Outcomes after resection of occupational cholangiocarcinoma

Introduction

An outbreak of cholangiocarcinoma among workers at a printing company was recently reported 1, 2. Although the mechanism underlying the development of cholangiocarcinoma is still unclear, long-term exposure to high concentrations of dichloromethane (DCM) and/or 1,2-dichloropropane (DCP) is strongly suspected to be a cause 1-3. The Ministry of Health, Labour and Welfare of Japan classified this type of cholangiocarcinoma as “occupational cholangiocarcinoma” on 1 October 2013 3. Thirty-seven patients in all, some of whom have been described in previous reports 1, 2, 4, 5, have been recognized as having occupational cholangiocarcinoma in Japan as of January 2016.

Our previous studies showed that in addition to the main tumor, chronic bile duct injury such as fibrosis of the bile duct wall and periductal tissue, precancerous lesions such as biliary intraepithelial neoplasia (BilIN) and intraductal papillary neoplasm of the bile duct (IPNB) were observed at various sites of the large bile ducts 2, 4, 5. In addition, neoplastic and non-neoplastic biliary lining epithelia at various sites of the bile ducts were found to be immunochemically positive for γ-H2AX, suggesting DNA damages 5, 6. These results indicate (1) the cholangiocarcinoma might have developed from chronic bile duct injuries with DNA injuries into precancerous or early cancerous lesions, and eventually developed into invasive cholangiocarcinoma, and (2) the patients with occupational cholangiocarcinoma are at high risk for development of cholangiocarcinoma at various sites of the bile ducts. However, the outcome of these patients after surgical treatment for occupational cholangiocarcinoma is still unknown. The aim of this study was to investigate the clinicopathological findings and outcomes after surgical intervention for occupational cholangiocarcinoma to establish a treatment strategy for this disease.

Patients and methods

Of the 37 patients with occupational cholangiocarcinoma experienced in Japan, 22 patients underwent surgical treatment. One patient was excluded from this study owing to a lack of information regarding clinicopathological data and another patient was excluded because the carcinoma was suspected to have originated in the pancreas, although the common bile duct was secondarily involved. Thus, the subjects in this study were 20 patients who underwent surgical treatment for occupational cholangiocarcinoma (Table 1). Nineteen (patient no. 1–17, 19, 20) of the 20 patients were former or current workers at eight printing companies in Hokkaido, Miyagi, Saitama, Tokyo, Shizuoka, Osaka, and Fukuoka. These 19 patients were exposed to high concentrations of 1,1,1-trichloroethane (TCE), DCP, and/or DCM over a long period of time 7-9. These chlorinated organic solvents were used to remove ink residues. Another patient (patient no. 18) was exposed to high concentrations of DCP and 1,1-dichloro-1-fluoroethane by removing the dirt from cleaning rolls of coating machines at a company manufacturing IC cards in Kyoto 9. We investigated the clinical findings, laboratory test results, operative methods, pathological findings of the operative specimens, postoperative complications, and the postoperative outcomes.

Patient data and clinical findings were obtained from the medical records from each hospital and/or interviews with the patients or their family members. The operative specimens of one patient (patient no. 3) were not available in the study because the specimens had been discarded.

The pathological findings were recorded and described according to the World Health Organization Classification of Tumors of the Digestive System 10. Intrahepatic cholangiocarcinoma was grossly classified as a mass-forming, periductal infiltrating, or intraductal growth. Extrahepatic cholangiocarcinoma (perihilar and distal cholangiocarcinoma) was grossly classified as a papillary, nodular, scirrhous constricting, or diffusely infiltrating tumor. Preneoplastic or early preinvasive neoplastic lesions of the biliary tracts were classified as flat dysplastic epithelial tumors (BilIN) or grossly visible papillary tumors (IPNB) 2, 4, 5, 10-14. BilIN lesions were histologically classified according to their cellular and structural features as BilIN-1 (mild atypia), BilIN-2 (moderate atypia), or BilIN-3 (severe atypia corresponding to in situ carcinoma). BilIN-1 lesions presented with mild atypical cellular and nuclear features, such as nuclear membrane irregularities or nuclear enlargements with only minimal disturbances to cellular polarity. BilIN-2 lesions had evident aberrant cellular and nuclear features not sufficient to suggest overt carcinoma; these lesions also had focal disturbances in cellular polarity. BilIN-3 lesions presented with diffuse disturbances in cellular polarity with or without distinct atypical cellular and nuclear features that corresponded to carcinoma in situ. In this study, primary BilIN-2 and BilIN-3 lesions were examined. IPNB was characterized by dilated intrahepatic and extrahepatic bile ducts filled with a papillary or villous biliary neoplasm that covers delicate fibrovascular stalks. The dilated bile ducts were fusiform or cystic (unilobular or multilocular), and the height of such lesions usually exceeds 10 mm, but papillary lesions < 10 mm but > 5 mm showing similar histologies were also occasionally encountered. IPNB was not infrequently associated with focal and minimal invasion (IPNBs with an associated invasive carcinoma). Other pathological terms used in this study were characterized or defined as follows 2, 4, 5. “Chronic bile duct injury” was used as a collective term to describe duct injuries such as epithelial damage, fibrosis of the duct wall and periductal tissue, and chronic inflammatory cell infiltration, in various combinations. Pathological examination for BilIN, IPNB, and chronic bile duct injury were performed mainly at the large bile ducts (the common hepatic duct, the left and right hepatic ducts or to the first to third branches of the intrahepatic bile duct). Pathological examination of the large bile ducts could not be performed in three patients (patient no. 18–20) because these patients underwent pancreaticoduodenectomy.

