Synchronous intracholecystic papillary-tubular neoplasm and pancreatic intraductal tubulopapillary neoplasm: A case report

Abstract

BACKGROUND

Intracholecystic papillary-tubular neoplasm (ICPN) and intraductal tubulopapillary neoplasm (ITPN) are grossly and radiologically visible intraductal neoplasms of the pancreatobiliary tract. Although these entities share several clinicopathological features, synchronous gallbladder ICPN and pancreatic ITPN have rarely been described and may provide insight into multifocal pancreatobiliary tumorigenesis.

CASE SUMMARY

A 30-year-old woman presented with a one-month history of intermittent right upper abdominal pain, particularly after fatty meals. Contrast-enhanced computed tomography and magnetic resonance imaging revealed a giant gallbladder with multiple intraluminal protrusions and multiple cystic-solid pancreatic lesions extending from the pancreatic head to the tail, with the largest measuring approximately 3.0 cm. Positron emission tomography/computed tomography showed increased fluorodeoxyglucose uptake in both the gallbladder and pancreatic lesions. Endoscopic ultrasound-guided fine-needle aspiration yielded only scant atypically proliferating glandular epithelial cells. Given the patient’s young age, multifocal pancreatobiliary involvement, and high radiologic suspicion for malignancy, total pancreatectomy with extended cholecystectomy and lymph node dissection was performed. Histopathological examination confirmed gallbladder ICPN with high-grade dysplasia and pancreatic ITPN with multifocal invasive carcinoma confined within the pancreas. Germline whole-exome sequencing did not identify a pathogenic variant. Postoperatively, the patient received endocrine follow-up and long-term oncologic surveillance.

CONCLUSION

This case expands the clinicopathological spectrum of pancreatobiliary intraductal neoplasia. Together with the literature review, it raises the possibility of a field effect or shared epithelial susceptibility when multifocal intraductal lesions arise across the gallbladder and pancreas. The case also highlights the need for long-term surveillance of the residual pancreatobiliary tract after surgical treatment.

Key Words: Intracholecystic papillary-tubular neoplasm; Intraductal tubulopapillary neoplasm; Pancreatobiliary tract; Field effect; Case report

Core Tip: Intracholecystic papillary-tubular neoplasm and pancreatic intraductal tubulopapillary neoplasm are usually discussed as related but separate intraductal neoplasms. We report a 30-year-old woman with synchronous multifocal cystic-solid lesions involving the gallbladder and the pancreas. Surgical pathology showed gallbladder intracholecystic papillary-tubular neoplasm with high-grade dysplasia and pancreatic intraductal tubulopapillary neoplasm with multifocal invasive carcinoma. Unlike most reported pancreatic-gallbladder double tumors, this case showed no evident pancreaticobiliary maljunction and involved two intraductal neoplasms. These findings suggest a possible field effect or shared epithelial susceptibility rather than simple reflux-related carcinogenesis, although this hypothesis remains unproven without somatic sequencing or clonality studies.

INTRODUCTION

Pancreatobiliary intraductal malignancies, including pancreatic, biliary tract, and gallbladder cancers, often have poor outcomes because they are frequently diagnosed at an advanced stage[1]. Recognition of mass-forming, radiologically visible precursor lesions in the pancreatobiliary tract is therefore clinically important, particularly when these lesions can be detected and resected before widely invasive carcinoma develops.

Gallbladder intracholecystic papillary-tubular neoplasm (ICPN) and pancreatic intraductal tubulopapillary neoplasm (ITPN) are both intraductal precursor neoplasms within the pancreatobiliary system. They share several features, including a localized growth pattern, malignant potential, and a lack of specific symptoms at an early stage[2]. However, they differ substantially in histologic architecture, mucin phenotype, immunophenotype, and molecular alterations. The coexistence of visible intraductal neoplasms in separate pancreatobiliary organs is rare and raises the question of a field effect (or field defect), in which a broader epithelial region is predisposed to synchronous or metachronous neoplasia[3].

Here, we report a young woman with synchronous gallbladder ICPN with high-grade dysplasia and pancreatic ITPN with multifocal invasive carcinoma confined within the pancreas. We also reviewed published pancreatic-gallbladder double tumors to clarify how the present case differs from previously reported cases.

CASE PRESENTATION

Chief complaints

A one-month history of right upper abdominal pain.

History of present illness

A 30-year-old woman was admitted with a one-month history of right upper abdominal pain, particularly after consumption of fatty food intake. She denied fever, nausea, vomiting, jaundice, or hematochezia.

History of past illness

The patient had been previously healthy and had no relevant medical history.

