Surgical Case of Metachronous Occurrence of Intracholecystic Papillary Neoplasm in the Remnant Cystic Duct 19 Years after Cholecystectomy

Abstract

INTRODUCTION: Intracholecystic papillary neoplasm (ICPN) is a recently identified disease characterized by papillary pre-invasive neoplasm of the gallbladder. Despite its characterization, the natural history of ICPN remains elusive. Furthermore, a few cases of metachronous ICPN in the remnant biliary system have been documented. Here, we report a surgical case involving metachronous ICPN in the remnant cystic duct 19 years post-cholecystectomy for primary ICPN.

CASE PRESENTATION: A 77-year-old man presented to our hospital with general fatigue and jaundice. He had previously undergone an open cholecystectomy and lithotomy for gallbladder cancer and common bile duct stones 19 years earlier. Blood tests revealed elevated levels of hepatobiliary enzymes and tumor markers. Both computed tomography and magnetic resonance imaging indicated dilatation of the intrahepatic and common bile ducts, and an enhanced nodule was observed in the common hepatic duct. Intraductal ultrasonography identified a papillary tumor infiltrating the distal bile duct from the common hepatic duct. Brush cytology subsequently helped confirm adenocarcinoma. Consequently, the patient was diagnosed with Bismuth type 1 perihilar cholangiocarcinoma and underwent subtotal stomach-preserving pancreaticoduodenectomy. Histological examination revealed the tumor as pancreatobiliary-type ICPN associated with invasive carcinoma, which had originated in the remnant cystic duct and invaded the common hepatic duct. A retrospective review of the resected gallbladder specimens from 19 years earlier confirmed ICPN according to the current classification, establishing this as a metachronous occurrence of ICPN.

CONCLUSIONS: These findings suggest that ICPN can recur as metachronous lesions in the remnant biliary system after resection of primary lesion, highlighting the necessity of sustained, long-term biliary surveillance following primary lesion resection.

Abbreviations

CBD

common bile duct

CHD

common hepatic duct

ICPN

intracholecystic papillary neoplasm

IPMN

intrapapillary mucinous neoplasm

IPNB

intraductal papillary neoplasm of the bile duct

INTRODUCTION

ICPNs were first recognized in the World Health Organization classification of bile duct tumors in 2010.¹⁾ They share clinicopathological similarities with pancreatic IPMN and IPNB, including intraluminal papillary growth patterns, variable dysplastic grades, and various phenotypes. Therefore, ICPN is considered a counterpart of IPMN and IPNB.²⁾ Given the recent identification and rarity of ICPN, the natural history of ICPN remains largely unknown. Although several metachronous occurrences of IPMN and IPNB following primary lesion resection have been documented,^3–6) a few reports have documented such occurrences in the biliary tract post-cholecystectomy for primary ICPN. In this report, we present a surgical case of metachronous ICPN in the remnant cystic duct 19 years following cholecystectomy for primary ICPN.

CASE PRESENTATION

A 77-year-old man presented to our hospital with general fatigue and jaundice. He had a history of hyperlipidemia and was taking oral medication. Nineteen years ago, he had undergone open cholecystectomy with cystic duct lymph node dissection and lithotomy for gallbladder cancer and CBD stones. The tumor was located in the neck of the gallbladder on the hepatic side and was diagnosed as gallbladder cancer, 21 × 19 mm, G1, papillary carcinoma, non-invasive, pTis pN0 M0, pStage 0. Blood tests indicated elevated levels of hepatobiliary enzymes and tumor markers as follows: aspartate aminotransferase 231 U/L (normal reference range at our institution, 13–30 U/L), alanine aminotransferase 261 U/L (normal range, 10–42 U/L), alkaline phosphatase 1653 U/L (normal range, 38–113 U/L), gamma-glutamyltransferase 1645 U/L (normal range, 13–64 U/L), total bilirubin 4.53 mg/dL (normal range, 0.4–1.5 mg/dL), and carbohydrate antigen 19-9 at 114.0 U/mL (normal range, 0–37 U/mL). Computed tomography and magnetic resonance cholangiopancreatography revealed dilatation of the intrahepatic bile duct and CHD, with a 22-mm gradually enhancing nodule on the CHD (Fig. 1A, 1B). Neither lymph node nor distant metastasis was detected.

Fig. 1 Computed tomography and magnetic resonance cholangiopancreatography findings. Computed tomography image displaying dilatation of the intrahepatic bile and common hepatic ducts. An enhanced nodule, 22 mm in diameter, is found in the confluence of the cystic duct (arrow) (A). Magnetic resonance cholangiopancreatography showing the defect in the common hepatic duct. Yellow arrowhead indicates the remnant cystic duct (B).