The cumulative recurrence-free and overall survival curves were calculated using the Kaplan–Meier method.

This study was approved by the ethics committee of Osaka City University, and all of the subjects or their legally authorized representatives (for deceased patients) provided written informed consent. This multicenter occupational cholangiocarcinoma study group consisted of investigators at 19 institutions.

Results

Outcomes

Cholangiocarcinoma recurred in 12 of the 20 patients. The recurrence-free survival rate is shown in Figure 1. In two patients (patient no. 1, 3), multiple intrahepatic metastasis with or without multiple lymph node metastasis occurred after the operation. In five patients (patient no. 2, 4, 14, 16, 18), recurrence occurred at the resection margin including the bile duct stump. In five patients (patient no. 6, 9, 12, 13, 15), solitary recurrent tumors, distant from the primary tumor, were detected after the operation. In one patient (patient no. 6), solitary intrahepatic recurrence (segment 7) developed 10 months after the first operation (segment 8) and radiofrequency ablation therapy (RFA) was performed. The second solitary intrahepatic recurrence (segment 8, the tumor is distant from the first cholangiocarcinoma) occurred 5 years and 10 months after the first operation and the tumor was resected (Fig. 2A–G). The patient is now alive (at 6 years and 10 months after the RFA and 2 years 3 months after the second liver resection) although the patient has tumor recurrence. In one patient (patient no. 9), solitary intrahepatic recurrence distant from the primary tumor occurred 4 years and 4 months after the first operation. The patient was treated with chemotherapy (gemcitabine and S-1) according to the patient's decision. In one patient (patient no. 12), the protruding tumor was detected at the common bile duct 9 months after the first operation (extended left hepatectomy for intrahepatic cholangiocarcinoma) and the tumor gradually enlarged. The extrahepatic bile duct with the tumor was resected at 1 year and 3 months after the first operation, and the pathological examination showed papillary type of the distal cholangiocarcinoma (intraductal papillary neoplasia, high grade), with BilIN lesions around the tumor (Fig. 2H–O). The invasion from the primary cholangiocarcinoma was not detected at the hepatic side stump of the bile duct. The patient is now alive without tumor recurrence (at 1 year and 1 month after the second operation). In one patient (patient no. 13), recurrence occurred at the distal side of the common bile duct 3 years after resection of hilar cholangiocarcinoma (the stump of the bile duct was negative for cancer). The recurrent tumors were distant from the primary cholangiocarcinomas and the pancreaticoduodenectomy was performed. The patient is now alive without tumor recurrence (at 1 year and 3 months after the second operation). In one patient (patient no. 15), a solitary intrahepatic recurrent tumor distant from the original tumors was resected 6 months after the first operation. The patient survived for 1 year and 4 months after the second operation. The recurrent tumors in five patients (patient no. 6, 9, 12, 13, 15) developed at different parts of the bile duct from the primary tumor, and consecutive invasion was not found between the primary lesion and recurrent tumor in the resected specimens obtained from four patients (patient no. 6, 12, 13, 15). Although one (patient no. 15) died 684 days after the first operation, the other four patients survived between 1224 to 2978 days after the first operation.

The cumulative recurrence-free and overall survival rates are shown in Figure 1. Eight of the 20 patients died of cholangiocarcinoma recurrence. One patient died of hepatic failure owing to progression of hepatic fibrosis, especially fibrosis of the bile duct wall and periductal tissue, without cancer recurrence 15. The survival time from the first operation to death or the end of this study (April 2016) ranged from 404 to 3241 days (median 1462 days).

Discussion

Our previous studies 2, 4, 16, 17 showed that elevated serum γ-glutamyl transpeptidase activities had increased several years before the diagnosis of cholangiocarcinoma. Regional dilated intrahepatic bile duct without tumor-induced obstruction and primary sclerosing cholangitis-like appearance such as multiple strictures of the bile ducts with or without fusiform dilatation on diagnostic imaging are characteristics of occupational cholangiocarcinoma. On pathological examination, chronic bile duct injuries, such as fibrosis, precancerous or early cancerous lesions, such as BilIN and IPNB, have been observed at the various sites of the large bile ducts 2, 4-6. These characteristics were also observed in most subjects in this study.

