© 2013, Hepatobiliary Pancreat Dis Int. All rights reserved.

doi: 10.1016/S1499-3872(13)60090-9

 

 

Contributors: FS proposed the study and wrote the whole article.

Funding: None.

Ethical approval: Not needed.

Competing interest: No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.

 

 

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy, with a poor overall five-year survival. Its dismal prognosis, even after curative resection, depends on its advanced stage at diagnosis, early metastatic spread, aggressive biological behavior and inefficacy of available systemic therapies.^[1] To date, epidemiological studies have identified some risk factors for this cancer, including cigarette smoking habit, family history as well as high dietary fat consumption, alcohol abuse, diabetes mellitus, metabolic syndrome and chronic pancreatitis history.^[1] Nevertheless, the causes of this tumor remain largely unknown. Therefore, additional researches are required to improve our knowledge of PDAC etiology and pathogenesis and to identify further factors involved in the initiation and/or promotion of this disease. In recent years, the active role of chronic infections in the process of carcinogenesis has been widely recognized in several human malignancies. In particular, according to experimental and epidemiological data, it has been demonstrated that some viruses act as powerful oncogenic agents, such as Epstein-Barr virus (Burkitt's lymphoma, nose-pharyngeal cancer, 10% of gastric carcinoma cases),^[2] human herpesvirus 8 (Kaposi's sarcoma and some lymphoproliferative disorders),^[3] human papilloma virus (uterine cervix carcinoma in women),^[4] human immunodeficiency virus (Kaposi's sarcoma and some forms of non-Hodgkin lymphoma),^[5] hepatitis B virus (HBV) and hepatitis C virus (HCV) (liver cancer, some variants of non-Hodgkin lymphoma, some cases of cholangiocarcinoma).^[6-8] Surprisingly, since the 1980s although antigens and replicative forms of HBV and HCV have been detected in pancreatic tissue of patients with severe forms of chronic hepatitis or hepatocellular carcinoma^{[9, 10]} as well as the presence of HBV genome has been described in carcinomatous specimens obtained from the pancreas in some case reports^[11] and the causal role of HBV and HCV in human carcinogenesis has been well established, until few years ago no epidemiological or pathogenetic studies had been designed and performed with the primary aim to investigate the potential activity of these pathogens in PDAC development in a systematic way. The absence of an adequate planning of clinical trials and experimental studies in this field of research depended, at least in part, on the difficulty in the study of this organ. The anatomic localization of the pancreas in one of the least accessible regions of the abdominal cavity, the retroperitoneal space, as well as the small size of the precursor neoplastic lesions, unlikely detectable even with modern imaging techniques and bioptic procedures, have contributed to hinder researchers' work and have hampered our understanding and knowledge of possible factors and mechanisms involved in pancreatic carcinogenesis.^[12] Therefore, the potential link between infection caused by both hepatitis viruses and the probability of developing PDAC remained to be explored for a long time. In recent years, however, this topic has gained an increasing interest and in 2008 the first case-control study by Hassan and colleagues assessed the possible association between HBV or HCV infection and risk of PDAC.^[13] Starting from this research, further case-control and cohort studies have been carried out in a period ranging from 2009 to 2013 and most of them have been performed in Asian peoples and in particular in China.^[14-25] The hypothesis that HBV and HCV may be risk factors not only for hepatocellular carcinoma, but also for pancreatic carcinoma, has been supported by a substantial part of these researches, although it has not been confirmed by other trials. Several factors, such as heterogeneity in study design, end-points and sample size of participants, may help to explain the lack of univocal conclusions, concerning this assumption. Therefore, in the last two years, almost 4 meta-analyses have been carried out to quantitatively assess PDAC risk in subjects with HBV and/or HCV infection and to date their results have been published in medical journals. They are characterized by differences in study selection and end-points. In particular, all these 4 pooled-analyses evaluated the impact of HBV infection on pancreatic cancer risk,^[26-29] 3 of them included all available case-control and cohort studies performing this evaluation, both in full-text or in abstract form and without language restriction.^[26-28] On the other hand, one of them considered only researches in full-text and published in English.^[29] A variable number of cases and controls as well as of subjects enrolled in cohort studies were considered in each meta-analysis. Methodological quality evaluation of included researches was performed by means of Newcastle-Ottawa Quality Assessment Scale by all authors. Irrespective of the underlined differences, these pooled-analyses agree in their main conclusions: subjects with persistent HBV infection present an increased risk of PDAC versus individuals without previous exposure to HBV. In particular, serum HBsAg positivity has been associated with a significant higher probability to develop this malignancy in comparison with its absence. Reported pooled odds ratio (OR) risk and relative risk (RR) for PDAC development in HBsAg carriers have been equal to 1.60 (95% CI: 1.26-2.05)^[26] and 1.18 (95% CI: 1.04-1.33),^[29] respectively. However, no certain conclusions have emerged, when the data concerning patients with signs of previous HBV exposure have been considered for analysis. In particular, up to now it has been generally accepted that the detection of serum HBsAg^–/HBcAb⁺/HBsAb^– or HBsAg^–/HBcAb⁺/HBsAb⁺ patterns characterizes patients, who recovered completely from a HBV-related infection and their presence would indicate viral clearance. When these serum profiles have been correlated with the risk of PDAC, no significantly enhanced probability of developing this malignancy occurred. On the other hand, two meta-analyses have assessed whether a higher incidence of pancreatic cancer occurs in subjects with signs of "past exposure to HBV".^{[26, 27]} A significantly increased risk was observed in HBcAb⁺/HBsAb⁺ vs HBsAg^–/HBcAb^– individuals, with RR equals to 1.41 (95% CI: 1.06-1.87)^[27] and in HBcAb⁺/HBsAb^– vs HBsAg^–/HBcAb^– subjects, with OR equals to 1.76 (95% CI: 1.05-2.93).^[26] This apparent discrepancy among results may depend on the different types of antigen/antibodies patterns considered in some case-control studies and on the heterogeneity of observed results. In particular, it should be considered that two case-control researches detected an increased risk of PDAC in HBsAg^–/HBcAb⁺/HBsAb^– individuals,^{[13, 16]} whereas one did not.^[15] On the other hand, concerning HBsAg^–/HBcAb⁺/HBsAb⁺ profile, two case-control studies showed an enhanced probability to develop this malignancy,^{[13, 15]} whereas one did not.^[16] Therefore, according to an increasing number of researches available in the literature, our previous concept that HBsAg^–/HBcAb⁺/HBsAb^– and HBsAg^–/HBcAb⁺/HBsAb⁺ profiles are associated with complete viral clearance in all patients should be revised. The contemporaneous assessment of HBsAg, HBcAb and HBsAb status might help us to better characterize these subjects and provide more detailed and accurate conclusions about their risk of PDAC development.

