Pancreatobiliary maljunction accompanied by synchronous carcinomas

A 47-year-old female presented with the chief complaint of dull pain in right upper quadrant of abdomen for 10 days without jaundice. Routine laboratory tests were as follows, liver function tests showed an alanine aminotransferase (ALT) level of 49 U/L (normal range, 15–40 U/L), an aspartate aminotransferase (AST) level of 96 U/L (normal range, 15–40 U/L), a gamma glutamyl transpeptidase (GGT) level of 164 U/L (normal range, 10–60 U/L), a total bilirubin (TBil) level of 23.4 µmol/L (normal range, 1.7–13.7 µmol/L), and a direct bilirubin (DB) level of 8.6 µmol/L (normal range, ≤6.8 µmol/L). Her carcinoembryonic antigen (CEA) level was 70.78 µg/L (normal range, 0–5.0 µg/L), carbohydrate antigen 19-9 (CA19-9) level was 244.62 U/mL (normal range, 0–37.0 U/mL), with the alpha fetoprotein (AFP) was 8.4 ng/mL within normal ranges (normal range, <20.0 ng/mL). The patient had no significant past medical history, no known occupational or environmental exposures, and no history of smoking or alcohol use. Abdominal magnetic resonance imaging (MRI) revealed irregular thickening of gallbladder wall which was strengthening (34 mm × 36 mm) (Figure 1A), occupying lesion of pancreas head (23 mm × 27 mm) (Figure 1B), at the position of coronal, obviously dilatation of choledochus and hilar bile duct, asymmetrical wall thickening of gallbladder, occupying lesion of pancreas head and pancreatobiliary maljunction (PBM) in biliary system (Figure 1C), magnetic resonance cholangiopancreatography (MRCP) was suggestive of PBM is in the biliary system (Figure 1D). The obstruction of the lower end of the common bile duct leads to the dilatation of the common bile duct and the intrahepatic bile duct. Based on these findings, the patient was scheduled for surgery under the suspicion of concurrent gallbladder and pancreatic tumors. She underwent laparoscopic hepatopancreatoduodenectomy (Figure 1E). The resected specimen demonstrated tumor invasion confined to the gallbladder wall layers (Figure 1F, above) without hepatic involvement, along with a distinct tumor in the pancreatic head (Figure 1F, below).

Figure 1 Imaging findings of PBM and synchronous tumors. (A,B) MRI showed irregular thickening of the gallbladder wall with enhancement and a space-occupying lesion in the pancreatic head. (C) The coronal plane display lesions of the gallbladder and pancreas, and PBM in the biliary system. (D) MRCP shows PBM in biliary system. (E) Sectional view after laparoscopic hepatopancreatoduodenectomy. (F) The resected specimen demonstrated tumor invasion confined to the gallbladder wall layers with a distinct tumor in the pancreatic head. CHA, common hepatic artery; GBC, gallbladder cancer; IVC, inferior vena cava; LRV, left renal vein; MRCP, magnetic resonance cholangiopancreatography; MRI, magnetic resonance imaging; PBM, pancreatobiliary maljunction; PC, pancreatic cancer; PV, portal vein; SMA, superior mesenteric artery.

Postoperative pathological examination confirmed two distinct malignancies: squamous cell carcinoma of the gallbladder (hematoxylin-eosin staining revealed keratin pearls and intercellular bridges) (Figure 2A) and pancreatic adenocarcinoma (hematoxylin-eosin staining showed irregular glandular structures, desmoplastic stroma, and nuclear atypia) (Figure 2B). Immunohistochemical staining showed expression of gallbladder squamous cell carcinoma markers CK5/6 and P40 were positive, CK7 was negative (Figure 2C-2E); while the expression of pancreatic adenocarcinoma markers CK7 was positive, CK5/6 and P40 were negative (Figure 2F-2H). The patient was diagnosed with a rare case of PBM accompanied by synchronous carcinomas: gallbladder squamous cell carcinoma and pancreatic adenocarcinoma. Although gallbladder cancer and pancreatic cancer are both highly malignant tumors of the digestive tract, the luckiest thing is that she received 6 months of adjuvant chemotherapy (gemcitabine combined with capecitabine) postoperatively and has remained disease-free for 81 months without evidence of recurrence. This is the longest reported survival time of synchronous carcinomas of the biliary system so far. All procedures performed in this study were in accordance with the ethical standards of the Committee of Affiliated Hospital of North Sichuan Medical College and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patient for publication of this article and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Figure 2 Histopathological and immunohistochemical features of gallbladder squamous cell carcinoma and pancreatic adenocarcinoma. (A) Postoperative pathological shows hematoxylin-eosin staining revealed keratin pearls and intercellular bridges (GBC tissue; HE, magnification ×100). (B) HE staining showed irregular glandular structures, desmoplastic stroma, and nuclear atypia (pancreatic adenocarcinoma tissue; hematoxylin-eosin, magnification ×100). Immunohistochemical staining (×200) showed expression of gallbladder squamous cell carcinoma markers CK5/6 (C) and P40 (D) were positive, CK7 was negative (E); the expression of pancreatic adenocarcinoma markers, CK5/6 (F) and P40 (G) were negative, CK7 was positive (H). GBC, gallbladder cancer; HE, hematoxylin-eosin; PC, pancreatic cancer.

