|Year : 2017 | Volume
| Issue : 5 | Page : 756-760
Role of surgical treatment for hepatolithiasis-associated intrahepatic cholangiocarcinoma: A retrospective study in a single institution
Jian Xiao, Jisheng Zhu, Zhanying Liu, Renhua Wan, Yong Li, Weidong Xiao
Department of General Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
|Date of Web Publication||13-Dec-2017|
Department of General Surgery, The First Affiliated Hospital of Nanchang University, No. 17, Yongwai Zhengjie, Nanchang 330006, Jiangxi
Source of Support: None, Conflict of Interest: None
Context: The extent of hepatectomy and lymph node dissection (LND) in the treatment of hepatolithiasis-associated intrahepatic cholangiocarcinoma (HL-iCCA) is still controversial.
Aims: The aim of this retrospective study was to evaluate the role of surgical treatment for HL-iCCA.
Methods: The clinical data of 63 patients with HL-iCCA who undergoing surgery between January 2005 and December 2015 were analyzed retrospectively.
Statistical Analysis Used: All data were analyzed by the SPSS 17.0 software program (IMB Inc., Chicago, IL, USA). Survival curves were analyzed by the Kaplan–Meier method and compared by the Log-rank test. A P < 0.05 was considered statistically significant.
Results: Forty-nine patients (77.8%) underwent surgical resection including 35 with LND and 14 without LND. The overall 1-, 3-, and 5-year survival rates were 58.1%, 28.2%, and 10.6%, respectively, and the median survival time was 19 months. The 1-, 3-, and 5-year survival rates of resection group were 78.9%, 36.3%, and 13.5%, respectively, while the 1-year survival rate of exploratory laparotomy group was 0 (P < 0.0001). The 1-, 3-, and 5-year survival rates of patients with LND were significantly superior to those of without LND (75.9%, 39.4%, and 20.2% vs. 71.4%, 17.9%, and 0, P = 0.043). According to the N status, the 1-, 3-, and 5-year survival rates of pN0 subgroup were 81.8%, 49.2%, and 28.1%; pN1 subgroup were 65.3%, 18.6%, and 0%; and pNx subgroup were 71.4%, 17.9%, and 0%, respectively (pN0 vs. pN1, P = 0.005; pN0 vs. pNx, P = 0.004; pN1 vs. pNx, P = 0.653). The 1-, 3-, and 5-year survival rates of R0 resection (n = 42) were 80.2%, 36.7%, and 14.9%, respectively, and those of R1 resection (n = 7) were 71.4%, 0%, and 0%, respectively (P = 0.028).
Conclusions: Radical resection is the most effective therapy for HL-iCCA. Regional lymphadenectomy is strongly recommended in resectable HL-iCCA, which is helpful in tumor staging and long-term survival.
Keywords: Hepatectomy, hepatolithiasis, intrahepatic cholangiocarcinoma, lymphadenectomy
|How to cite this article:|
Xiao J, Zhu J, Liu Z, Wan R, Li Y, Xiao W. Role of surgical treatment for hepatolithiasis-associated intrahepatic cholangiocarcinoma: A retrospective study in a single institution. J Can Res Ther 2017;13:756-60
|How to cite this URL:|
Xiao J, Zhu J, Liu Z, Wan R, Li Y, Xiao W. Role of surgical treatment for hepatolithiasis-associated intrahepatic cholangiocarcinoma: A retrospective study in a single institution. J Can Res Ther [serial online] 2017 [cited 2019 Nov 15];13:756-60. Available from: http://www.cancerjournal.net/text.asp?2017/13/5/756/220471
| > Introduction|| |
Intrahepatic cholangiocarcinoma (iCCA) is the second common primary hepatic tumor following hepatocellular carcinoma, which is a primary adenocarcinoma of the liver arising from the intrahepatic bile ducts. It is estimated that iCCA accounts for 5%–15% of primary liver cancers. Although it is a rare digestive system malignancy, its incidence is increasing steadily worldwide. Globally, the age-adjusted incidence of iCCA has risen from 0.32/100,000 to 0.85/100,000 over the past three decades. There are no specific etiological factors that have been identified for iCCA, and various established risk factors included hepatitis B virus and hepatitis C virus related liver diseases,, primary sclerosing cholangitis, hepatolithiasis, choledochal cysts, and exposure to certain toxins.,, In East Asian countries, hepatolithiasis and biliary parasitic infection are more common risk factors, whereas in Western countries, primary sclerosing cholangitis is the main risk factor.
