Background
Pancreatic cancer (PC) is one of the most aggressive diseases among digestive system malignancies. With both high incidence and mortality rate, it is responsible for the fourth leading cause of cancer in the USA [
1]. Though less common in developing countries, the mortality rate of PC has been keeping increasing in the past decades and reached the sixth place among all malignancies in China [
2]. Radical surgery, which is the only possible way to cure the disease, can be conducted in only about 20% patients. Approximately 60% patients are found to have metastases at the time of diagnosis [
3]. Palliative treatments, mainly chemotherapy, radiotherapy, interventional therapy and immunotherapy, contribute limited survival benefit.
The prevalence of hepatitis B virus (HBV) infection is common worldwide, while the infection rate is especially high in some developing countries, including China [
4]. It used to be one of the major public health problems in China, where 58.2% of the population had ever suffered from the infection of HBV in the 1980s. Since the introduction of universal infant immunization policy, the HBV carrier rate had dropped from 9.75% in 1992 to 7.18% in 2006 among the general Chinese population [
5]. HBV infection has been demonstrated to play an important role in the development of hepatocellular carcinoma (HCC) and cholangiocarcinoma [
6,
7]. In addition, there have been increasing reports about the existence of HBV in extrahepatic tissues, such as pancreas, kidneys, skin, bone marrow, colon, lymph nodes, and vessel walls [
8,
9], with the manifestation of various severities of extrahepatic symptoms [
10]. Moreover, there’re also investigations indicating that HBV infection is associated with a higher risk of some extrahepatic malignancies, including PC and non-Hodgkin’s lymphoma [
11‐
15]. Some studies further presented a hypothetical mechanism of the development of PC with HBV infection: a multistep process from pre-neoplastic pancreatic lesions to invasive cancer resulted from persistent inflammation in the pancreas caused by HBV infection [
16].
There are some reports available regarding the influence of HBV infection on metastatic pattern of colorectal cancer (CRC). Interestingly, compared with patients not infected with HBV, hepatic metastasis rate was shown to be decreased while the extrahepatic metastasis rate elevated in patient infected with HBV [
17,
18], and in HCC with HBV infection, multiple occurrences happened more frequently than intrahepatic metastasis [
19], suggesting HBV infection might play an important role in the progression of some extrahepatic malignancies. In addition, studies showed that HBV infection also affected the survival of HCC and CRC patients [
17,
20]. However, the investigation about the impact of HBV infection on metastatic pattern is still blank, and the influence of different HBV infection status on survival in PC has not been fully studied. Thus, we embarked on this study to evaluate whether HBV infection status was associated with metastatic pattern and survival in PC.
Discussion
Our research found that the incidence of synchronous liver metastasis of pancreatic cancer (PC) was higher in patients with HBsAg positive than those negative, while no significant difference of extrahepatic metastasis was found between the two groups. Compared with non HBV infection group, only chronic hepatitis B (CHB) group was demonstrated to have significant higher rate of liver metastasis, which indicated that HBV infection with active replication had the greatest influence on liver metastasis of PC. What’s more, CHB and non HBV infection group showed significant better overall survival than IC group, indicating HBV infection status to be an independent prognostic factor in PC patients.
There were mounts of studies investigating the impact of HBV infection on metastatic patterns of other malignancies. Incidence of liver metastasis was demonstrated to be significantly decreased, and extrahepatic metastasis significantly increased in colorectal cancer (CRC) patients with HBV infection than non-infection ones, and significance of the difference existed in all status of HBV infection, including CHB, IC, and resolved HBV infection [
18]. This impact had nothing to do with coexisting liver injury [
17]. In hepatocellular carcinoma (HCC) with HBV infection, multiple occurrences happened more frequently than intrahepatic metastasis [
19]. To date, our study was the first report about influence of HBV infection on metastatic pattern of PC. We found that compared with non HBV infection group, only chronic HBV infection group (CHB) showed a significant higher liver metastasis rate. Thus, it can be concluded that the impacts of HBV infection on liver metastasis vary in different malignancies. Tumor progression was pushed by intrinsic mutations and influenced by the microenvironment [
23]. Although before tumor cell implantation, the microenvironment in the liver might share much similarity, the differences of tumor intrinsic properties and the microenvironment nurtured by the interaction between tumor cells and surroundings after preliminary implantation would result in discriminated outcomes. Besides, HBV infection had been proved to be one of the risk factors in PC [
11,
12], and HBV DNA and antigens were identified in PC tissues [
24]. Moreover, both liver and pancreas progenitors had the same origin of the endoderm cells in the embryonic foregut [
25,
26], and the two organs shared the same conduct for external secretion and blood vessels. It was reasonable to postulate that the current understanding of the relationship between liver, pancreas, and HBV infection was only a tip of the iceberg. It was also reasonable to assume that developed from an HBV infected microenvironment with persistent inflammation, PC cells might have a predilection for the analogous hepatic nest infected with HBV. Furthermore, HBV proteins were able to trigger the self-maintaining and amplifying looped generation of certain cytokines in liver, such as prostaglandin E2 (PGE2) and growth factors, which activated cell signal pathways, and promoted growth of cancer cells [
27,
28]. While current study concentrating on the correlation between HBV and PC were mainly restricted in epidemiologic investigation and carcinogenesis mechanism, regarding HBV infection as a risk factor of PC, perhaps further attention should also be paid to understand how HBV infection affects PC progression.
