Prognosis of the intrahepatic cholangiocarcinoma after resection: hepatitis B virus infection and adjuvant chemotherapy are favorable prognosis factors

Intrahepatic cholangiocarcinoma (ICC) is the second most common form of primary hepatic tumor accounting for 3.3% of all such cancers. It originates from epithelial cells located in the intrahepatic bile duct or at the end of the bile duct. The incidence and mortality associated with ICC are increasing in many countries [1]. Due to the lack of typical symptoms that define early stage disease, many patients present with lymph node metastasis at the time of diagnosis. These patients are not suitable candidates for hepatic resection which is the only therapy associated with prolonged survival [2]. Consequently prognosis is generally poor.

Recent studies have identified HBV infection as an independent risk factor for ICC [3, 4]. However the impact of HBV infection on the outcome ICC remains unclear [5, 6]. In the present study we investigated the impact of HBV infection on the survival of patients undergoing surgical resection for ICC. Generally speaking, anti-hepatitis B core (HBc)-positivity alone is either indicative of previous HBV infection or the disappearance of hepatitis B surface antigen (HBsAg). Anti-HBs, therefore, provides evidence of recent infection, and acts as a sentinel marker for HBV infection (HBsAg carrier). Occult HBV infection is sometimes identified by molecular techniques even in patients who show HBsAg seronegativity [7, 8]. However, previous hepatitis B vaccination does not result in anti-HBc, because the components of hepatitis B vaccine do not relate to hepatitis B core antigen (HBcAg). Thus, the consensus is that anti-HBc + alone indicates current or previous HBV infection, while anti-HBs positivity is indicative of previous infection or injection of HBV vaccine.

Much controversy surrounds the use of adjuvant chemotherapy for ICC. Most data come from small, uncontrolled trials that include cases of gallbladder, pancreatic and biliary system carcinoma [9], making it difficult to draw meaningful conclusions regarding efficacy. In addition, there is no consensus about standard chemotherapy.

The prognosis of ICC remains poor and surgery offers the only chance of a clinical cure [2]. Although many traials have reported that cytokine-induced killer (CIK) cell therapy is safety and effective for hepatocellular carcinoma [10], its use in ICC requires further study.

The overall 1- and 3-year survival rate for our series of 81 patients (51% and 20%, respectively) was lower than that reported by other recent studies [5, 6, 11]. The reasons for poor survival in our study were related to the fact that approximately 26.0% of patients were not well enough to undergo radical surgery. In addition, 61.7% presented with lymphatic metastasis, 38.3% had intrahepatic metastasis and between 35.8% and 71.6% patients had abnormal liver function at the time of diagnosis.

We showed that HBV infection or vaccine prior to surgery were favorable prognostic factors for survival after resection. Patients with occult HBV infection represented by HBsAg + or anti-HBc + (n = 37) and those who had undergone vaccination (n = 21) had a better prognosis than patients without HBV infection or injection prior to surgery (n = 23). Multivariate analysis indicated that chronic HBV infection and anti-HBs positivity both acted as favorable prognostic factors for overall survival.

Previous studies have investigated the association between chronic HBV infection and ICC [3, 4]. However, the true impact of HBV on survival of patients with ICC remains unclear [5, 6]. It has been proposed that some of the mechanisms which underlie ICC related to HBV infection might be similar to those responsible for hepatocellular cancer (HCC) which accounts for the shared clinical features of ICC and HCC [12]. It has been speculated that ICC might originate from a hepatic precursor cell with a hidden multi-differentiation potential, that can be activated to proliferate and differentiate into mature hepatocytes or biliary cells [13]. It is also possible that fragments of HBV gene may integrate into the host genome, resulting in cellular transformation and recruitment of hepatocytes or cholangiocytes with oncogenic potential. Another possibility is that innate or acquired immune responses activated by current or recent HBV infection, might enhance antitumor activity against ICC. ICC associated with HBV infection, may activate immunologic memory arising from previous HBV infection and thereby strengthen antitumor immunity [14].

Vaccination is a protective strategy against HBV infection and the resulting immune responses may explain why prognosis was improved in patients who had been vaccinated. However, the exact mechanisms involved require further study.

