Papillary Neoplasms of the Gallbladder and Extrahepatic Bile Ducts: A Report of Two Cases With Associated Invasive Carcinoma.

Intracholecystic papillary neoplasm (ICPN) of the gallbladder is a macroscopically visible premalignant lesion protruding into the gallbladder lumen, with infrequent association with invasive adenocarcinoma. Intraductal papillary neoplasm of the bile ducts (IPNB) is a non-invasive lesion characterized by intraductal papillary or villous architecture. Both ICPN and IPNB are rare findings in the gallbladder and biliary tract pathology. Diagnosis relies on clinical manifestations, imaging techniques, and comprehensive histological examination. Here, we present two cases: a 63-year-old male with mild abdominal pain found to have a gallbladder mass, diagnosed histologically as ICPN with associated invasive carcinoma; and a 65-year-old female with chronic jaundice and a large tumor mass in the common bile duct, histologically diagnosed as IPNB with associated invasive carcinoma. These cases highlight the importance of a careful and thorough microscopic examination to rule out differential diagnoses and to reveal any potential invasive carcinoma associated with these uncommon lesions.

Intraductal neoplasms of the pancreatobiliary tract: navigating the alphabet.

Cancers of the pancreatobiliary tract are diseases with unfavourable prognoses. In the last couple of decades, two types of lesions have been described as precursors that precede pancreatobiliary cancers. These include incidental microscopic (flat) lesions known as pancreatic intra-epithelial neoplasia and biliary intra-epithelial neoplasia, and grossly visible, mass-forming lesions (tumoral intra-epithelial neoplasia) including intraductal papillary mucinous neoplasms, intraductal oncocytic papillary neoplasms, intraductal tubulopapillary neoplasms, intraductal papillary neoplasms of the bile duct and intracholecystic papillary neoplasms. Early detection and adequate treatment of these precursor lesions, especially the second group, have the potential to prevent pancreatobiliary cancer or at least improve its prognosis. In this review, we discuss their histopathology and recent updates on molecular profiling of these intraductal neoplasms of the pancreatobiliary tract.

Lymph node metastatic status could predict the prognosis of intracholecystic papillary neoplasm of gallbladder.

Intracholecystic papillary neoplasm (ICPN) is a non-invasive epithelial tumor that presents as a grossly identifiable mass arising in the mucosa and protruding into the lumen. ICPN is associated with invasive carcinoma. There are few studies on the clinicopathological features of ICPN, including that with invasive carcinoma. We evaluated the clinicopathological characteristics of 42 ICPNs and 41 conventional gallbladder adenocarcinomas (cGBAs). Subserosa or deeper (≥ss) invasion was significantly lower in ICPN (61.9%) than that in cGBA (90.2%) (P = 0.004). Cox regression analysis revealed that lymph node metastasis (hazard ratio [HR] [95% confidence interval (CI)]: 2.610 [1.131, 6.024], P = 0.025) and positive margin (HR [95% CI]: 5.143 [2.113, 12.516], P < 0.001), but not ≥ss invasion (HR [95% CI]: 1.541 [0.479, 4.959], P = 0.469), were independent prognostic factors. In addition, there was a significant interaction between histological type and lymph node metastasis (HR [95% CI]: 0.191 [0.042, 0.983], P = 0.033). In cGBA, the presence or absence of lymph node metastasis did not affect prognosis; however, ICPN without lymph node metastasis had better prognosis. Therefore, the histological classification of ICPN and cGBA and the pathological evaluation of lymph node metastasis in ICPN are crucial for determining prognosis.

Diagnostic usefulness of SpyGlass in intracholecystic papillary neoplasm with pancreaticobiliary maljunction: a case report and comparison with conventional gallbladder cancer with pancreaticobiliary maljunction.

BACKGROUND: Intracholecystic papillary neoplasm (ICPN) is one of the precursors of gallbladder cancer defined in the 2010 World Health Organization classification of tumors. We herein report ICPN with pancreaticobiliary maljunction (PBM), which is a high-risk factor for biliary cancer. CASE PRESENTATION: A 57-year-old female presented with abdominal pain. Computed tomography showed a swollen appendix and gallbladder nodules with bile duct dilatation. Endoscopic ultrasonography revealed a gallbladder tumor spreading into the cystic duct confluence accompanying PBM. Based on papillary tumors around the cystic duct detected using the SpyGlass DS II Direct Visualization System (SpyGlass DS), ICPN was suspected. We performed extended cholecystectomy, extrahepatic bile duct resection, and appendectomy with a diagnosis of ICPN and PBM. The pathological diagnosis was ICPN (90 × 50 mm) with high-grade dysplasia spreading into the common bile duct. The absence of residual cancer in the resected specimen was pathologically confirmed. P53 staining was totally negative in both the tumor and normal epithelium. The overexpression of CTNNB1 was not observed. CONCLUSIONS: We encountered a patient with a very rare gallbladder tumor, ICPN with PBM. SpyGlass DS contributed to a precise assessment of the extent of the tumor as well as a qualitative diagnosis.