Personal and family history

She had no notable personal habits or family history.

Physical examination

Physical examination revealed a firm, mobile palpable mass in the right upper abdomen, measuring approximately 15 cm in maximal diameter. There was no abdominal tenderness, hepatomegaly, or positive Murphy’s sign.

Laboratory examinations

Complete blood cell count, liver function tests, pancreatic enzymes, and serum immunoglobulin G4 were within normal ranges. Tumor markers were within reference ranges except for a mild elevation of carbohydrate antigen 125 U/mL to 68.7 U/mL (reference range, ≤ 35.0 U/mL). Given its limited specificity, particularly in women of reproductive age, this finding was not considered diagnostic.

Imaging examinations

Contrast-enhanced abdominal computed tomography demonstrated multiple cystic-solid space-occupying lesions distributed from the pancreatic head to the tail, multiple soft-tissue lesions along the gallbladder wall, and a giant gallbladder with heterogeneous enhancement (Figure 1). Hepatobiliary magnetic resonance imaging revealed multiple irregular papillary intraluminal protrusions in the gallbladder, with the largest lesion measuring approximately 18.8 cm × 5.4 cm, and multiple quasi-circular cystic-solid pancreatic lesions, with the largest pancreatic lesion measuring approximately 3.0 cm. Positron emission tomography/computed tomography showed a cystic-solid mass in the gallbladder fossa measuring 7.9 cm × 7.0 cm × 15.1 cm with a maximum standardized uptake value of 11.1, and multiple cystic-solid pancreatic masses with indistinct boundaries and heterogeneous uptake (maximum standardized uptake value: 7.9) (Figure 2). No pancreaticobiliary maljunction (PBM) or distant metastasis was evident on imaging. All imaging results did not show any ovarian mass or pelvic lesion suggestive of ovarian malignancy.

Figure 1 Contrast-enhanced computed tomography findings. A: The gallbladder shows multiple soft-tissue lesions along the gallbladder wall and heterogeneous enhancement of a giant gallbladder; B: The pancreas shows multiple cystic-solid lesions distributed from the pancreatic head to the tail.

Figure 2 Positron emission tomography/computed tomography findings. A: A cystic-solid mass in the gallbladder fossa shows a maximum standardized uptake value of 11.1; B: Multiple cystic-solid pancreatic masses show indistinct boundaries and heterogeneous uptake, with a maximum standardized uptake value of 7.9.

FINAL DIAGNOSIS

The patient was diagnosed with synchronous cystic-solid masses in both the pancreas and gallbladder.

TREATMENT

The coexistence of cystic-solid masses in both the pancreas and gallbladder in this young woman raised a strong suspicion of malignancy. To obtain a tissue diagnosis, endoscopic ultrasonography-guided fine-needle aspiration was performed. Endoscopic ultrasonography showed multiple cystic and solid lesions extending from the pancreatic head to the tail; however, cytopathological analysis of the aspirate demonstrated only scant atypically proliferating glandular epithelial cells.

Given the patient’s young age, multifocal pancreatobiliary lesions, and radiologic suspicion for malignancy, she subsequently underwent total pancreatectomy combined with extended cholecystectomy and lymph node dissection under general anesthesia. Histopathological assessment of the resected specimens confirmed the diagnosis of two distinct intraductal neoplastic processes: Gallbladder ICPN with high-grade dysplasia, and pancreatic ITPN with multifocal invasive carcinoma confined within the pancreas (Figure 3). Immunohistochemical analysis of the pancreatic lesion showed mucin 1 (MUC1) positivity, focal MUC6 positivity, and negativity for MUC2 and MUC5AC, supporting the diagnosis of pancreatic ITPN. Because of the unusually young age at onset, germline whole-exome sequencing was performed, but no pathogenic variant was identified. Somatic sequencing of the resected gallbladder and pancreatic tumors was not performed.

Figure 3 Histopathological features of gallbladder intracholecystic papillary-tubular neoplasm and pancreatic intraductal tubulopapillary neoplasm. A: The gallbladder lesion shows an intraluminal papillary-tubular neoplastic proliferation with high-grade dysplasia; B: The pancreatic lesion shows predominantly intraductal epithelial neoplasm composed of tightly packed tubular and tubulopapillary structures with multifocal invasive carcinoma infiltrating the pancreatic parenchyma. Hematoxylin and eosin staining.