In this series, intraabdominal infection developed in nine of the 20 patients. The high incidence of intraabdominal infection might be related to the damage of the bile ducts such as chronic bile duct injuries and precancerous or early cancerous lesions. Innate immunity inherent in the biliary tree might have been disturbed in these patients, and this disturbance may be responsible for frequent intraabdominal infection 18.

Surgical resection is a curative treatment for cholangiocarcinoma 19, 20. However, surgical treatments have been performed in only 22 of the 37 patients with occupational cholangiocarcinoma because the stage of the cholangiocarcinoma was too advanced at the diagnosis in the other 15 patients. These findings indicate that screening and surveillance are important for detecting occupational cholangiocarcinoma at an early stage 16. Of the 20 patients in this study, curative operation could not be performed in four patients because the stump of the bile duct was positive for cancer cells. In this study, BilIN lesions were observed in 15 of 16 patients examined. In patients with the stump of the bile duct positive for cancer cells, invasive carcinoma or BilIN-3 lesion (early cancerous lesion), that involved various sites of the bile ducts, was observed at the stump. Therefore, it is sometimes difficult to perform curative resection for occupational cholangiocarcinoma.

After resection, local recurrence (recurrence at the resection stump including the bile duct stump and adjacent tissue) occurred in five patients and multiple intrahepatic metastasis with or without multiple lymph node metastasis occurred in two patients. In the other five patients, solitary intrahepatic recurrence distant from the primary carcinoma occurred in three patients and solitary recurrence occurred at the distal common bile duct in the other two patients. Consecutive invasion was not observed between the primary tumor and the recurrent tumor. In patients with occupational cholangiocarcinoma, chronic bile duct injuries with DNA injuries and precancerous or early cancerous lesions such as BilIN and IPNB were observed at the various sites of the bile ducts 5, 6, which indicate that the bile ducts have high potential for malignant transformation. Therefore, the recurrent tumors in the five patients might have originated from other sites of the bile ducts; the recurrence occurred in multicentric origin. In the patients with occupational cholangiocarcinoma, it is important to pay attention to not only metastasis from the primary tumor but also multicentric recurrence after the operation.

Recently, the usefulness of aggressive treatments for recurrent cholangiocarcinoma, such as resection or RFA for select patients such as patients with isolated intrahepatic recurrence has been reported 21, 22. In this series, repeated resection or RFA was performed in four patients with solitary recurrent tumors in the intrahepatic or extrahepatic bile duct. It is difficult to evaluate the usefulness of such treatments because the duration after repeated resection or RFA was short. However, if the recurrent tumors are originated from the other site in the bile duct (multicentric origin), as described above, aggressive treatment such as second resection and RFA must be effective because relatively long survival can be expected from the curative treatment for a recurrent tumor of multicentric origin.

In this series, one patient underwent scheduled chemoradiotherapy before surgery, three patients underwent radiation therapy at the stump of the bile duct, and 12 patients underwent adjuvant chemotherapy. However, the clinical significance of such therapies is still unclear because the contents of anticancer agents and radiotherapy were different in each patient.

The extensive fibrotic changes in the bile duct wall and periductal area are also characteristics of patients with occupational cholangiocarcinoma 2, 4, 5, 20. In one patient (patient no. 7), hepatic fibrosis progressed gradually after the operation and eventually hepatic failure developed although the exposure to chlorinated organic solvents had ended 3 years and 2 months before the operation 15. The clinical course of the patient indicated that chlorinated organic solvents caused the progression of fibrosis even after the end of the exposure. The mechanism of such progress of fibrosis should be clarified.

In conclusion, it is sometimes difficult to perform curative resection for occupational cholangiocarcinoma because of extensive tumor invasion and the presence of precancerous or early cancerous lesions such as BilIN and IPNB at the various sites of the large bile ducts. The incidence of postoperative complications such as intraabdominal infection seemed to be high. The recurrence from multicentric origin occurred after surgery in some patients because the bile ducts have a high potential for carcinogenesis due to the presence of precancerous or early cancerous lesions such as BilIN and IPNB at the various sites of the bile ducts. The aggressive treatment including second resection for such multicentric recurrences appeared to be effective, although the clinical significance of adjuvant chemotherapy is still unclear.

Conflict of interest

None declared.

Author contributions

Study design: Kubo S. Acquisition of data: Kubo S, Takemura S, Tanaka S, Shinkawa H, Kinoshita M, Hamano G, Ito T, Yamamoto T, Terajima H, Tachiyama G, Yamada T, Nakamori S, Arimoto A, Fujikawa M, Tomimaru Y, Sugawara Y, Nakagawa K, Unno M, Mizuguchi T, Takenaka K, Kimura K, Shirabe K, Saiura A, Uesaka K, Taniguchi H, and Fukuda A. Pathological aspects of the study: Yamamoto T, Sato Y, and Nakanuma Y. Data analysis: Kubo S, Kinoshita M, Hamano G, Sato Y, and Nakanuma Y. Manuscript drafted: Kubo S. All authors reviewed the manuscript.