Endoscopic retrograde cholangiography and subsequent intraductal ultrasonography showed that the tumor was located between the CHD and distal bile duct and extended into the intrapancreatic duct (Fig. 2). Subsequently, a drainage tube was inserted into the CBD to improve jaundice. After brush cytology of the CBD revealed strong cellular atypia and suspected malignancy, the patient was diagnosed with Bismuth type 1 perihilar cholangiocarcinoma. Therefore, subtotal stomach-preserving pancreaticoduodenectomy was performed. During the laparotomy, no liver metastasis or peritoneal dissemination was observed. The hepatoduodenal ligament exhibited severe adhesions around the duodenum from the initial surgery. A frozen section of the cut edge of the CHD showed negative finding for malignancy; therefore, we performed a subtotal stomach-preserving pancreaticoduodenectomy with modified Child’s reconstruction and regional lymphadenectomy. The operative time was 376 minutes, and estimated blood loss was 283 mL. Macroscopic examination of the surgical specimen revealed a 5-mm papillary nodule in the cystic duct (Fig. 3). Microscopic examination indicated that high columnar epithelium with papillary growth proliferated and infiltrated into the stroma and submucosa of the CBD (Fig. 4A, 4B). High-grade dysplasia was observed in the CBD (Fig. 3B, 3C).

Fig. 2 Endoscopic and ultrasonographic tumor assessments. Endoscopic retrograde cholangiopancreatography and intraductal ultrasonography displaying infiltration of the tumor from the common hepatic duct into the distal bile duct. Focal wall thickness is observed in the common hepatic duct (arrowheads), and the distal bile duct is obstructed by the tumor (arrow).

Fig. 3 Macroscopic view of the papillary nodule. Macroscopic findings of surgical specimen (A). A 5-mm papillary nodule in the cystic duct is observed (arrow). Red and green dotted lines represent the areas of invasive cancer and high-grade dysplasia, respectively (B–C).

Fig. 4 Microscopic analysis and MUC staining. Microscopically, the high columnar epithelium with papillary growth infiltrates into the stroma and submucosa of the common bile duct (A, B). MUC staining of the resected specimen showing positive expression for MUC 1, negative for MUC2, and positive for MUC5AC and MUC6 on the surface of the tumor (C–F).

MUC, Mucin

Immunohistochemical analysis confirmed that the tumor cells were positive for MUC1, positive for MUC5AC and MUC6 on the surface, and negative for MUC2 (Fig. 4C–4F). Thus, the patient was diagnosed with pancreatobiliary-type ICPN associated with invasive carcinoma, 30 × 25 mm, G2-3, papillary carcinoma, invasive, pT3 pN1 M0, pStage IIIB. The cut edge of the bile duct showed negative finding for neoplastic cells. A retrospective review of the gallbladder specimen resected 19 years ago helped identify a papillary tumor with carcinoma in situ and low-grade dysplasia. MUC staining profiles showed focally positive findings for MUC1, negative findings for MUC2 and MUC6, and positive findings for MUC5AC (Fig. 5A–5G). The resection margin was located at the edge of cystic duct of gallbladder side, and the cut edge showed neither malignancy nor dysplasia. The distance from the tumor to the cystic duct stump was 6 mm. Although the concept of ICPN was not established 19 years ago, the tumor was diagnosed as ICPN under current classifications. Given the similarity in both the pathological morphology and MUC staining between the gallbladder lesion from 19 years ago and the current cystic duct lesion, the patient was diagnosed with metachronous occurrence of ICPN.

Fig. 5 Histological analysis and MUC staining of the previously resected gallbladder tumor. Specimen of the gallbladder resected 19 years earlier showing a papillary tumor without invasion (A–C). Green dotted line and yellow line represent the areas of carcinoma in situ and low-grade dysplasia, respectively (B). MUC staining demonstrating focally positive finding for MUC1, negative finding for MUC2 and MUC6, and positive finding for MUC5AC (D–G).

MUC, Mucin

Although the patient developed a pancreatic fistula (International Study Group of Pancreatic Fistula grade B), we removed the drainage tube on postoperative day 24. He was discharged on postoperative day 26. At the time of this report, the patient has remained well and showed no signs of recurrence 6 months postoperatively.

DISCUSSION

In 2012, Adsay et al. defined ICPN as gallbladder papillary neoplasms characterized by being intramucosal, pre-invasive, mass-forming, exophytic (either papillary or polypoid), at least 1.0 cm in size, compact, and distinct from the neighboring mucosa.²⁾ The 2019 World Health Organization classification of digestive system tumors recognizes ICPN as a unique pre-invasive neoplasm of the gallbladder, with lesions containing invasive carcinoma components classified under ICPN with associated carcinoma.⁷⁾ ICPN shares clinicopathological features with IPMN and IPNB and is therefore acknowledged as a counterpart to these conditions. While metachronous occurrences in the remnant pancreatobiliary tract have been documented for IPMN and IPNB,^3,4,8–10) such reports are rare in ICPN. Although several cases of metachronous biliary tract papillary carcinoma following resection of primary gallbladder lesions have been reported,^11–15) these cases are located in the common bile duct. Therefore, to the best of our knowledge, we present the first surgical report of metachronous ICPN in a remnant cystic duct.