Hepatolithiasis is defined as a gallstone disorder in the intrahepatic bile ducts, which is prevalent primarily in Southeast Asia. Long-term of hepatolithiasis may cause secondary biliary stricture, liver cirrhosis, and even cholangiocarcinoma. It is estimated that 5%–10% of hepatolithiasis is known to be associated with iCCA. Since the symptoms and signs of hepatolithiasis-associated iCCA (HL-iCCA) are vague and nonspecific, most patients are treated at an advanced stage with a poor prognosis. In recent years, aggressive surgical treatment has improved the long-term survival in selected patients with HL-iCCA. However, the extent of hepatectomy and lymph node dissection (LND) in the treatment of HL-iCCA is still controversial. The aim of this retrospective study was to evaluate the role of surgical treatment of HL-iCCA at a single institution over 10 years.
| > Methods|| |
A total of 1528 consecutive patients underwent surgical procedures for hepatolithiasis, and 63 patients associated with iCCA were confirmed by postoperative pathology at our institution between January 2005 and December 2015. There were 19 men and 44 women with a median age of 57 years (range 38–77 years). Forty-one (65.1%) patients had a history of hepatolithiasis >1 year (≥10 years: 27 patients, 5–10 years: 6 patients, 1–5 years: 8 patients, and ≤1 year 22 patients). Abdominal pain was the most common symptom (76.2%, 48/63), followed by fever and chills (39.7%, 25/63), nausea or vomiting (20.6%, 13/63), and jaundice (17.5%, 11/63). Twenty-four patients had undergone previous surgery for cholelithiasis.
Serum carbohydrate antigen 19–9 (CA19–9) was elevated in 50 (79.4%) patients, carbohydrate antigen 125 (CA125) was elevated in 31 (49.2%) patients, and carcinoembryonic antigen (CEA) was elevated in 25 (39.7%) patients. The mean value of CA19–9, CA125, and CEA was 376.3 U/mL (normal range 0–27 U/mL), 86.14 U/mL (normal range 0–35 U/mL), and 14.7 ng/mL (normal range 0–6.5 ng/mL), respectively. Serum alpha fetoprotein was elevated in four patients (6.3%). The preoperative diagnostic coincidence rates of abdominal ultrasonic, computed tomography, and magnetic resonance imaging were 66.1% (37/56), 77.2% (44/57), and 87.8% (43/49), respectively. Fifty-five (87.3%) patients were preoperatively diagnosed, and 8 (12.7%) patients were intraoperatively diagnosed. All tumors were near or at the site of the stones, which located at the left liver in 48 (76.2%) patients and the right liver in 15 (23.8%) patients. The mean size of tumor was 5.6 cm in diameter, varying from 3.3 to 10.4 cm.
Forty-nine (77.8%) patients underwent surgical resection. The main surgical procedures included hepatectomy, choledocholithotomy, LND, and extrahepatic bile duct resection [Table 1]. The extent of regional lymphadenectomy is according to the origination of tumor. For the left hemiliver, lymphadenectomy included stations 1, 3, 7, 8a, 9, 12a, 12b, 12p lymph nodes (LNs) and 8a, 9, 12a, 12b, 12p, 13 LNs when iCCA originating from the right hemiliver. Fourteen (22.2%) patients underwent exploratory laparotomy and biopsy because of extrahepatic metastasis.
The most common morphological type was mass-forming (MF) (61.9%, 39/63), followed by periductal infiltrating (PI) (22.2%, 14/63), intraductal growing (7.9%, 5/63), and MF + PI (7.9%, 5/63). Forty-seven patients were moderately or poorly differentiated adenocarcinoma, 12 well differentiated, and 4 undifferentiated. Among these 49 patients undergoing surgical resection, 13 were positive lymph node metastasis (LNM) (pN1), 22 negative LNM (pN0), and 14 unknown (pNx). According to the 7th Edition American Joint Committee on Cancer TNM staging system, 10 patients were Stage I, six II, six III, 13 IVa, 14 IVb, and 14 unknown. In patients with LND, the median number of LNs harvested was six nodes (3–15 nodes). R0 resection was defined as negative resection margin observed during histopathological examination. As a result, 42 patients achieved R0 resection, and seven were R1 resection in the resection group.