 

Moreover, to date only one research has quantitatively evaluated the possible association between anti-HCV positivity and probability of carcinogenesis in this organ. The observed risk estimate for this malignancy reached a borderline, but not statistically significant value. The small number of available studies, investigating this potential association (only 3), has prevented the achievement of conclusive results.

 

The present meta-analysis has been conceived in this continuously changing and evolving scenario, confirming the increased interest for this emerging field of search.^[30] It includes all available case-control and cohort studies, that have been performed to evaluate the potential relationship between HBV and/or HCV infection and PDAC, both in full-text or in abstract form and without language restriction. Methodological quality evaluation of the included researches has been performed by means of Newcastle-Ottawa Quality Assessment Scale. This meta-analysis confirms not only that HBsAg positivity is associated with an enhanced probability to develop this malignancy (OR=1.28, 95% CI: 1.11-1.48), but also it adds further factors, helping to improve our understanding on this topic. In particular, what about two considerable problems, underlined in the previous sections of this Editorial, concerning the risk of PDAC in subjects with "past exposure to HBV" or in HCV positive individuals? This meta-analysis suggests that in subjects with previous HBV-related infection, the presence of serum HBsAb and HBeAb positivity might have a protective role and it would be associated with a lower probability of developing this tumor, in comparison with individuals with a former HBV infection, but without these antibodies. However, no significantly increased risk of PDAC was observed, when HBsAg/HBsAb/HBcAb markers were considered all at once and HBsAg^– patients with HBsAb and/or HBcAb positivity were grouped together. The small number of available studies may explain, at least in part, the absence of definitive conclusions concerning this relationship, but additional factors have to be taken into account. In recent years, a considerable improvement in molecular biology has occurred and highly sensitive techniques are now at disposal for HBV genotyping. Their wide use in clinical practice have helped us to understand that HBV may persist and replicate, at a low rate in some HBsAg negative individuals, with or without the presence of HBcAb and/or HBsAb in serum, but with HBV-DNA detectable in liver specimens. The clinical significance of this very complex biological entity, defined as "occult infection", is still unclear. However, some authors suggested its possible substantial role in several pathological conditions, such as cryptogenic chronic liver diseases and hepatocellular carcinoma.^[31]

 

On the other hand, this meta-analysis, including a larger number of studies in comparison with the previously mentioned work,^[29] reports for the first time a clear association between anti-HCV positivity and a significantly increased risk of PDAC (OR=1.21, 95% CI: 1.02-1.44). This result has to be underlined for its potential crucial importance in clinical practice.