Pathologies of Precursor Lesions of Biliary Tract Carcinoma.

Carcinomas and precursor lesions of the biliary tract belong to a spectrum of pancreatobiliary neoplasms that share common histology and cell lineages. Over the past two decades, preinvasive precursors to biliary tract carcinomas (BTCs) have been identified such as high-grade biliary intraepithelial neoplasm (high-grade BilIN), intraductal papillary neoplasm of bile duct (IPNB) and intracholecystic papillary neoplasm of the gallbladder (ICPN). While a majority of these precursors may arise from the biliary tract mucosa, some originate from the peribiliary glands and Rokitansky-Aschoff sinuses in the walls of the biliary tract. High-grade BilIN is a microscopically identifiable intraepithelial neoplasm of the biliary tract, whereas IPNB and ICPN are grossly visible intraductal or intraluminal preinvasive neoplasms in the bile duct and gallbladder, respectively. These neoplasms show characteristic histologic features according to four cell lineages and two-tiered grading, and show intraepithelial spreading to the surrounding mucosa and involve non-neoplastic glands in the walls of the biliary tract. These precursors are not infrequently associated with stromal invasion, and high-grade BilIN, in particular, are frequently identified in the surrounding mucosa of BTCs. Taken together, it seems likely that progression from these precursors to invasive carcinoma is a major process in biliary carcinogenesis.

The Clinical and Pathologic Features of Intracholecystic Papillary-Tubular Neoplasms of the Gallbladder.

Intracholecystic papillary-tubular neoplasm denotes a discrete mucosal-based neoplastic proliferation into the gallbladder lumen. It is diagnosed incidentally during cholecystectomy or radiologically during a workup for abdominal pain. The majority of polypoid lesions in the gallbladder are non-neoplastic; therefore, pathologic examination is the gold standard to establish this diagnosis. Intracholecystic papillary-tubular neoplasm is considered as premalignant, although associated invasive carcinomas may be present in the specimen. Invasive carcinoma arising from intracholecystic papillary-tubular neoplasm have a better prognosis than de novo gallbladder carcinomas. The pathology of intracholecystic papillary-tubular neoplasm, including the challenges involved in the diagnosis of this entity, is discussed.

Natural history of intracholecystic papillary neoplasm (ICPN): a rare case of ICPN whose natural history was closely followed by ultrasound.

The natural history of intracholecystic papillary neoplasm (ICPN), especially the speed of growth from small benign to a carcinomatous lesion, is quite unrevealed. Here, we report an extremely rare case of ICPN, in which the papillary lesion was observed transforming from small and benign to malignant using abdominal ultrasound (AUS) over 2 years during routine health checks. A 44-year-old man underwent a routine health check-up. The initial AUS showed a small sessile polyp in the gallbladder, which enlarged slightly at the next AUS, a year later. In the third year, the polypoid lesion enlarged markedly, with a maximum diameter of 10 × 9 × 7 mm. Therefore, a laparoscopic cholecystectomy was performed. Microscopically, the 10 mm tumor had intracytoplasmic mucus, and a clear cytoplasm compatible with gastric-type features. Immunohistochemical analysis showed positive staining of atypical cells for MUC6 and PAS. These findings led to the diagnosis of ICPN with high-grade intraepithelial neoplasia of the gastric type. In conclusion, sessile polyps with rapid growth might be a crucial finding in the early stage of ICPN.

Bifocal intracholecystic tubulopapillary neoplasm: A rare and distinct tumor of the gallbladder.

Intracholecystic papillary-tubular neoplasms are rare precancerous and polypoid lesions of the gallbladder, found in nearly 0.4% of cholecystectomy specimens. They follow the adenoma-carcinoma sequence. About half the cases are associated with invasive carcinoma. Their diagnosis relies on histopathological examination with extensive sampling of the surgical specimen.

Intracholecystic Papillary Neoplasm Localized to the Cystic Duct: A Case Report.

