ICPN is defined as a grossly visible, mass-forming, non-invasive epithelial neoplasm arising in the mucosa and projecting into the lumen of the gallbladder . ICPN is defined as gallbladder lesions of intraductal papillary neoplasms of the bile duct, which is a premalignant lesion of the biliary tract and a counterpart of intraductal papillary mucinous neoplasm of the pancreas (IPMN). ICPN is more common in women older than 60 years of age and is found in 0.4% of cholecystectomies . ICPN shows various degree of dysplasia from low- to high-grade and finally to invasive carcinoma, and histological findings are often mixed; therefore, this variable dysplastic degree demonstrates the adenoma–carcinoma sequence [1, 7, 8]. If there is a component of invasive carcinoma, the lesion is called ICPN with associated invasive carcinoma . ICPN is classified as four morphological subtypes, namely biliary, gastric, intestinal, and oncocytic morphologies, and is separate from pyloric grand adenoma . Although ICPN more commonly displays morphological heterogeneity compared with IPMN, and clinical significance of these morphological subtypes is unclear, the biliary morphology is reportedly the most common subtype [1, 2, 8]. ICPN with associated invasive carcinoma is identified in approximately half of all resected ICPNs, particularly in lesions with a predominantly biliary morphology or extensive high-grade dysplasia [2, 8]. In the present patient, the lesion was diagnosed as biliary morphologic ICPN with associated invasive carcinoma according to the predominant morphological pattern. Although ICPN is considered a precancerous lesion , the natural history of ICPN has not been well investigated. In this case, the accurate time when ICPN developed in the patient’s remnant gallbladder and when the lesion became invasive are uncertain. Moreover, the lesion might already have been invasive at the time of the detection of the small nodule in the remnant gallbladder. However, the present case suggests the existence of biliary morphologic ICPN that can progress to invasive disease during a short period.
ICPN without invasive carcinoma has a good prognosis after cholecystectomy. The 5-year survival rate for patients with non-invasive ICPN is 78%, whereas patients with invasive carcinoma have a 5-year survival rate of 60% . Even when only ICPN with associated invasive carcinoma is considered, the overall survival outcome of ICPN is incomparably better than that of the non-ICPN-associated ordinary-type gallbladder adenocarcinoma, which has a 5-year survival rate ranging from 18 to 30% [2, 9]. In contrast, the fact that some patients with non-invasive ICPN die of biliary tract cancer, typically long after the diagnosis of ICPN, suggests that a field effect rendering the remainder of the biliary tract at risk of carcinoma . This feature of ICPN resembles that of IPMN, which sometimes occurs concomitantly with pancreatic ductal adenocarcinoma . Therefore, long-term surveillance is needed after resection of ICPN as well as IPMN.
Because of the rarity of ICPN, its imaging features have not been well described. Several case reports have described the imaging findings of ICPN [11,12,13,14,15]; however, no report has summarized the findings. According to previous reports, ICPN manifests as a polypoid lesion by AUS, and strong enhancement is observed in the early phase of contrast-enhanced studies. T2-weighted MRI of ICPN lesions reveal a filling defect, and a hypointense stalk is sometimes identified. Thickening or deformity of the gallbladder wall is rarely observed. Diffusion-weighted MRI usually shows restricted diffusion. The imaging features of FDG-PET/CT are unknown although FDG accumulation was confirmed in the present patient. The sensitivity and specificity of a ≥ 5-mm enhanced mural nodule for predicting invasive carcinoma derived from IPMN is reportedly high ; however, the specific preoperative imaging findings predicting ICPN with associated invasive carcinoma are unknown. ICPN is most commonly detected incidentally by imaging studies ; therefore, the natural imaging changes in ICPN are also unclear. The novelty of the present case is that a temporal change in the imaging findings until ICPN became invasive disease could be observed.