OUTCOME AND FOLLOW-UP

At the three-month follow-up, the patient had recovered satisfactorily after surgery and was receiving pancreatic enzyme supplementation. After total pancreatectomy, insulin therapy was initiated for post-pancreatectomy diabetes and maintained stable blood glucose levels. She was subsequently referred to an endocrinologist for long-term glycemic management. At an updated telephone follow-up approximately 12 months after surgery, the patient reported a stable general condition without new symptoms. Continued long-term oncologic and metabolic surveillance was recommended. Supplementary Table 1 shows the clinical timeline of the present case.

DISCUSSION

ICPN and ITPN are mass-forming radiologically visible intraductal neoplasms with malignant potential. When completely resected, they usually have more favorable outcomes than conventional pancreatobiliary carcinomas, even when an associated invasive component is present[1,4]. Awareness of their characteristic histologic, radiologic, immunophenotypic, and molecular features is therefore important for early recognition and appropriate management. ICPN and ITPN share related ductal epithelial phenotypes but retain distinct histological and molecular features[1,5]. ICPN usually arises in older women, commonly grows as an intraluminal papillary, tubular, or tubulopapillary mass, and may show gastric, biliary, intestinal, or oncocytic differentiation[4,6,7]. In contrast, ITPN tends to arise in older men and is classically a pancreatic ductal tumor composed predominantly of back-to-back tubules with high-grade cytology, and minimal or absent mucin[8,9]. Table 1 summarizes the major differences and clinically relevant overlaps between ICPN and ITPN[4,6-12].

Table 1 Clinicopathological comparison between intracholecystic papillary-tubular neoplasm and intraductal tubulopapillary neoplasm[4,6-12].

Feature	ICPN	ITPN
Age/sex tendency	Usually older adults; female predominance	Usually older adults; slight male predominance
Gross/imaging pattern	Polypoid or mass-forming intraluminal gallbladder lesion; may coexist with gallbladder wall thickening or suspected gallbladder cancer	Solid or mixed solid-cystic intraductal pancreatic mass; ductal dilatation may be present, and the lesions may mimic other pancreatic cystic neoplasms
Histological architecture	Papillary, tubular, or tubulopapillary architecture; heterogeneous epithelial lineages may include biliary, gastric, intestinal, and oncocytic phenotypes	Back-to-back tubules, cribriform or abortive papillary structures, high-grade cytology, and minimal or absent mucin
Dysplasia/invasion	Low- or high-grade dysplasia; invasive carcinoma may be present, but resected ICPN often has more a favorable prognosis than conventional gallbladder cancer	High-grade dysplasia is characteristic; invasive carcinoma is common in resected series, but prognosis after resection is generally better than that of conventional pancreatic ductal adenocarcinoma
Immunophenotype	Variable according to lineage; biliary-type lesions often express CK7 and MUC1, gastric-type lesions may express MUC5AC/MUC6, and intestinal-type lesions may express CDX2/CK20	Typically MUC1 and MUC6 positive, MUC2 negative, and MUC5AC absent or limited
Molecular features	Heterogeneous; reported alterations include KRAS, STK11, CTNNB1, APC, TP53, and lineage-associated changes	KRAS/GNAS alterations are uncommon, whereas PI3K pathway alterations, chromatin-remodeling alterations, FGFR2 fusions, and rare ALK fusions have been reported
Clinical implication	Surgical resection is recommended when feasible; if invasive carcinoma is present, management should follow gallbladder cancer principles and pathologic stage	Surgical resection is recommended when feasible; the invasive component, margin status, nodal status, and recurrence risk should guide surveillance

ICPN: Intracholecystic papillary-tubular neoplasm; ITPN: Intraductal tubulopapillary neoplasm; CK7: Cytokeratin 7; CK20: Cytokeratin 20; MUC1: Mucin 1; MUC5AC: Mucin 5AC; CDX2: Caudal type homeobox 2; PI3K: Phosphatidylinositol 3-kinase; FGFR2: Fibroblast growth factor receptor 2; ALK: Anaplastic lymphoma kinase.

Although ICPN and ITPN are classified as distinct premalignant lesions, their coexistence may raise the possibility of a field effect in the pancreatobiliary tract. A field effect refers to a situation in which a background epithelial region is at increased risk of developing independent synchronous or metachronous neoplasms[3]. The field-effect phenomenon in the pancreatobiliary tract has been discussed mainly in the context of IPMN[13]. In one prospective study, 60 patients with branch-duct IPMN of < 10 mm who were followed for a mean of 87 months, and pancreatic ductal carcinoma distinct from IPMN developed in 5 patients (8%)[13]. In addition, ICPN accompanied by intraductal papillary neoplasm of the bile duct and intra-ampullary papillary-tubular neoplasm has been reported[1]. By analogy, multifocal visible intraductal lesions across the gallbladder and pancreas may indicate shared epithelial susceptibility, a common environmental or reflux-related injury, or, less likely, a clonal process. However, in the absence of paired somatic sequencing, clonality analysis, or shared molecular alterations, a field effect in this case should be regarded as a biological hypothesis rather than a proven mechanism.

