Abstract
Background/Aim: This study aimed to characterize intraductal papillary neoplasm of the bile duct (IPNB) in patients undergoing initial and recurrent surgical resection and to evaluate the appropriateness of surgical treatment strategies. Patients and Methods: This study included 14 patients who underwent liver resection for intrahepatic IPNB. We assessed intraoperative and postoperative clinicopathological factors in patients undergoing both initial and recurrent surgeries. Results: Four patients experienced recurrence after initial surgery; all underwent pancreaticoduodenectomy. Postoperative complications were classified as Clavien-Dindo Grade 1-2 in three patients and Grade IIIb in one patient. There were no in-hospital deaths. Conclusion: Pancreaticoduodenectomy for recurrent cases following hepatectomy for IPNB is considered safe within an acceptable range and contributes to a favorable long-term prognosis.
Intraductal papillary neoplasm of the bile duct (IPNB) was first reported in 2001 as an epithelial tumor characterized by papillary growth with mucus production within the bile duct lumen (1) and was included in the World Health Organization (WHO) classification in 2010 (2, 3). In the 2019 WHO classification, IPNB was distinguished from conventional adenocarcinoma (4) based on its site of origin, excessive mucus production, prognosis, and histological features. Although the prognosis for IPNB is relatively favorable (5), recurrent cases have been reported (6-8). The treatment for recurrence varies depending on the location of the recurrence: intrahepatic bile duct recurrences are treated with re-hepatectomy while distal bile duct recurrences are managed with pancreatoduodenectomy (PD). Both surgical options are highly invasive and complex. In this study, we aimed to assess the efficacy of surgical interventions for recurrent intrahepatic IPNB through a clinicopathological review of cases where hepatic resection and PD were performed for postoperative recurrence.
Patients and Methods
A clinicopathological study was conducted on 14 cases of intrahepatic IPNB resected at Kurume University Hospital from 2005 to 2021, along with four cases of distal bile duct recurrence resected postoperatively. The study was approved by the Research Ethics Committee of Kurume University (approval number: 34697) and was conducted in accordance with the tenets of the Declaration of Helsinki. The need for informed consent was waived owing to the retrospective nature of the study.
The excised specimens were fixed in 10% neutral buffered formalin solution. Subsequently, 5 mm thick sections were prepared and stained with hematoxylin–eosin. The stained sections underwent pathological examination using microscopy. Clinicopathological investigations were performed according to the fourth edition of the WHO Classification of Tumors of the Digestive System (5-7). IPNB subclassifications were determined according to the classifications reported by Fukumura et al. (8).
Immunohistochemistry. Immunohistochemical analysis was performed on 4-μm-thick sections of formalin-fixed, paraffin-embedded tissues. The sections, mounted on glass slides, were incubated with anti-mouse monoclonal antibodies against human MUC-1 (clone Ma695, IgG1, 1:100 dilution; Leica Biosystems Newcastle, Ltd., Newcastle, UK), anti-mouse monoclonal antibody against human MUC-2 (clone Cep58, IgG1, 1:100 dilution; Leica Biosystems), anti-mouse monoclonal antibody against human MUC-5AC (clone CLH2, IgG1, 1:100 dilution; Leica Biosystems), and anti-mouse monoclonal antibody against human MUC-6 (clone CLH5, IgG1, 1:100 dilution; Leica Biosystems). These procedures were conducted using the fully automated Bond-III system (Leica Microsystems) with onboard heat-induced antigen retrieval in epitope retrieval solution 2 for 20 min at 99°C. Each slide was incubated with its respective antibody for 30 minutes at room temperature. A Refine polymer detection kit with horseradish peroxidase-polymer as a secondary antibody and DAB was used, and incubation with the secondary antibody was also performed for 30 min at room temperature.
All Immunohistochemical analyses were performed by two experienced observers blinded to the patients’ conditions. Postoperative complications were assessed using the Clavien-Dindo classification. Additionally, we reviewed case reports of PD in patients with recurrent IPNB.