Cholecystectomy, including laparoscopic procedure, is difficult to perform in some patients with acute cholecystitis with severe inflammation and fibrosis . The occurrence of bile duct injury and vasculobiliary injury, which affect patients’ prognosis , is alarming in these cases. The 2018 revised international guidelines for the management of acute cholecystitis (Tokyo Guidelines 2018) recommend subtotal cholecystectomy as a bail-out procedure to prevent iatrogenic complications . Meta-analyses revealed that the rates of bile duct injury, postoperative complications, reoperation, and mortality after subtotal cholecystectomy for difficult gallbladders were low, although the rate of bile leakage was relatively high, ranging from 10.6 to 18.0% [18, 19]. Techniques for subtotal cholecystectomy have been classified as “reconstituting” when a closed remnant gallbladder is left or “fenestrating” when the remnant is left open or the internal opening of the cystic duct is closed . The distinction between these procedures is whether a remnant gallbladder is produced (reconstituting) vs not produced (fenestrating). Both techniques are associated with specific complications. Bile leakage is significantly more common after fenestrating techniques, whereas the rate of recurrent biliary events is lower after fenestrating than after reconstituting techniques . Additionally, the choice of a reconstituting or fenestrating procedure depends on the intraoperative conditions. The present patient previously underwent a reconstituting procedure at another institution. Because a produced cystic remnant gallbladder was left in the present patient, intracystic change might have been noticed early.
Remnant cholecystectomy is an uncommon procedure, although several researchers have reported studies of this procedure [4,5,6]. In these reports, the major operative indications for the remnant gallbladder related to retained or recurrent biliary stones. Although gallbladder cancer, including ICPN, can arise in the remnant gallbladder, to the best of our knowledge, this is the first resected case of ICPN associated with invasive carcinoma of the remnant gallbladder. The speculative reasons why resectable cases of remnant gallbladder cancer are extremely rare are as follows: (1) long-term surveillance after subtotal cholecystectomy is not generally performed, and in most patients who underwent subtotal cholecystectomy, clinicians were not aware of the remnant gallbladder . (2) The remnant gallbladder is anatomically adjacent to major vessels. Therefore, most remnant gallbladder cancers are likely to be unresectable when patients complain of symptoms. Although long-term surveillance for all patients after subtotal cholecystectomy is not realistic, resectable invasive cancer of the remnant gallbladder could have been detected incidentally in the present case because of surveillance for other diseases.
Remnant cholecystectomy is technically difficult because of adhesions, fibrosis, and anatomical change owing to the initial surgery [4,5,6]. In the present case, preoperative endoscopic retrograde cholangiopancreatography was useful to evaluate the status of the cystic duct, and extrahepatic bile duct resection was planned to be omitted. Moreover, intraoperatively, the cystic duct located behind the bile duct could be safely exposed using tapes, which allowed for pulling the bile duct. Therefore, bile duct injury could be prevented and extrahepatic bile duct resection could be omitted. Accurate preoperative investigation and surgical planning are essential in similar cases.
Extrahepatic bile duct resection is performed as part of radical cholecystectomy for gallbladder cancer. However, the indication for extrahepatic bile duct resection remains a major controversy in the surgical management of gallbladder cancer that has not invaded the hepatoduodenal ligament. The 2019 clinical practice guidelines for the management of biliary tract cancers advocated by the Japanese Society of Hepato-Biliary-Pancreatic Surgery recommend not to perform routine prophylactic extrahepatic bile duct resection for gallbladder cancer without bile duct invasion . Because of the patient’s age and activities of daily living, we considered that minimally invasive surgery was desirable. Moreover, preoperative imaging studies did not reveal evidence of extramural, cystic ductal, and bile ductal invasion, or evidence of regional lymph node metastasis. Therefore, extrahepatic bile duct resection was planned to be omitted in this case, although lymph node dissection around the hepatic portal region without extrahepatic bile duct resection may carry a risk of bile duct ischemia and can cause acute or chronic bile duct stenosis [23, 24]. Surgery with strict attention to conservation of blood flow to the bile duct was performed, then remnant cholecystectomy without extrahepatic bile duct resection was completed after confirmation of negative cystic ductal and surgical margins on intraoperative frozen section.