The prognosis of ICC was associated with the presence or absence of HBV infection suggesting that the pathogenesis and tumor microenvironment were different in these subgroups of patients. Based on this finding, patients with HBV infection may be sensitive to antiviral or immunological therapy, which may contribute to the control of the disease.

The use of adjuvant chemotherapy and radiation in ICC remains controversial [15, 16]. Most previous studies of adjuvant chemotherapy in ICC are uncontrolled, with small sample sizes and include patients with gallbladder and pancreatic cancer making it difficult to draw clinically meaningful conclusion regarding efficacy. In previous studies, 5-FU based chemotherapy resulted in response rates of 8%-40%, and a median survival of 2 to 12 months. Gemcitabine-based chemotherapy is associated with response rates ranging from 8% to 60% and median survival times ranging from 6.5 to 16 months [9]. In present study, multivariate analysis identified adjuvant chemotherapy was an independent prognostic factor which was associated with an improved median survival of 15 months. This finding suggests that high risk patients with ICC should receive adjuvant chemotherapy.

In our study 18 patients received adjuvant chemotherapy including 12 who underwent transcatheter hepatic arterial chemoembolization (TACE) and six patients who received systemic venous antineoplastic therapy. Chemotherapy included 5-FU, cisplatin, gemcitabine, doxorubicine and oxaliplatin. The impact of individual chemotherapy regimens on prognosis and survival in patients with ICC requires further study in larger populations of patients.

High preoperative CA19-9 levels (> 37 U/ml) have been shown to influence overall survival of ICC patients after hepatic resection [17]. Serum CA19-9 has been shown to be associated to tumor burden [18] and levels > 1000 U/ml has been shown to be a negative prognostic factor for survival [19]. In our study, the median survival (12 months) among patients with preoperative CA19-9 level < 200 U/ml was far longer than that among patients with CA19-9 levels > 200 U/ml (8 months).

It has also been reported that high CA19-9 levels are significantly correlated with important histopathologic factors such as major vessel, bile duct, and perineural invasion. These findings indicate that high preoperative CA19-9 levels may predictof histopathologic invasiveness of ICC as well as poor survival [20].

Lymph node status has been shown to be of prognostic significance among patients without distant metastases [4, 5]. In a previous study 3- and 5-year survival rates were shown to be 40% and 25% respectively for patients with N0M0 disease compared to 21% and 4% respectively for those with N1M0 disease [21]. In our study, survival was compromised by the presence of lymph node metastasis as demonstrated by both univariate and multivariate analysis. In accordance with our findings lymphatic invasion has been shown to be an independent prognostic factor for survival, and a more important predictor for outcomes of ICC than lymph node metastasis [20].

Hepatolithiasis is a common disease in China, and 5% to 10% of cases of this condition are known to be associated with cholangiocarcinoma [22]. The clinicopathologic features of hepatolithiasis and hepatobiliary cancer (IHHCC) are similar, and the overall survival associated with IHHCC is poor [23]. In our study we found that the presence of intrahepatic duct stones was associated with improved postoperative survival. This observation was contrary to previous findings [5, 24] indicating that further research is needed to ascertain the underlying mechanism of action.

In our study, median survival was longer in patients undergoing radical resection (12 months) than in those receiving palliative resection (5 months). However, both survival times were lower than those previously reported (36 and 10 months, respectively) [16]. This may be related to the fact that only 60 (84.5%) of the 81 patients in the study received radical tumor resection.

In common with other studies we found that intrahepatic metastasis was a poor prognostic factor for survival [5, 11, 16]. Diabetes has also been reported to be a risk factor for the development of ICC [25]. In our study the relationship diabetes and the prognosis of ICC was unclear. However, we did demonstrate that ICC patients with diabetes had a very short survival time.

Prospective validation of our results based on a larger multicenter population is required before our findings can be applied to clinical practice. However, this initial analysis suggests that current or previous HBV infection or vaccination may be associated with significantly better prognosis than in patients without HBV infection. Our findings also highlight the need to improve early diagnostic accuracy in order to allow radical tumor resection in as many patients as possible. Adjuvant chemotherapy appears to prolong survival for patients unable to tolerate radical resection.