Literature search. A literature search was performed using PubMed (National Center for Biotechnology Information at the National Institutes of Health in Bethesda, MD, USA), utilizing the keywords “IPNB” and “recurrence”.
Results
During the study period, 14 patients with IPNB underwent liver resection. The median follow-up period was 39.5 months (range=15-182 months). The majority of the patients were male, with a median age of 68 years (range=49-83 years). The surgical procedures performed included extended left lobectomy and bile duct resection in four cases, extended left lobectomy in one case, left lobectomy in four cases, left hepatic tri-segmentectomy in one case, central bisegmentectomy in one case, hepatic left lateral segmentectomy in one case, right lobectomy and bile duct resection in one case, and hepatopancreatoduodenectomy in one case. The median maximum diameter of the tumors was 33 mm (range=12-56 mm).
Microscopic mucus production was observed in all cases, with seven cases (50%) also showing gross mucus production. Intraepithelial carcinoma in the bile ducts was identified in eight cases, six of which demonstrated invasion beyond the epithelium. No cases showed lymph node metastasis. The subtypes were classified as oncocytic (six cases), gastric (four cases), pancreatobiliary (two cases), intestinal (one case), and unclassifiable (one case). The mean disease-free interval for the patients was 39 months (SD: 3.03), and the mean overall survival was 112 months (SD: Not Applicable). Recurrence was observed in 7 out of 14 cases (50%). Among these, four patients (28.6%) experienced recurrence in the distal bile duct and underwent PD. The other three patients, with intrahepatic recurrence, peritoneal dissemination, lymph node metastasis, and pulmonary metastasis in one case, were deemed ineligible for surgery due to unfavorable tumor factors or poor performance status (Table I). Table II presents a detailed analysis of surgical outcomes, postoperative complications, and hospital stay lengths for the four recurrence cases. The median operative time was 614 min (range=474-770 min), and the median blood loss was 1,268 ml (range=670-2,295 ml). The median postoperative hospital stay was 52 days (range=24-82 days). Postoperative complications included cholangitis (Grade I) in one case, bile leak and delayed gastric emptying (Grade II) in two cases, and postoperative bleeding (Grade IIIb) in one case, according to the Clavien-Dindo classification. The patient with Grade IIIb postoperative hemorrhage required laparotomy. There were no mortality cases. The histopathological findings in the four re-resected cases were remarkably similar to those observed during the initial surgeries, displaying consistent intraepithelial carcinoma histology and mucus expression. The median observation period for the patients undergoing re-resection was 45 months (range=18-141 months), with all currently under outpatient observation without the need for adjuvant chemotherapy.
Clinical character and histological factors in patients undergoing liver resection for intraductal papillary neoplasm of the bile duct (IPNB).
Surgical outcomes in patients treated with pancreatoduodenectomy (PD) for recurrent intraductal papillary neoplasm of the bile duct (IPNB).
Discussion
In the 2019 WHO classification (4), IPNB was distinguished from conventional adenocarcinoma. Tumors exhibiting uniform and regular papillary growth upon pathological examination were categorized as type 1 IPNBs, whereas those exhibiting irregular tissue architecture, such as irregular papillary branching, mixed tubular components, and papillary architecture of varying thicknesses, were classified as type 2 IPNBs. According to this classification, type 1 IPNB predominantly occurs in the intrahepatic bile ducts, with 70% of these tumors exhibiting excessive mucus production. Curative surgical resection remains the primary treatment for both types of IPNB. Lee et al. (5) reported an 81% 5-year survival rate for IPNB patients who underwent curative resection. Although radical resection is deemed to offer a favorable prognosis for IPNB (6, 7), recurrences after radical resection have been reported but are considered rare (7, 8).