Intracholecystic papillary neoplasm (ICPN) of the gallbladder is a premalignant lesion. An ICPN arising from the cystic duct is rare. A woman in her 60s exhibited dilatation of the common bile duct on computed tomography (CT) performed for screening of respiratory disease. The CT revealed an enhancing mass, 3.3 cm in diameter, in the cystic duct. Endoscopic ultrasonography showed a well-demarcated, hyperechoic mass in the dilated cystic duct. Endoscopic retrograde cholangiography showed that the common bile duct was slightly retracted by the dilated cystic duct. Cytological analysis of the bile juice did not show any evidence of malignancy. She was diagnosed with a cystic bile duct tumor suggestive of ICPN. Cholecystectomy, resection of the extrahepatic bile duct, and lymph node dissection were performed. Macroscopically, the papillary-proliferated tumor was localized to the cystic duct. No critical lesions were evident in the common bile duct. Histologically, the tumor in the cystic duct showed intraluminal growth with a papillary configuration without malignancy. Based on these findings, the tumor was diagnosed as an ICPN. We encountered a rare case of ICPN localized to the cystic duct of the gallbladder.

Precursor Lesions of Gallbladder Carcinoma: Disease Concept, Pathology, and Genetics.

Understanding the pathogenesis and carcinogenesis of gallbladder adenocarcinoma is important. The fifth edition of the World Health Organization's tumor classification of the digestive system indicates three types of preinvasive neoplasm of the gallbladder: pyloric gland adenoma (PGA), biliary intraepithelial neoplasia (BilIN), and intracholecystic papillary neoplasm (ICPN). New terminologies have also been introduced, such as intracholecystic papillary-tubular neoplasm, gastric pyloric, simple mucinous type, and intracholecystic tubular non-mucinous neoplasm (ICTN). Pancreatobiliary maljunction (PBM) poses a markedly high risk for bile duct carcinoma, which was analyzed and investigated mainly by Asian researchers in the past; however, recent studies have clarified a similar significance of biliary carcinogenesis in Western countries as well. In this study, we reviewed and summarized information on three gallbladder neoplastic precursors, PGA, BilIN, and ICPN, and gallbladder lesions in patients with PBM.

Association of precursors with invasive adenocarcinoma of the gallbladder: A clinicopathological study.

BACKGROUND: The current WHO classification proposed high-grade biliary intraepithelial neoplasm (BilIN) and intracholecystic papillary neoplasm (ICPN) as precursors of the gallbladder carcinoma (GBC). Herein, conventional GBCs (cGBCs) were pathologically examined with respect to these two precursors. METHODS: Forty-seven cases of GBC with grossly visible invasions were collected from Fukui Saiseikai Hospital. The association of two precursors was analyzed referring to pathologic features of cGBCs and post-operative survival. RESULTS: 20 cGBCa (42.6%) were associated with either of two precursors in the surrounding mucosa: high-grade BilIN in 15 cases (31.9%) or ICPN in 5 cases (10.6%). Association of precursors was not related to gross types of and histological differentiation of cGBC. cGBCs without precursors showed frequent vascular/perineural invasion and lymph node metastasis, though cGBCs with and without precursors presented a similar post-operative survival. High-grade BilIN and ICPN associated with cGBCs showed more complicated cytoarchitectural features compared with those with no or focal invasion. CONCLUSION: More than 40% of cGBCs were associated with high-grade BilIN or ICPN, and the former was a frequent precursor. cGBCs without precursors showed aggressive pathologic features. Clinical detection of these precursors may make early treatment of cGBCs possible.

Intracholecystic papillary neoplasm associated with invasive carcinoma of the remnant gallbladder after subtotal cholecystectomy: a case report.

BACKGROUND: Intracholecystic papillary neoplasm (ICPN) of the gallbladder is a rare tumor and a relatively new concept. Therefore, the natural history and imaging characteristics of ICPN have not yet been fully documented. Moreover, cases who underwent curative resection for remnant gallbladder cancer, including ICPN with associated invasive carcinoma, have been rarely reported. We report a resected case of ICPN of the remnant gallbladder with associated invasive carcinoma for which we could observe a temporal change in imaging findings until malignant transformation. CASE PRESENTATION: A 79-year-old female patient with a surgical history of subtotal cholecystectomy for acute cholecystitis was an ambulatory patient of our institution because of postoperative surveillance for colon cancer. Ultrasonography and computed tomography incidentally detected a small nodule in the cystic remnant gallbladder. The nodule had increased in size 3 months later; thus, additional investigations were performed. Magnetic resonance imaging revealed a 10-mm enhanced nodule without evidence of extraluminal invasion. Diffusion-weighted magnetic resonance imaging revealed restricted diffusion of the lesion, and positron emission tomography revealed marked accumulation in the lesion. The lesion was diagnosed as suspicious for a malignant remnant gallbladder tumor. Therefore, remnant cholecystectomy with gallbladder bed resection was performed. Because preoperative endoscopic retrograde cholangiography revealed a relatively long intact cystic duct, extrahepatic bile duct resection was planned to be omitted. Intraoperatively, the hepatic and duodenal side bile duct where the cystic duct diverged was taped. Using these tapes, which permitted pulling the bile duct, the cystic duct located behind the bile duct could be safely exposed. The lesion was pathologically diagnosed as biliary morphologic ICPN with associated invasive carcinoma. CONCLUSIONS: Because remnant cholecystectomy is an uncommon procedure and technically difficult, accurate preoperative investigation and surgical planning are important to prevent bile duct injury and omit extrahepatic bile duct resection. In the present case, intracystic change could be detected incidentally at an early stage because of previous remnant gallbladder producing (reconstituting) subtotal cholecystectomy and surveillance for other disease. This case suggests the existence of ICPN that can progress to invasive carcinoma during a short period.