The survival was measured from the day of operation until death because of cancer or unrelated diseases or the last day of follow-up. All data were analyzed by the SPSS 17.0 software program (IMB Inc., Chicago, IL, USA). Survival curves were analyzed by the Kaplan–Meier method and compared by the Log-rank test. A P < 0.05 was considered statistically significant.
| > Results|| |
The postoperative complications included incisional infection in two patients, biliary leakage in four patients, and one of whom died of hepatic failure, pleural effusion in five patients. The total morbidity was 17.4% (11/63), and the mortality was 1.6% (1/63). The mean postoperative hospital stay was 11.7 ± 3.7 days (range 6–20 days).
By the end of follow-up in June 2016, the mean follow-up time was 24.9 months. The survival rate and median survival time for different groups are shown in [Table 2]. The overall 1-, 3-, and 5-year survival rates were 58.1%, 28.2%, 10.6%, respectively, and the median survival time was 19 months [Figure 1]a. The 1-, 3-, and 5-year survival rates of resection group were 78.9%, 36.3%, and 13.5%, respectively, while the 1-year survival rate of exploratory laparotomy group was 0 [P < 0.0001, [Figure 1]b. The median survival time of resection group and exploratory laparotomy group was 29 and 6 months, respectively. The 1-, 3-, and 5-year survival rates of patients with LND and without LND were 75.9%, 39.4%, and 20.2% and 71.4%, 17.9%, and 0, respectively [P = 0.043, [Figure 2]a. The median survival time of patients with LND and without LND was 35 and 21 months, respectively. According to the N status, the 1-, 3-, and 5-year survival rates of pN0 subgroup were 81.8%, 49.2%, and 28.1%; pN1 subgroup were 65.3%, 18.6%, and 0%; and pNx subgroup were 71.4%, 17.9%, and 0%, respectively [pN0 vs. pN1, P = 0.005; pN0 vs. pNx, P = 0.004; pN1 vs. pNx, P = 0.653, [Figure 2]b. The median survival time of pN0, pN1, and pNx subgroups was 36, 18, and 21 months, respectively. The 1-, 3-, and 5-year survival rates of R0 and R1 resection were 80.2%, 36.7%, and 14.9% and 71.4%, 0, and 0, and the median survival time was 33 and 19 months, respectively [P = 0.028, [Figure 2]c.
|Figure 1: (a) Survival curves for all patients. (b) Survival curves for resection or not (*resection group, **laparotomy group)|
Click here to view
|Figure 2: (a) Survival curves for with LND or not. (b) Survival curves according to the N status. (c) Survival curve for R0 and R1 resection|
Click here to view
| > Discussion|| |
Hepatolithiasis is an established risk factor for iCCA, probably through repeated mechanical injury and inflammation of the intrahepatic biliary tract epithelium. Although hepatolithiasis are known to be associated with iCCA, only few literature involved the diagnosis and treatment of HL-iCCA.,, Zhu et al. reported 107 patients of hepatolithiasis combined with cholangiocarcinoma; the overall survival rates were 45.4%, 29.8%, and 20.2% at 1, 3, and 5 years, and the cumulative survival rates in the curative resection group (n = 38) at 1, 3, and 5 years were 71.1%, 57.9%, and 50.0%. Herein, we present a series of 63 patients with HL-iCCA, the resection rate was 77.8%, and the overall 1-, 3-, and 5-year survival rates were 58.1%, 28.2%, and 10.6%, respectively.