 

Does the current meta-analysis end the debate, concerning this topic? Certainly not, of course. It represents a further important step in our attempt to clarify etiology and pathogenesis of PDAC and to evaluate the possible crucial role of some viruses in pancreatic carcinogenesis. Therefore, taking advantage from the results reported in this and in the other meta-analyses, we should plan additional well-designed clinical researches with this purpose, according to the model of researchers, who, in the past years, have studied the impact of HBV and HCV in liver pathology.^[6] The usefulness of this approach is suggested by several objective reasons, such as the recognition that: a) liver and pancreas present common features in embryological development, originating from a multi-potent cells of endoderm origin; b) both viruses may infect and replicate not only in hepatocytes, but also in pancreatic cells; c) antigens and genomes of these viruses are detectable in both organs in experimental studies; and d) cellular pathways altered in the process of HBV- and/or HCV-related liver carcinogenesis might be similar to those perturbed in PDAC development.^[12] Several points remain uncertain and they have to be explored and explained, as well as some limiting factors, in the published meta-analyses, should be taken into account. Next epidemiological and pathogenetic researches should provide an answer to the following questions:

 

1) How might HBV and HCV infections increase the risk of PDAC? A previous report has suggested some potential common pathogenetic mechanisms, accounting for hepatocellular carcinoma and pancreatic carcinoma development in subjects with serum markers of present or previous HBV or HCV infection.^[12] In particular, although both viruses present important differences in their genome organization and in transcription/translation paths, they share intracellular targets and cause perturbation of several signal transduction cascades, by means of their proteins. These events may induce alteration of important cellular function, including energy production, cell growth, differentiation and apoptosis. Further researches will have to be performed to definitively establish whether the known mechanisms, promoting HBV- and HCV-related liver carcinogenesis, are common with those involved in pancreatic cancer development.

 

2) Might the ethnicity of patients with past or persistent HBV or HCV exposure influence the risk of pancreatic carcinogenesis? To date this point is still uncertain, because, as previously reported, most of trials have been carried out in populations of Asian origin,^[15-25] whereas, only 1 case-control^[13] and 2 cohort studies^{[14, 23]} have been performed in USA. The majority of subjects included in these researches were white, but there were also African Americans or individuals of unknown ethnicity. No studies have been carried out in Europe and in Africa, or in Southern America. Therefore, this is an important limit, concerning the available researches and meta-analyses, and further trials are required to clarify this important point.

 

3) What is the potential role of "occult" HBV infection in carcinogenesis of this organ? This is a crucial question, because, it is well-known that HBsAg positive subjects are carriers of persistent HBV infection and, therefore, they are at higher risk to have serious hepatic complications, during their lifetime, although most of them will present no serious liver sequelae. However, low levels of HBV-DNA remain detectable both in serum and in hepatic tissue, by means of available highly sensitive techniques, also in variable percentages of patients who successfully clear HBsAg,^[7] with or without serum HBsAb and/or HBcAb development. A recent large-scale study has assessed the impact of HBV genome and antigens in pancreatic cancer and adjacent non-cancerous tissues. Among HBV-DNA positive patients with PDAC, a high percentage of these subjects had no detectable serum HBsAg, showing, according to authors' conclusions, an elevated prevalence of occult HBV infection in individuals with this malignancy.^[32] Therefore, further investigations are required to clarify this point, which may be important, mainly in some of the most developed regions in the world. In these countries, HBsAg prevalence has significantly dropped because of long-term vaccination programs, but a significant prevalence of subjects with markers of past exposure to HBV (serum HBsAb and/or HBcAb positivity) still exists in some of these regions and these individuals might present a higher risk of PDAC.

 

4) What is the possible impact of different HBV and/or HCV genotypes as well as the potential cooperation of some pathological conditions, such as diabetes, smoking status and alcohol intake, in PDAC development in subjects with coexisting markers of persistent or "past" HBV and/or HCV-related infection? To date, 10 (A-J) HBV-^[33] and 7 (1-7) HCV-genotypes^[34] have been described, with variable geographical distribution, pathogenicity and treatment response. However, to date, no studies have been carried out in an attempt to explain whether some HBV or HCV genotypes have a major oncogenetic role in comparison with others. On the other hand, concerning the second point, it has to be underlined that three of 4 available meta-analyses have adjusted the risk of PDAC for smoking status, alcohol use and diabetes and have found that it is independent of these potential confounding factors, although at least one case-control study has suggested the existence of synergism between HBsAg and diabetes mellitus. No data are available on the possible cooperation between HCV and smoking, alcohol or diabetes in pancreatic carcinogenesis.

 

5) What are the possible reasons, explaining the absence of correlation between areas of HBV/HCV prevalence and PDAC incidence in the world, as described in a recent meta-analysis?^[29] According to age-standardized rates, this malignancy presents peculiar geographical distributions in the world. In particular, the incidence of PDAC appears to be higher in the most developed countries and in regions at more elevated distance from equator.^[35] These results^[29] indicate that there is not a correlation between areas of HBV/HCV prevalence and PDAC incidence. Anyway, it should be considered that several factors might, at least in part explain the absence of this association. The precision of data collection to assess the incidence of this cancer as well as the accuracy of diagnostic and methodological techniques used to detect this malignancy may strongly influence the final results. Further researches are required to clarify this important point, because significant differences in accuracy of estimation of PDAC incidence rates might exist among the most and the least developed regions in the world.

 

An adequate answer to these questions will help us to improve our knowledge about the causes, course and treatment of this cancer, as well as to understand whether the magnitude of PDAC risk in these subjects justifies additional screening tests to detect malignancies other than hepatocellular carcinoma and whether an adequate treatment of HBV- and/or HCV-persistent infections could prevent the development of PDAC.

 

 

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