Both IPMN and IPNB can develop multiple synchronous or metachronous lesions, with the following three possible mechanisms for the postoperative development of secondary lesions: metastatic or local recurrence of the primary lesion, metachronous secondary occurrence of new lesions, and progression of untreated lesions.^5,6,8–10) In our patient, the resected margin of the cystic duct during the initial surgery was malignancy- and dysplasia-free; however, secondary lesions developed 19 years post-cholecystectomy. Although determining the precise origin of the secondary tumor is challenging, these findings suggest a metachronous secondary occurrence of ICPN.

The prognosis for ICPN after resection is reportedly more favorable than that of conventional gallbladder carcinoma, with a 5-year overall survival of 78% for non-invasive ICPN, 60% for ICPN associated with carcinoma, and 18%–30% for conventional gallbladder carcinoma.²⁾ Although the treatment strategy for recurrent ICPN in the biliary tract remains unclear, complete surgical resection is believed to yield favorable outcomes, as similarly reported for recurrent IPMN¹⁶⁾ and IPNB.¹⁷⁾ Given the negative margins at the initial surgery, we believe further resection was unnecessary at that time. However, complete resection of the biliary tree during the initial surgery might have prevented the metachronous occurrence of ICPN.

The natural history of ICPN remains to be fully elucidated. Although some studies report that ICPN progression could span several years,^18,19) others have observed progression or recurrence within months.^20,21) In our case, the development of a secondary lesion occurred over 19 years, supporting the “field defect” theory advocated in IPMN, which suggests that all pancreatic ductal epithelial cells harbor the risk of dysplasia, and therefore, the remnant pancreas after partial pancreatectomy remains susceptible to developing significant lesions.²²⁾

European guidelines and revised international guidelines for managing IPMN recommend lifetime surveillance for patients with IPMN post-pancreatectomy, provided the patients are fit for surgery.^23,24) As ICPN is considered the counterpart of IPMN, follow-up of the remnant biliary system is recommended, even after surgery for the primary lesion, through lifelong surveillance every 6 months during the early postoperative period and at least once a year in the late postoperative period.²⁵⁾

CONCLUSIONS

Our case involving a patient who had a secondary ICPN lesion 19 years post-initial surgery highlights the imperative for persistent surveillance. Given the incompletely understood natural history of ICPN, thorough long-term monitoring is crucial to effectively detect and manage potential recurrences.

ACKNOWLEDGMENTS

We would like to thank Editage (www.editage.com) for the English language editing.

DECLARATIONS

Funding

The authors declare that this work was not supported by any grants or funding.

Authors’ contributions

All authors have read and approved the manuscript.

H.K. drafted the manuscript. K.D. and M.T. supervised this study.

Y.K., T.A., S.Y., E.I., K.Shig., K.Shim., T.T., R.I., H.N., K.K., G.H., and Y.S. performed perioperative patient management.

Availability of data and materials

Not applicable.

Ethics approval and consent to participate

Ethical approval was obtained from the Ethics Committee of St. Mary’s Hospital (Approval No.: 24-1103).

Consent for publication

Written informed consent was obtained from the patient for the publication of this report and its accompanying images.

Competing interests

The authors declare that they have no competing interests.