Intracholecystic papillary neoplasm arising in the cystic duct and extending into common bile duct: a case report.

An 83-year-old man without specific symptoms was referred to our hospital for further evaluation and treatment of apparent double primary tumors of the cystic duct and common bile duct. Computed tomography showed contrast-enhanced solid tumors in the cystic duct and common bile duct. Magnetic resonance imaging showed that the bile duct tumor was isointense on T1-weighted images and had low intensity on T2-weighted images. In addition, the bile duct tumor showed high intensity on diffusion-weighted images. Endoscopic ultrasonography revealed the tumor of the common bile duct and endoscopic retrograde cholangiopancreatography demonstrated a filling defect in the bile duct. The cystic duct was not identified on endoscopic ultrasonography or endoscopic retrograde cholangiopancreatography. Transpapillary biopsy of the bile duct tumor showed adenocarcinoma. The patient was diagnosed with double primary tumors of the cystic duct and the common bile duct and underwent subtotal stomach-preserving pancreaticoduodenectomy. Microscopic examination with molecular profiling of the tumors revealed a high-grade noninvasive intracholecystic papillary neoplasm of the cystic duct extending into the common bile duct and forming a tubulopapillary neoplasm with invasion of the common bile duct.

Progression to invasive cancer after snare polypectomy of intracholecystic papillary neoplasms during gallbladder stone removal by percutaneous transhepatic choledochoscopy: a case report.

BACKGROUND: Intracholecystic papillary neoplasms (ICPNs) of the gallbladder are rare, preinvasive lesions characterized by an intracholecystic papillary growth that may be associated with invasive adenocarcinoma. The natural history of ICPN is unknown. Here, we report a case of ICPN, highlighting its natural course. CASE PRESENTATION: A 79-year-old woman presented to the emergency department with perforated cholecystitis. After percutaneous transhepatic gallbladder drainage, due to the presence of surgical risk factors, we opted to perform gallstone removal through percutaneous transhepatic cholangioscopy instead of cholecystectomy. ICPN, which was accidentally detected after the removal of the gallbladder stones, was also endoscopically removed. After 4 years, the patient came back to the hospital with a large gallbladder mass. After cholecystectomy, pathological examination revealed ICPN with invasive adenocarcinoma. CONCLUSION: The current case showed endoscopic findings of ICPN and its natural progression, particularly its clinicopathological features and outcomes.

Intracholecystic papillary neoplasm arising in a patient with pancreaticobiliary maljunction: a case report.

BACKGROUND: Pancreaticobiliary maljunction (PBM) is a congenital abnormality in which the pancreatic and biliary ducts join anatomically outside the duodenal wall resulting in the regurgitation of pancreatic juice into the biliary tract (pancreatobiliary reflux). Persistent pancreatobiliary reflux causes injury to the epithelium of the biliary tract and promotes the risk of biliary cancer. Intracholecyctic papillary neoplasm (ICPN) has been highlighted in the context of a cholecystic counterpart of intraductal papillary mucinous neoplasm of the pancreas and the bile duct, but the tumorigenesis of ICPNs remains unclear. CASE PRESENTATION: A 52-year-old Japanese woman was referred for the assessment of dilation of the bile duct. Computed tomography which revealed an enhanced mass in the gallbladder and endoscopic retrograde cholangiopancreatography confirmed that the confluence of the main pancreatic duct and extrahepatic bile duct (EHBD) was located outside the duodenal wall. Under the diagnosis of gallbladder cancer with PBM, cholecystectomy with full thickness dissection, EHBD resection, lymph node dissection, and hepaticojejunostomy were performed. Macroscopic examination of the resected specimen showed that the cystic duct was dilated and joined into the EHBD just above its confluence with the pancreatic duct, and the inflamed change of non-tumorous mucosa of gallbladder indicating that there was considerable mucosal injury due to pancreatobiliary reflux to the gallbladder. Histopathological examination revealed that the gallbladder tumor was a gastric-type ICPN with non-invasive component. Either KRAS gene mutation or p53 protein expression that were known to be associated with the carcinogenesis of biliary cancer under the condition of pancreatobiliary reflux was not detected in the tumor cells of ICPN. CONCLUSION: The present case might suggest that there was no association between PBM and ICPN. To reveal the tumorigenesis of ICPN and its attribution to pancreatobiliary reflux, however, further study is warranted.