Radical resection with histologically negative margin remains the only curative option for patients with iCCA,,, and the basic principle of treatment for HL-iCCA is same to that for iCCA alone. Depending on the size and location of lesions, different types of anatomical hepatectomy are the major procedure. Sometimes, the extrahepatic biliary resection should be performed to obtain negative microscopic margin. Yeh et al. reported that the median survival time of R0, R1, and R2 resection was 26.1, 11.4, and 5.8 months in patients with iCCA, and the 5-year survival rate was 28.6%, 4.5%, and 0, respectively. Hepatic margin plays an important role in the surgical treatment of iCCA because it is the most location of tumor remnant and recurrence. Even in patients with an R0 resection, the prognosis of patients with negative hepatic margin width >1 cm was significantly better than those of 1–4 mm and 5–9 mm. However, Tamandl et al. pointed out that there were no significant statistical differences between the wide margin (>10 mm) and close margin (1–10 mm) on survival and recurrence as long as complete tumor clearance. Therefore, the safety hepatic margin width is still not fully defined. Regarding as the incidence of satellite lesions is high to 40% and the infiltrating growth characteristics of iCCA, most hepatobiliary centers prefer to perform hemihepatectomy or extended hemihepatectomy than atypical liver resection to achieve negative histological margins., In Europe, the resection rate of iCCA was 51%–87% with 63%–86% R0 resection rate, and the 5-year survival was 20%–31%. In the present study, 98% of patients underwent at least two-segment hepatectomy and five patients combined resection of extrahepatic bile duct. As a result, 66.7% of all patients achieved R0 resection and the 1-, 3-, and 5-year survival rates were 80.2%, 36.7%, and 14.9%, which were significantly superior to R1 resection.
LNM is an important negative prognosis factor of iCCA. In an analysis of 658 iCCA patients in whom histologic regional LN evaluation was performed, the 5-year overall survival of node-negative patients was significantly better than node-positive patients (19.3% vs. 3.7%, P < 0.001). A systematic review showed that the 3- and 5-year survival rates of iCCA without LNM (n = 413) were 55.6% and 45.1%, while those of with LNM (n = 343) were only 0.2% and 0%, respectively. Despite this, the real role of routine lymphadenectomy is still controversial. Regional LND was commonly performed at hepatobiliary centers in Japan, while it is rarely performed in Western countries. Recent data from the National Cancer Institute's SEER Registry show that only 55% of patients have pathologic evaluation of at least one regional LN. Some investigators suggested that routine LND for iCCA did not show survival benefit.,, For example, Kim et al. reported 215 patients with iCCA who under liver resection during the year 1995–2012. For these 113 patients with LND, in whom the mean number of harvested LNs was 12.8 ± 8.0 (range 4–51) and the mean number of involved LNs was 2.4 ± 3.6 (range 0–18), the median overall survival was 27.6 compared with 35.9 months for patients without LND (P = 0.101). The cumulative 1-, 3-, and 5-year survival rates of LND group were 67.7%, 45.5%, and 30.0%, and those of without LND group were 74.3%, 47.8%, and 42.5%, respectively. Nevertheless, there are still many investigators holding opposite opinions. In a study encompassing 248 patients with iCCA who underwent lymphadenectomy, 74 (30%) of these had LNM. Bagante et al. reported 561 patients undergoing liver surgery for iCCA, 45.2% of patients who underwent LND had LNM, and the disease-specific survival was worse among patients compared with N0 patients within 18 months after surgery (N0 vs. Nx, 70.2% vs. 60.6%, P = 0.019). Because of its prognostic relevance and high incidence, many investigators have argued in favor of routine LND in resectable iCCA. Regarding the extent of LND, the ideal lymphadenectomy should include all regional nodal stations. According to the expert consensus advice, the hepatoduodenal ligament lymph node and the hepaticartery lymph node are the first lymph nodes to be involved in the metastatic process and should be removed in all patients. Moreover, for iCCA originating in the right hemiliver, the retropancreatic LNs is recommended to routine removal, and for iCCA originating from the left hemiliver, the nodes around the cardiac portion of the stomach and along the lesser curvature should also be removed. Nevertheless, there is no specific evidence for the minimum number of LNs required to facilitate accurate staging up to now. In the present study, 35 patients underwent regional LND with a median of six LNs per patient retrieved, and the positive rate of LNM was 37.1%. Meanwhile, our results showed that the survival of patients with LND was significantly superior to those of without LND, and the survival of pN0 was also significantly superior to those of pN1 and pNx. Furthermore, without LND, nodal assessment is incomplete, and the essential component of TNM staging is compromised in 14 patients. Taken together, we recommended regional lymphadenectomy in resectable HL-iCCA.
| > Conclusions|| |
Radical resection is the most effective therapy for HL-iCCA. Regional lymphadenectomy is strongly recommended in resectable HL-iCCA, which is helpful in tumor staging and long-term survival. Nevertheless, this study is only a single-institution retrospective study with limited cases. Additional large-scale, multicenter randomized controlled trials are still needed to further define the standard treatment for HL-iCCA.