To better characterize the rarity and context of this presentation, we reviewed previously reported pancreatic-gallbladder double tumors after excluding metastatic lesions, intraductal dissemination, and neuroendocrine tumors (Supplementary Table 2). Thirteen eligible cases were retrieved from the literature and are summarized together with the present case in Table 2[14-26]. Several features are informative. First, the previously reported patients were generally older than the present patient, whereas our patient developed synchronous disease at only 30 years of age. Second, most reported tumors were conventional adenocarcinomas rather than intraductal precursor-type neoplasms. Third, PBM, congenital biliary dilatation, or reflux-related injury was repeatedly implicated as a possible carcinogenic background in the literature. In contrast, no PBM was evident in the present case on available imaging, making the common reflux-injury explanation less convincing. Finally, only 3 out of 13 cases involved pancreatic intraductal neoplasms such as IPMN or ITPN, and none of the cases documented synchronous gallbladder ICPN and pancreatic ITPN. The present case therefore differs from previous reports in three clinically important ways: It occurred in a young woman, involved two visible intraductal neoplasms rather than two conventional invasive carcinomas, and lacked radiologic evidence of PBM. Moreover, the negative germline whole-exome sequencing result reduces the likelihood of a known hereditary cancer syndrome but does not exclude somatic mutations driving independent neoplasms. These features may shift the emphasis away from a simple PBM-driven reflux-mediated mechanism toward a broader concept of pancreatobiliary epithelial susceptibility, although this interpretation remains speculative without paired molecular analysis.

Table 2 Reported synchronous or metachronous pancreatic and gallbladder epithelial tumors.

Ref.	Sex/age	Pancreatic lesion	Gallbladder lesion	Timing	Molecular/genetic evidence	Possible mechanism or key finding
Ueda et al[14]	Male/58	Papillary adenocarcinoma	Papillary adenocarcinoma of the gallbladder and CBD	Synchronous	Not mentioned	Associated with anomalous arrangement of the pancreaticobiliary ductal system; gallbladder, CBD, and pancreatic duct tumors were not continuous
Sato et al[15]	Male/74	Mucinous cystadenocarcinoma	Well-differentiated tubular adenocarcinoma of the gallbladder; poorly differentiated tubular adenocarcinoma of CBD	Synchronous	p53-positive nuclei were detected only in the pancreatic tumor	Triple synchronous tumors with different histopathology; findings suggested different oncogenic mechanisms rather than a single DNA-repair abnormality
Minami et al[16]	Female/50	Moderately differentiated ductal adenocarcinoma	Moderately differentiated tubular adenocarcinoma	Metachronous; pancreatic cancer 10 years after cholecystectomy	Not mentioned	Associated with PBM without bile duct dilatation; emphasized long-term surveillance of the pancreas and biliary tract after biliary diversion
Lahmar et al[17]	Female/68	Adenosquamous carcinoma	Moderately differentiated adenocarcinoma of the gallbladder invading CBD	Metachronous; pancreatic cancer 4 years after cholecystectomy	Not mentioned	Associated with PBM and cystic dilatation of the CBD; pancreatobiliary or biliopancreatic reflux was proposed as a carcinogenic mechanism
Chen et al[18]	Female/56	Ductal adenocarcinoma	Well-differentiated adenocarcinoma	Metachronous; pancreatic cancer 3 years after cholecystectomy	Not mentioned	No recurrence after 33 months of follow-up after pancreaticoduodenectomy; mechanism not specified
Rungsakulkij and Boonsakan[19]	Female/46	Well-differentiated ductal adenocarcinoma	Well-differentiated adenocarcinoma	Synchronous	Not mentioned	Associated with PBM and pancreaticobiliary reflux; authors emphasized the possibility of double primary cancer in PBM
Mori et al[20]	Female/72	Moderately differentiated ductal adenocarcinoma	Well-differentiated tubular adenocarcinoma	Synchronous	Not mentioned	Associated with congenital biliary dilatation and PBM; reported as an extremely rare synchronous primary gallbladder-pancreatic cancer case in this setting
Ikeda et al[21]	Female/71	IPMN with invasive carcinoma	Gallbladder cancer arising in polypoid lesions; histological not specified	Metachronous; pancreatic cancer 5 years after cholecystectomy	IHC: Pancreatic tumor MUC1+, MUC5AC+, MUC2-	Associated with non-dilated PBM; supports surveillance for pancreatic as well as biliary tract cancer in PBM
Kuhara et al[22]	Female/65	First well-differentiated adenocarcinoma in pancreatic head; later moderately differentiated adenocarcinoma in remnant pancreas	Advanced papillary adenocarcinoma	Metachronous; pancreatic cancers 6.2 and 12.5 years after cholecystectomy	Not mentioned	Associated with PBM; bile pigment and marked inflammation in non-cancerous pancreatic ducts supported chronic inflammation and reflux-related carcinogenesis
Sato et al[23]	Male/72	IPMN	Adenocarcinoma	Synchronous	IHC: MUC6-positive pyloric gland metaplasia in both the dilated pancreatic duct and gallbladder background mucosa	Associated with PBM; authors suggested a possible common phenotypic origin and recommended comprehensive pancreaticobiliary evaluation
Kato et al[24]	Female/77	ITPN with invasive carcinoma	Papillary adenocarcinoma	Metachronous; pancreatic cancer 2 years after cholecystectomy	IHC: MUC1 focal weak+, MUC2-, MUC5AC-	Associated with PBM; supports careful long-term follow-up after diversion surgery because pancreatic or biliary cancers may still occur
Kogure et al[25]	Female/in her 80s	Adenosquamous carcinoma	Carcinoma; histological not specified	Synchronous	Not mentioned	Associated with PBM; co-occurrence of pancreatic adenosquamous carcinoma and gallbladder carcinoma was described as extremely rare
Miyazawa et al[26]	Male/63	Adenocarcinoma	Gallbladder cancer; histological not specified	Metachronous; pancreatic cancer 5 years after cholecystectomy	Not mentioned	PBM was diagnosed after cholecystectomy; progressive pancreatic changes suggested biliopancreatic reflux-related pancreatic carcinogenesis
Present case	Female/30	ITPN with multifocal invasive carcinoma	ICPN with high-grade dysplasia	Synchronous	No pathogenic variant identified by germline WES; somatic sequencing was not performed	No PBM was evident on available imaging; synchronous gallbladder ICPN and pancreatic ITPN suggest a possible field effect or shared epithelial susceptibility