Intracholecystic papillary neoplasm of the gallbladder protruding into the common bile duct: A case report.

The current study indicates the case of intracholecystic papillary neoplasm (ICPN) protruding into the common bile duct (CBD) without superficial spread. A 58-year-old woman presented to hospital with a fever that lasted for three days. Laboratory tests revealed elevated hepatobiliary enzyme levels. CT, MRI and endoscopic ultrasonography revealed a polypoid, papillary tumor inside the gallbladder cavity, which also extended to the CBD. On peroral cholangioscopy, a papillary tumor with mucin production was found at the middle bile duct. Biliary biopsy and bile cytology indicated adenocarcinoma. Based on a diagnosis of ICPN extending to the CBD, the patient underwent subtotal stomach-preserving pancreaticoduodenectomy and gallbladder bed resection. However, pathological examination revealed that the ICPN was confined to the gallbladder and cystic duct, whereas the CBD was tumor-free. The present case indicates that when ICPN increases in size, it may protrude into the CBD due to an increased intracholecystic pressure, which increases the risk of overestimation of tumor extension and may result in unnecessary additional bile duct resection.

A case report of intracholecystic papillary neoplasm of the gallbladder resembling a submucosal tumor.

BACKGROUND: Intracholecystic papillary neoplasm (ICPN) is defined as papillary tumors detected macroscopically in the gallbladder. We report a case of ICPN which exhibited the atypical form like a submucosal tumor. CASE PRESENTATION: A 70-year-old man was admitted to our hospital because of hepatic disorder. Computed tomography and magnetic resonance imaging showed irregular thickening of the wall within the gallbladder fundus. Because the lesion might have been malignant, we performed laparoscopic cholecystectomy and liver bed resection. Macroscopic findings showed the mucosal surface of the tumor was smooth, and its form was similar to that of a submucosal tumor. Histopathological examination revealed papillary tumors within the mass with low-grade dysplasia; therefore, we diagnosed ICPN. CONCLUSION: In the present case, ICPN was resembling a submucosal tumor macroscopically because the tumors arose into the Rokitansky-Aschoff sinus and the adenomyomatous hyperplasia was merged with the ICPN. It is necessary to consider the possibility of tumor lesions within adenomyomatous hyperplasia.

Intracholecystic papillary-tubular neoplasm in a patient with choledochal cyst: a link between choledochal cyst and gallbladder cancer?

BACKGROUND: Intracholecystic papillary-tubular neoplasms are rare precursor lesions of gallbladder cancer. They were proposed as a separate pathologic entity in 2012 by Adsay et al. for the unification of a variety of mass-forming precursor lesions including papillary adenomas, tubulopapillary adenomas, intestinal adenomas, and others. They are considered homologous to intrapapillary mucinous neoplasms of the pancreas and intrabiliary papillary neoplasms of the common bile duct. In contrast with the commoner flat-type precursor gallbladder cancer lesions, they follow a more indolent clinical course and probably different genetic pathways to carcinogenesis. They are largely uninvestigated with only a handful of studies providing biological and clinical information. Choledochal cysts are dilation of the common bile duct. Diagnosis is usually established during childhood, and only a minority of patients are diagnosed at adulthood. They are of major clinical importance as they are known predisposing factors for biliary carcinogenesis. CASE PRESENTATION: The current report describes a patient with a simultaneous diagnosis of choledochal cyst and intracholecystic papillary-tubular neoplasm. The patient underwent excision of the extrahepatic biliary tree for a Todani I choledochal cyst, and histological examination of the specimen revealed an intracholecystic papillary-tubular neoplasm of the gallbladder. Authors describe diagnostic and clinical course of the patient alongside clinical and biological characteristics of these rare lesions. CONCLUSIONS: To the best of our knowledge, this is the first report of a patient with a simultaneous diagnosis of choledochal cyst and intracholecystic papillary-tubular neoplasm. Those rare lesions shed light on different forms of gallbladder cancer carcinogenesis and its relationship with choledochal cysts and cholestasis.