Financial support and sponsorship
This research was supported by the Graduate Student Innovation Special Fund Project of Nanchang University, No.cx2016341.
Conflicts of interest
There are no conflicts of interest.
| > References|| |
Gil E, Joh JW, Park HC, Yu JI, Jung SH, Kim JM, et al.
Predictors and patterns of recurrence after curative liver resection in intrahepatic cholangiocarcinoma, for application of postoperative radiotherapy: A retrospective study. World J Surg Oncol 2015;13:227.
Sakamoto Y, Kokudo N, Matsuyama Y, Sakamoto M, Izumi N, Kadoya M, et al.
Proposal of a new staging system for intrahepatic cholangiocarcinoma: Analysis of surgical patients from a nationwide survey of the Liver Cancer Study Group of Japan. Cancer 2016;122:61-70.
Lubezky N, Facciuto M, Harimoto N, Schwartz ME, Florman SS. Surgical treatment of intrahepatic cholangiocarcinoma in the USA. J Hepatobiliary Pancreat Sci 2015;22:124-30.
Li H, Hu B, Zhou ZQ, Guan J, Zhang ZY, Zhou GW, et al.
Hepatitis C virus infection and the risk of intrahepatic cholangiocarcinoma and extrahepatic cholangiocarcinoma: Evidence from a systematic review and meta-analysis of 16 case-control studies. World J Surg Oncol 2015;13:161.
Li L, Lan X. Association between hepatitis B virus/hepatitis C virus infection and primary hepatocellular carcinoma risk: A meta-analysis based on Chinese population. J Cancer Res Ther 2016;12:C284-7.
Guo L, Mao J, Li Y, Jiao Z, Guo J, Zhang J, et al.
Cholelithiasis, cholecystectomy and risk of hepatocellular carcinoma: A meta-analysis. J Cancer Res Ther 2014;10:834-8.
Brown KM, Parmar AD, Geller DA. Intrahepatic cholangiocarcinoma. Surg Oncol Clin N
Zhou YM, Yin ZF, Yang JM, Li B, Shao WY, Xu F, et al.
Risk factors for intrahepatic cholangiocarcinoma: A case-control study in China. World J Gastroenterol 2008;14:632-5.
Liu ZY, Zhou YM, Shi LH, Yin ZF. Risk factors of intrahepatic cholangiocarcinoma in patients with hepatolithiasis: A case-control study. Hepatobiliary Pancreat Dis Int 2011;10:626-31.
Cai H, Kong WT, Chen CB, Shi GM, Huang C, Shen YH, et al.
Cholelithiasis and the risk of intrahepatic cholangiocarcinoma: A meta-analysis of observational studies. BMC Cancer 2015;15:831.
Bridgewater J, Galle PR, Khan SA, Llovet JM, Park JW, Patel T, et al.
Guidelines for the diagnosis and management of intrahepatic cholangiocarcinoma. J Hepatol 2014;60:1268-89.
Li HY, Zhou SJ, Li M, Xiong D, Singh A, Guo QX, et al.
Diagnosis and cure experience of hepatolithiasis-associated intrahepatic cholangiocarcinoma in 66 patients. Asian Pac J Cancer Prev 2012;13:725-9.
Guglielmi A, Ruzzenente A, Valdegamberi A, Bagante F, Conci S, Pinna AD, et al.
Hepatolithiasis-associated cholangiocarcinoma: Results from a multi-institutional national database on a case series of 23 patients. Eur J Surg Oncol 2014;40:567-75.
Zhu QD, Zhou MT, Zhou QQ, Shi HQ, Zhang QY, Yu ZP, et al.
Diagnosis and surgical treatment of intrahepatic hepatolithiasis combined with cholangiocarcinoma. World J Surg 2014;38:2097-104.