In our study, no lymph node metastases were observed following the initial hepatic resection and the depth of resection was confined to the bile duct wall, indicating the effectiveness of surgical radical resection. However, recurrence was noted in 7 out of 14 cases, with treatment approaches varying based on the recurrence type and site. Generally, distant metastasis and peritoneal dissemination are contraindications for radical resection, a principle that was also adhered to in this study. Among the seven patients with recurrence, four experienced recurrence in the distal bile duct, yet were suitable candidates for radical resection. Yokode et al. (9) suggested that implantation by bile flow might cause recurrences, as recurrence sites are often located downstream (distal) from the primary site. In their study, while 84% of primary sites were intrahepatic bile ducts, 80% of recurrence sites were in downstream extrahepatic bile ducts. Furthermore, Nakayama et al. (10) found in their literature review that 14 out of 18 cases (77.8%) recurred in the lower bile ducts. Furthermore, despite the expectation of lower mucus production in extrahepatic bile ducts, where IPNB type 2 is more common, cases of recurrence in these ducts showed high mucus production, suggesting that implantation from the primary site could be a possible mechanism for recurrence (11). Both our study and the literature review found that the subtypes at the time of initial presentation and at recurrence were similar, yielding consistent results (Table III). While IPNB resembles intraductal papillary mucinous neoplasm and recurrence due to multicentric occurrence is possible, the likelihood of recurrence due to bile flow-mediated implantation of disseminated metastasis seems higher. These aspects of the recurrence mechanism warrant further investigation.
Evaluation of clinical and histopathological factors and postoperative outcomes and prognosis in pancreatoduodenectomy (PD) patients with intraductal papillary neoplasm of the bile duct (IPNB) recurrence of the remnant common bile duct.
It has been reported that invasive IPNB has a lower incidence of recurrence-free survival compared to non-invasive IPNB (11). However, our study observed recurrence even in patients with intraepithelial carcinoma, underscoring the need for follow-up considering recurrence even in cases lacking lymph node metastasis or invasion. Recent comparative studies between open PD and minimally invasive pancreaticoduodenectomy (12, 13) have highlighted shorter operation times and less blood loss in open PD compared to our surgery. This difference may be due to the initial liver resection in all patients and the increased surgical complexity due to bile duct resection and biliary reconstruction in two cases. Postoperative complications were considered to be within a safe range, with only one instance of Grade III or higher according to the Clavien-Dindo classification, and no mortality cases, including the six cases for which data was available. There was only one case (16.7%) of recurrence after resection with lymph node metastasis at the time of the second operation. The median recurrence-free survival of patients with PD was 22 months (range=12-141 months), but the four cases from our study showed a notably longer median recurrence-free survival of 45 months without adjuvant chemotherapy. For patients experiencing recurrence in the distal bile duct after liver resection for intrahepatic IPNB, PD as a secondary operation is relatively safe and may contribute to an improved long-term prognosis.
Conclusion
Recurrence in the distal bile duct following liver resection for IPNB can occur through seeding or other mechanisms, underscoring the importance of long-term follow-up, even in cases of intraepithelial carcinoma. Our study suggests that PD as a secondary intervention for patients with recurrent IPNB in the distal bile duct is relatively safe and can contribute to long-term prognosis.
Acknowledgements
The Authors thank present and previous members of our laboratory for their support in data management, and the proofreaders for editing our manuscript.
Footnotes
Authors’ Contributions
Conceptualization, S.A. and H.S.; Methodology, M.A. and Y.G.; Validation, S.A., R.M., and S.F.; Investigation, D.M. and K.H; Data Curation, S.A.; Writing – Original Draft Preparation, S.A.; Writing – Review & Editing, S.A.; Supervision, F.F.; Project Administration, T.H. All Authors discussed the content of the manuscript, read, and approved the final manuscript.
Conflicts of Interest
All Authors declare no conflicts of interest or competing financial interests for this article.
Funding
This research did not receive any grants from funding agencies in the public, commercial, or not-for-profit sectors.
- Received May 21, 2024.
- Revision received June 12, 2024.
- Accepted June 13, 2024.
- Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
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