Discussion

PBM is a rare congenital malformation, Synchronous or metachronous cancers in the biliary system are often attributed to PBM (1). Synchronous gallbladder and bile duct cancer are the most common association reported in patients with PBM, synchronous gallbladder and pancreatic cancer with PBM is rarely reported (2). PBM is more common in the Asian population, especially in Japan (1,3,4). This condition includes abnormal connection of the pancreatic duct and common bile duct outside the duodenal wall, which can cause abnormal flow of the pancreatic juice and bile due to the absence of control of the sphincter of oddi, and eventually it would lead to the occurrence of tumors (5). Synchronous gallbladder and bile duct cancer are the most common association reported in patients with PBM, synchronous gallbladder and pancreatic cancer with PBM is rarely reported. There are few reports of synchronous gallbladder cancer and other biliary tract cancers (5-7). Ueda firstly reported a 74-year-old man with triple synchronous cancers occurring in the gallbladder, common bile duct, and pancreas in 1992 (5); Mori also reported a patient with synchronous gallbladder and pancreatic cancer whom finally underwent pancreatoduodenectomy managed as two separate primary tumors in 2017 (6). Sivade reported a patient with synchronous gallbladder and pancreatic cancer in 2019 (7). We reported this patient about PBM accompanying gallbladder cancer and pancreatic cancer which had not been reported before in China.

Gallbladder cancer is commonly associated with bile duct cancer in PBM patients, synchronous gallbladder and pancreatic cancer is extremely rare (4,6,7), the incidence is slightly more common in women, gallbladder cancer can metastases in liver and peritoneal cavity, the bones, the lungs and any others are less commonly involved (8). The most interesting thing is that several patients with PBM combined with gallbladder cancer and pancreatic cancer have been reported in the previous literature, which of whom pathological types are all the same, however, this patient we reported is PBM combined with gallbladder squamous cell carcinoma and pancreatic cancer, which is different from the previously reported pathology, and it has different pathological types.

PBM generally leads to atypical hyperplasia of the glandular epithelium of the pancreatic and biliary duct walls, ultimately resulting in cancer. However, PBM causes squamous cell carcinoma of the gallbladder, which is the first occurrence, and this is also a question.

We initially suspected that we had made a mistake in the pathological type of gallbladder cancer, but immunohistochemical results confirmed squamous cell carcinoma of the gallbladder—CK5/6(+) and P40(+). Although definite evidence of gallbladder squamous cell carcinoma in PBM is still lacking, the possible factor is gene mutations, which may be proved to be associate with heredity and carcinogenesis, such as in the BRCA2, KRAS and TP53 genes (9). It should be noted that germline genetic testing and next-generation sequencing of the tumors were not performed in this case, which could have provided further insight into the molecular pathogenesis of these synchronous malignancies. Coincidentally, the patient’s mother died of gallbladder cancer 33 years ago, but due to time constraints, its pathological type cannot be confirmed.

The present case offers several critical implications for the clinical management of patients with PBM and suspected synchronous tumors (3,4,7): In any patient with a confirmed diagnosis of PBM, clinicians must maintain a high index of suspicion for synchronous or metachronous cancers, not only within the biliary tree (gallbladder and bile ducts) but also in the pancreas. The entire pancreatobiliary system is at risk due to the shared pathophysiology of reflux and epithelial injury. Preoperative imaging, particularly high-resolution MRI/MRCP, should be meticulously scrutinized for abnormalities in all these organs. When synchronous cancers are suspected, an aggressive but curative-intent surgical approach should be considered. In our case, laparoscopic hepatopancreatoduodenectomy, though highly complex, achieved R0 resection for both tumors and was likely instrumental in the patient’s long-term survival. The surgical plan must be tailored to the extent of disease, aiming to resect all malignant foci in a single procedure whenever feasible. The possibility of differing histopathological types, as seen in our case of gallbladder squamous cell carcinoma and pancreatic adenocarcinoma, underscores the necessity for a thorough postoperative pathological examination of all resected specimens. Immunohistochemistry is crucial for accurate classification, which can have significant implications for adjuvant therapy selection and prognostic stratification. Given the lifelong cancer risk in PBM, even after successful resection of one malignancy, continuous and rigorous surveillance is mandatory. This should include periodic serum tumor markers (CEA, CA19-9) and cross-sectional imaging [e.g., annual computed tomography (CT) or MRI] of the abdomen. This strategy is essential for the early detection of metachronous tumors or recurrence. We recommend that patients with PBM and a personal or strong family history of biliary/pancreatic cancers be referred for genetic counseling. Germline testing for genes associated with inherited cancer syndromes (e.g., BRCA2, TP53) and next-generation sequencing (NGS) of tumor tissue, if resources permit, could provide invaluable insights for personalized risk assessment, family screening, and potentially targeted therapies in the future.

