, with focal capsular invasion and suspected vascular tumor thrombus. The resection margins were negative, an R0 resection, and all 16 examined regional lymph nodes showed only reactive hyperplasia. Immunohistochemistry was positive for CK7, CK19, MUC5AC, and CEA and negative for MUC2, CDX2, and CK20, with a Ki-67 index of 30 percent and wild-type p53. Given the high-risk features, adjuvant chemotherapy was strongly recommended, but the patient declined all postoperative systemic therapies, including targeted and immunotherapy, and was managed with observation alone. Eleven months after surgery she developed recurrence with widespread peritoneal and distant metastases, confirmed pathologically as metastatic pancreatobiliary-type IPNB.

The authors propose a plausible carcinogenic sequence: non-standardized drainage without duct transection creates a blind pouch, the blind pouch sustains enterobiliary reflux, reflux drives recurrent cholangitis and chronic inflammation, and chronic inflammation promotes stepwise malignant transformation of the biliary epithelium. The long interval between the initial drainage procedures and the diagnosis of IPNB in both patients is consistent with a prolonged, inflammation-driven process. However, the team is explicit that with only two cases and no comparator group, these findings cannot establish a causal relationship between non-standardized biliary-enteric drainage and IPNB. The proposed pathway should be regarded as a plausible association rather than an established cause, and larger studies with standardized reconstruction techniques and long-term follow-up are needed to clarify the relationship between reflux, inflammation, and tumor development.

The two cases also illustrate the striking biological heterogeneity of IPNB, which encompasses intestinal, gastric, pancreatobiliary, and oncocytic subtypes. Current evidence suggests prognosis tracks more closely with tumor stage, degree of invasion, anatomical location, multiplicity, and completeness of resection than with histological subtype alone, and pancreatobiliary-type IPNB is generally considered more aggressive at the population level, though substantial variability exists across all subtypes. The apparent paradox of a higher Ki-67 index in the patient who remained recurrence-free likely reflects sampling bias, since the high labeling in Case 1 came predominantly from the high-grade intraepithelial component while the invasive component was minute, and the two cases’ Ki-67 values were assessed by different methods and cannot be directly compared. Mucin production, traditionally associated with earlier detection because intraductal mucin can cause intermittent obstruction and jaundice, proved an unreliable prognostic guide here: the mucin-producing pancreatobiliary tumor in Case 2 was the one that metastasized early, indicating that mucin phenotype alone is insufficient for prognostication.

The clinical implications are practical. When biliary-enteric reconstruction is indicated for hepatolithiasis, the authors recommend techniques that avoid a residual blind pouch and minimize reflux, with complete transection of the extrahepatic bile duct and Roux-en-Y hepaticojejunostomy preferred, although they caution that this rests on pathophysiological reasoning rather than proven preventive efficacy. For patients with a history of non-standardized drainage and long-standing biliary inflammation, long-term surveillance extending beyond 10 years may be warranted, using MRI, MRCP, and where feasible cholangioscopy to define the extent of intraductal disease. The report’s limitations are acknowledged: only two cases, incomplete prior operative records, a 12-month follow-up too short to judge the significance of residual non-invasive disease, and a patient-driven refusal of adjuvant therapy whose impact on recurrence cannot be determined. Complete surgical resection remains the cornerstone of curative treatment, but the aggressive course in the second patient despite clear margins shows the limits of surgery alone for high-risk invasive disease.

Subject of Research: Malignant transformation of intraductal papillary neoplasm of the bile duct after non-standardized biliary-enteric drainage for hepatolithiasis

Article Title: Malignant transformation of intraductal papillary neoplasm of the bile duct following non-standardized biliary-enteric drainage for hepatolithiasis: two case reports and literature review

Article References: Peng, J., Yang, P., Huang, H., Peng, C., & Tan, Z. (2026). Malignant transformation of intraductal papillary neoplasm of the bile duct following non-standardized biliary-enteric drainage for hepatolithiasis: two case reports and literature review. Frontiers in Oncology, 16, Article 1980694. https://doi.org/10.3389/fonc.2026.1980694

Image Credits: AI Generated

DOI: 10.3389/fonc.2026.1980694

Keywords: intraductal papillary neoplasm of the bile duct, IPNB, hepatolithiasis, biliary-enteric drainage, enterobiliary reflux, chronic cholangitis, cholangiocarcinoma, Roux-en-Y hepaticojejunostomy, case report, biliary carcinogenesis, Ki-67 index, blind pouch syndrome