REFERENCES

• 1)  Bosman FT, Carneiro F, Hruban RH, et al. WHO classification of tumors of the digestive system. WHO Classification of Tumours, 4th ed. Geneva: World Health Organization; 2010.
• 2)  Adsay V, Jang KT, Roa JC, et al. Intracholecystic papillary-tubular neoplasms (ICPN) of the gallbladder (neoplastic polyps, adenomas, and papillary neoplasms that are ≥1.0 cm): clinicopathologic and immunohistochemical analysis of 123 cases. Am J Surg Pathol 2012; 36: 1279–301.
• 3)  Matthaei H, Norris AL, Tsiatis AC, et al. Clinicopathological characteristics and molecular analyses of multifocal intraductal papillary mucinous neoplasms of the pancreas. Ann Surg 2012; 255: 326–33.
• 4)  Ohtsuka T, Kono H, Tanabe R, et al. Follow-up study after resection of intraductal papillary mucinous neoplasm of the pancreas; special references to the multifocal lesions and development of ductal carcinoma in the remnant pancreas. Am J Surg 2012; 204: 44–8.
• 5)  Kageyama Y, Yamaguchi R, Watanabe S, et al. Intraductal papillary neoplasm of the bile duct with rapidly progressive multicentric recurrence: a case report. Int J Surg Case Rep 2018; 51: 102–6.
• 6)  Narita M, Endo B, Mizumoto Y, et al. Multicentric recurrence of intraductal papillary neoplasms of bile duct in the remnant intrahepatic bile duct after curative resection. Int J Surg Case Rep 2015; 12: 123–7.
• 7)  Basturk O, Aishima S, Esposito I. Intracholecystic papillary neoplasm. In: WHO Classification of Tumours Editorial Board. Digestive System Tumours : WHO Classification of Tumours, 5th ed. Lyon: International Agency for Research on Cancer; 2019. p. 276–8.
• 8)  Hayashi M, Date K, Kodama T, et al. Recurrent intraductal papillary mucinous neoplasms of the pancreas mimicking ampullary cancer. Ann Gastroenterol 2020; 33: 536–9.
• 9)  Nakayama Y, Tomino T, Ninomiya M, et al. Recurrent intraductal papillary neoplasm of the bile duct due to intraductal dissemination: a case report and literature review. Surg Case Rep 2021; 7: 238.
• 10)  Date K, Ohtsuka T, Fujimoto T, et al. Molecular evidence for monoclonal skip progression in main duct intraductal papillary mucinous neoplasms of the pancreas. Ann Surg 2017; 265: 969–77.
• 11)  Fujii T, Kaneko T, Sugimoto H, et al. Metachronous double cancer of the gallbladder and common bile duct. J Hepatobiliary Pancreat Surg 2004; 11: 280–5.
• 12)  Sato H, Sato Y, Harada K, et al. Metachronous intracystic and intraductal papillary neoplasms of the biliary tree. World J Gastroenterol 2013; 19: 6125–6.
• 13)  Joo HJ, Kim GH, Jeon WJ, et al. Metachronous bile duct cancer nine years after resection of gallbladder cancer. World J Gastroenterol 2009; 15: 3440–4.
• 14)  Yuzawa H, Ikematsu Y, Ito Y, et al. Successful surgical treatment for metachronous advanced cancers of the gallbladder and the common bile duct--case report. Hepatogastroenterology 2004; 51: 664–7.
• 15)  Takai S, Shiratori Y, Kanematsu M, et al. Usefulness of MR imaging in the postsurgical monitoring of gallbladder cancer in a patient with bile duct cancer that developed 7 years after resection of mucinous adenocarcinoma of the gallbladder. J Gastroenterol 2001; 36: 787–9.
• 16)  Tamura K, Ohtsuka T, Ideno N, et al. Treatment strategy for main duct intraductal papillary mucinous neoplasms of the pancreas based on the assessment of recurrence in the remnant pancreas after resection: a retrospective review. Ann Surg 2014; 259: 360–8.
• 17)  Arai S, Sakai H, Akashi M, et al. Clinicopathological study of resected and recurrent cases of intrahepatic intraductal papillary neoplasm of the bile duct. Anticancer Res 2024; 44: 3623–8.
• 18)  Koike D, Kato H, Asano Y, et al. Natural history of intracholecystic papillary neoplasm (ICPN): a rare case of ICPN whose natural history was closely followed by ultrasound. BMC Gastroenterol 2022; 22: 377.
• 19)  Oh CH, Dong SH. Progression to invasive cancer after snare polypectomy of intracholecystic papillary neoplasms during gallbladder stone removal by percutaneous transhepatic choledochoscopy: a case report. BMC Gastroenterol 2020; 20: 404.
• 20)  Watanabe Y, Mochidome N, Nakayama H, et al. Intracholecystic papillary neoplasm associated with invasive carcinoma of the remnant gallbladder after subtotal cholecystectomy: a case report. Surg Case Rep 2022; 8: 31.
• 21)  Hashimoto S, Horaguchi J, Fujita N, et al. Intracholecystic papillary-tubular neoplasm of the gallbladder presenting with jaundice. Intern Med 2014; 53: 2313–7.
• 22)  Izawa T, Obara T, Tanno S, et al. Clonality and field cancerization in intraductal papillary-mucinous tumors of the pancreas. Cancer 2001; 92: 1807–17.
• 23)  European Study Group on Cystic Tumours of the Pancreas. European evidence-based guidelines on pancreatic cystic neoplasms. Gut 2018; 67: 789–804.
• 24)  Ohtsuka T, Fernandez-del Castillo C, Furukawa T, et al. International evidence-based Kyoto guidelines for the management of intraductal papillary mucinous neoplasm of the pancreas. Pancreatology 2024; 24: 255–70.
• 25)  Kang JS, Lee KB, Choi YJ, et al. A comparison of outcomes in patients with intracholecystic papillary neoplasms or conventional adenocarcinomas of the gallbladder. HPB (Oxford) 2021; 23: 746–52.