Conclusions

In summary, patients with an abnormal pancreaticobiliary junction should undergo regular monitoring of the hepatobiliary and pancreatic systems. This includes periodic evaluations via ultrasound, CT, MRCP, or endoscopic retrograde cholangiopancreatography (ERCP) to assess the liver, gallbladder, and pancreas. Any detected abnormalities should be managed promptly. Additionally, a thorough family medical history should be obtained to evaluate potential hereditary risk factors.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was a standard submission to the journal. The article has undergone external peer review.

Peer Review File: Available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-2025-707/prf

Funding: This work was supported by Sichuan Natural Science Foundation (2024NSFSC1933, 2024NSFSC1896 to J.X.), Bureau of Science and Technology Nanchong City (23JCYJPT0065, 23JCYJPT0069, 23JCYJPT0071, 23JCYJPT0031 to J.X.), Research Project of Sichuan Medical Association (S23033 to J.X.), Outstanding Youth Fund Project of North Sichuan Medical College (CBY23-JQ02 to J.X.), and Central-guided Local Science and Technology Project (2025ZYD0168).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-2025-707/coif). J.X. reports grants from Sichuan Natural Science Foundation (2024NSFSC1933, 2024NSFSC1896), Bureau of Science and Technology Nanchong City (23JCYJPT0065, 23JCYJPT0069, 23JCYJPT0071, 23JCYJPT0031), Research Project of Sichuan Medical Association (S23033), and Outstanding Youth Fund Project of North Sichuan Medical College (CBY23-JQ02). The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the Committee of Affiliated Hospital of North Sichuan Medical College and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patient for publication of this article and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Minami Y, Hasuike Y, Takeda Y, et al. Metachronous double cancer of the gallbladder and pancreas associated with pancreaticobiliary maljunction. J Hepatobiliary Pancreat Surg 2008;15:330-3. [Crossref] [PubMed]
2. Sato K, Maekawa T, Yabuki K, et al. A case of triple synchronous cancers occurring in the gallbladder, common bile duct, and pancreas. J Gastroenterol 2003;38:97-100. [Crossref] [PubMed]
3. Resende V, Roda R, Pedrosa MS. Gallbladder Papillary Neoplasia Associated With Intrahepatic Carcinoma and Pancreaticobiliary Malformation. Gastroenterology Res 2012;5:245-8. [Crossref] [PubMed]
4. Kamisawa T, Ando H, Suyama M, et al. Japanese clinical practice guidelines for pancreaticobiliary maljunction. J Gastroenterol 2012;47:731-59. [Crossref] [PubMed]
5. Ueda N, Nagakawa T, Ohta T, et al. Synchronous cancer of the biliary tract and pancreas associated with anomalous arrangement of the pancreaticobiliary ductal system. J Clin Gastroenterol 1992;15:136-41. [Crossref] [PubMed]
6. Mori H, Iida H, Maehira H, et al. Synchronous primary gallbladder and pancreatic cancer associated with congenital biliary dilatation and pancreaticobiliary maljunction. Surg Case Rep 2017;3:113. [Crossref] [PubMed]
7. Sivade A, Sempoux C, Voutsadakis I, et al. Synchronous tumors of the pancreas and the gallbladder: a case report with targeted NGS evaluation. Ann Transl Med 2019;7:696. [Crossref] [PubMed]
8. Sato K, Maekawa T, Yabuki K, et al. A case of triple synchronous cancers occurring in the gallbladder, common bile duct, and pancreas. J Gastroenterol 2003;38:97-100. [Crossref] [PubMed]
9. Agarwal N, Kumar S, Sharma S. Synchronous adenocarcinoma of the gall bladder and pancreas in a young woman. Trop Gastroenterol 2013;34:50-2. [Crossref] [PubMed]