Bektas H, Yeyrek C, Kleine M, Vondran FW, Timrott K, Schweitzer N, et al.
Surgical treatment for intrahepatic cholangiocarcinoma in europe: A single center experience. J Hepatobiliary Pancreat Sci 2015;22:131-7.
Ellis MC, Cassera MA, Vetto JT, Orloff SL, Hansen PD, Billingsley KG, et al.
Surgical treatment of intrahepatic cholangiocarcinoma: Outcomes and predictive factors. HPB (Oxford) 2011;13:59-63.
Yeh CN, Hsieh FJ, Chiang KC, Chen JS, Yeh TS, Jan YY, et al.
Clinical effect of a positive surgical margin after hepatectomy on survival of patients with intrahepatic cholangiocarcinoma. Drug Des Devel Ther 2015;9:163-74.
Spolverato G, Yakoob MY, Kim Y, Alexandrescu S, Marques HP, Lamelas J, et al.
The impact of surgical margin status on long-term outcome after resection for intrahepatic cholangiocarcinoma. Ann Surg Oncol 2015;22:4020-8.
Tamandl D, Herberger B, Gruenberger B, Puhalla H, Klinger M, Gruenberger T, et al.
Influence of hepatic resection margin on recurrence and survival in intrahepatic cholangiocarcinoma. Ann Surg Oncol 2008;15:2787-94.
de Jong MC, Nathan H, Sotiropoulos GC, Paul A, Alexandrescu S, Marques H, et al.
Intrahepatic cholangiocarcinoma: An international multi-institutional analysis of prognostic factors and lymph node assessment. J Clin Oncol 2011;29:3140-5.
Spolverato G, Kim Y, Alexandrescu S, Popescu I, Marques HP, Aldrighetti L, et al.
Is hepatic resection for large or multifocal intrahepatic cholangiocarcinoma justified? Results from a multi-institutional collaboration. Ann Surg Oncol 2015;22:2218-25.
Clark CJ, Wood-Wentz CM, Reid-Lombardo KM, Kendrick ML, Huebner M, Que FG, et al.
Lymphadenectomy in the staging and treatment of intrahepatic cholangiocarcinoma: A population-based study using the national cancer institute SEER database. HPB (Oxford) 2011;13:612-20.
Amini N, Ejaz A, Spolverato G, Maithel SK, Kim Y, Pawlik TM, et al.
Management of lymph nodes during resection of hepatocellular carcinoma and intrahepatic cholangiocarcinoma: A systematic review. J Gastrointest Surg 2014;18:2136-48.
Uenishi T, Yamamoto T, Takemura S, Kubo S. Surgical treatment for intrahepatic cholangiocarcinoma. Clin J Gastroenterol 2014;7:87-93.
Marubashi S, Gotoh K, Takahashi H, Ohigashi H, Yano M, Ishikawa O, et al.
Prediction of the postoperative prognosis of intrahepatic cholangiocarcinoma (ICC): Importance of preoperatively-determined anatomic invasion level and number of tumors. Dig Dis Sci 2014;59:201-13.
Morine Y, Shimada M, Utsunomiya T, Imura S, Ikemoto T, Mori H, et al.
Clinical impact of lymph node dissection in surgery for peripheral-type intrahepatic cholangiocarcinoma. Surg Today 2012;42:147-51.
Kim DH, Choi DW, Choi SH, Heo JS, Kow AW. Is there a role for systematic hepatic pedicle lymphadenectomy in intrahepatic cholangiocarcinoma? A review of 17 years of experience in a tertiary institution. Surgery 2015;157:666-75.
Bagante F, Gani F, Spolverato G, Xu L, Alexandrescu S, Marques HP, et al.
Intrahepatic cholangiocarcinoma: Prognosis of patients who did not undergo lymphadenectomy. J Am Coll Surg 2015;221:1031-40.e1.
Weber SM, Ribero D, O'Reilly EM, Kokudo N, Miyazaki M, Pawlik TM, et al.
Intrahepatic cholangiocarcinoma: Expert consensus statement. HPB (Oxford) 2015;17:669-80.
[Figure 1], [Figure 2]
[Table 1], [Table 2]