CBD: Common bile duct; PBM: Pancreaticobiliary maljunction; IPMN: Intraductal papillary mucinous neoplasm; IHC: Immunohistochemistry; MUC1: Mucin 1; ICPN: Intracholecystic papillary-tubular neoplasm; ITPN: Intraductal tubulopapillary neoplasm; WES: Whole-exome sequencing.

This case also highlights the diagnostic challenges of pancreatobiliary intraductal neoplasms and the importance of long-term surveillance. For multifocal cystic-solid pancreatobiliary lesions, definitive diagnosis may require surgical pathology, especially when tissue sampling is limited by tumor architecture or cystic-solid heterogeneity. Complete surgical resection remains the principal treatment for resectable ICPN and ITPN, particularly when high-grade dysplasia or invasive carcinoma is suspected. After total pancreatectomy, follow-up should also include management of exocrine pancreatic insufficiency and post-pancreatectomy diabetes. No evidence-based follow-up protocol exists for synchronous gallbladder ICPN and pancreatic ITPN; therefore, postoperative surveillance should be individualized.

Several limitations should be acknowledged. First, pair somatic sequencing was not performed, so shared driver mutations, clonal relatedness, and characteristic pancreatic ITPN alterations could not be evaluated. Second, comparative immunohistochemistry for mucin phenotype or lineage markers was not performed for both lesions. Therefore, the available data cannot determine whether the gallbladder and pancreatic lesions shared a common molecular origin or represented clonally related tumors. The proposed field effect should therefore be regarded as a biological hypothesis rather than a proven mechanism in this case.

CONCLUSION

We report an unusual case of synchronous gallbladder ICPN with high-grade dysplasia and pancreatic ITPN with invasive carcinoma confined within the pancreas in a young woman presenting with multifocal, cystic-solid pancreatobiliary masses. The case expands the diagnostic spectrum of pancreatobiliary intraductal neoplasia. Compared with previously reported pancreatic-gallbladder double tumors, this case is notable for the absence of evident PBM, the young age at onset, and the coexistence of two radiologically visible intraductal neoplasms. These findings raise the possibility of a field effect or shared epithelial susceptibility, but this hypothesis requires confirmation by paired somatic, immunophenotypic, or clonality studies.