HBV infection was proved to have more or less influence on survival in some malignancies. Hatanaka K, et al. found the survival of HCC patients infected with HBV to be the poorest compared with patients infected with HCV or non HBV/HCV [
20]. In terms of CRC, previous studies didn’t reach consistent conclusion about the survival impact of HBV infection [
17,
18,
29]. Concerning the impact of HBV infection on PC in our study, both CHB and non HBV infection group had significantly longer OS compared with IC group in multivariate analysis.
It was interesting that different HBV infection status showed differences in the overall survival in PC patients. The results that patients infected with actively replicative HBV (CHB group) showed better survival than inactive HBsAg carriers (IC group), and patients classified into resolved HBV infection had no significant OS difference compared with inactive HBsAg carriers (IC group) might seem to be somewhat confusing. Here we listed some explanation for the results of survival analysis in our research.
Firstly, HBV antigens might influence the overall survival in PC patients. Some previous studies gave us clues. HBsAg, which existed in CHB and IC groups, was found to down-regulate the production of interleukin-12 (IL-12), a cytokine which was identified to possess the anti-cancer power [
30]. However, the expression of HBeAg in liver cells was demonstrated to be associated with more serious liver cell damage, and enhanced production of inferferon (IFN)-gamma [
31,
32]. Considering the HBeAg expression was also demonstrated to exist in PC tissues with HBV infection [
24], such mechanism might likewise contribute to anti-pancreatic cancer cell activity. These findings partly explained why CHB group (with both HBeAg and HBsAg positive) showed better survival than IC group (with HBsAg positive and HBeAg negative), although patients in CHB group had active HBV proliferation, which might bring liver dysfunction and make patients’ condition worse. It could also partly explain why IC group showed worse survival than non HBV infection group.
Secondly, starting from the time they received chemotherapy, patients with active HBV infection in our center were routinely given anti-HBV therapy to control the activation of HBV and prevent the outbreak of hepatitis B virus. Anti-HBV drugs were shown to have immunoregulatory effects [
33] and might also influence the anti-cancer effectiveness of the immune system.
Thirdly, HBV was hepatotrophic virus and active HBV replication in liver cells triggered the immune response, mainly cellular immunity, which induced the death of liver cells and caused hepatic fibrosis. Because HBV was also demonstrated to be existed in PC tissues, such immune response acted on liver cells might also work on pancreatic cancer cells. Here we would like to share a case reported by Fujimoto, K, et al. They reported a case of complete remission of splenic marginal zone lymphoma after an acute flare-up of hepatitis B in a hepatitis B virus carrier [
34]. There were studies finding HBV to be a risk factor for non-Hodgkin lymphoma, and HBV infection was also found to be existed in B-cell non-Hodgkin lymphoma tissues [
35]. The case reported might be an extreme example of the possible mechanism we listed above to kill the cancer cells in which HBV replicate actively.
Last but not the least, patients in resolved HBV infection group and IC group showed no significant difference in OS. This conclusion was hard to explain since patients in resolved HBV group might possess a more effective immune system, thus shall have a better survival than patients in IC group. Because the P value (0.073) in the multivariate analysis of “resolved HBV group vs IC group” was quite close to the cut point of 0.05 we set and the sample size for survival analysis was relatively small (41 for IC group, and 123 for resoled HBV infection group), there was a possibility that our research didn’t reach the existed difference between the two groups. But, there were also possible small number of inactive HBV infection cases in the “resolved HBV infection” group we defined according to the serum test result, depending on the sensitivity of the serum test for HBV infection, and they might confound the result of survival analysis between the two groups.
To summarize, the mechanism of how different HBV infection status affect the progression of PC was still not clear, more researches about the clinical data and laboratory mechanism are both needed.
There were some limitations in our study. To start with, our data was retrospectively collected from medical records, considering inevitably missed information about progress free survival (PFS) and disease free survival (DFS) during follow up, we didn’t introduce PFS or DFS into analysis. In addition, we investigated the impact of HBV infection only on synchronous metastasis, owning to our concern about imprecision of the information about metachronous metastasis. However, the information about synchronous metastasis was qualified, because we collected it from the medical records of first visit of patients, for each of them, a chest, abdominal and pelvic CT or MRI were conducted and evaluated by imaging specialists, and those underwent surgery were further evaluated by surgeons during operations. What’s more, we enrolled PC patients in all tumor stages, which was an aggregation of PC patients with metastasis all along the disease progress, thus the result of our study was in line with the metastasis status of general PC population. Last but not least, although we collected cases from the time duration of more than 10 years, the number of cases in each group was still limited, more data and work are needed in future.
In conclusion, our study discovered that the incidence of liver metastasis in PC patients with HBsAg positive was higher than those with HBsAg negative. Compared with patients with no history of HBV infection and those with resolved HBV infection, chronic HBV infection promoted liver metastasis in PC. What’s more, patients with chronic HBV infection and non HBV infection had significantly better overall survival compared with inactive HBsAg carriers in pancreatic cancer.
Competing interests
We have no financial or personal relationships with other people or organizations that would bias our work. No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of our article. We declare that we have no competing interests.
Authors’ contributions
XLW and MZQ participated in the clinical data collecting of the pancreatic cancer patients and drafted the manuscript. XLW and WWC performed the statistical analysis. YJ, CR, FHW and FW participated in the design of the study. HYL, ZQW, DSZ and YHL participated in the statistical analysis. RHX conceived of the study, participated in the design and coordination and helped to draft the manuscript. All authors read and approved the final manuscript.