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Increased incidence of cancer and cancer-related mortality among persons with chronic hepatitis C infection, 2006–2010
Robert D. Allison et al, for the Chronic Hepatitis Cohort Study (CHeCS) Investigators
 Journal of Hepatology 2015, 63:822–828.

Persons chronically infected with the hepatitis C virus (HCV) may be at higher risk for developing and dying from non-liver cancers than the general population.
CHeCS is a multi-center cohort of adult patients infected with chronic HCV infection who had a service provided between January 1, 2006 and December 31, 2010 at one of four U.S. healthcare systems.
Patients were considered HCV infected based upon measurable viral load by PCR.
Tumor registry data were collected and stored in each health system according to Surveillance, Epidemiology, and End Results (SEER) program standards.
Each health system compared cohort patient records to the electronic state death registry to enhance death ascertainment through 2010.
Thirteen tumor registries from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER13) Program database were used for comparisons of incidence rate, and age, grade and stage at cancer diagnosis with CHeCS.
Measurements included standardized rate ratios (SRR) and relative risk (RR).
Of 2,143,369 adult patients who had a service provided from 2006 to 2010 at one of four participating U.S. healthcare systems, 12,126 (0.57%) were diagnosed with chronic HCV infection and contributed 39,984 person-years of follow-up time. These 12,126 HCV infected patients were compared to 133,795,010 records from 13 Surveillance, Epidemiology and End Results Program (SEER) cancer registries, and approximately 12 million U.S. death certificates from Multiple Cause of Death (MCOD) data.
The incidence of the following cancers was significantly higher among patients with chronic HCV infection:

Age-adjusted mortality was significantly higher among patients with: liver (RR, 29.6 [95% CI, 29.1–30.1]), oral (5.2 [5.1–5.4]), rectum (2.6 [2.5–2.7]), NHL (2.3 [2.2–2.31]), and pancreatic (1.63 [1.6–1.7]) cancers.
The mean ages of cancer diagnosis and cancer-related death were significantly younger among CHeCS HCV cohort patients compared to the general population for many cancers.

n conclusion, incidence and mortality of many types of non-liver cancers were higher, and age at diagnosis and death younger, in patients with chronic HCV infection compared to the general population.

Expert's Perspective

The analysis of the CHeCS multicenter cohort, by Allison et al., demonstrates that the incidence and mortality of many types of non-liver cancers (pancreas, rectum, kidney, non-Hodgkin lymphoma and lung) were higher and that the age at diagnosis and death was younger in patients infected by HCV as compared to the general population.

This work has some limitations which are clearly acknowledged by the authors, especially the absence of controlling for alcohol use or other important behavorial risk factors related to cancer incidence and mortality. Nevertheless it is another “brick in the wall” of evidence adding to several retrospective cohorts which have reported a higher risk of hepatic and extra-hepatic cancers in HCV-infected patients (Nyberg AH et al. EASL 2015; Abs 058) and a significant decrease of their occurrence in patients achieving a sustained virologic response, including co-infected patients (Berenguer J. Clin Infect Dis 2012; 55:728–36).

Despite the published data, the link between HCV infection and cancer still remains in debate as:

  1. Four of the five non-liver malignancies (kidney, lung, pancreas and rectum) are also smoking-related cancers and smoking rates are higher in HCV-infected population, including the CHeCS participants (33.7%) as compared to controls (20.2%);
  2. The rate of breast cancer which has been reported higher in females of less than 55 years in the Taiwan cohort ( Su F-H. BMC Cancer 2011; 11:495) is reported to be lower in the CHeCS participants (relative risk of 0.42 ; 95% confidence interval : 0.41-0.43).

However, we have strong arguments to support that non-Hodgkin lymphoma (villous splenic lyphoma for example) is, in most cases, associated with chronic HCV infection, as HCV antiviral treatment leading to a sustained virologic response results in lymphoma remission, and a virologic relapse can result in a relapse of the lymphoma. The causal relationship is multifactorial and could be due to chronic inflammation and cryoglobulinemia or a direct infection of B lymphocytes resulting in a clonal selection. The chronic inflammation seen is associated with qualitative immune disturbances which may reverse with a sustained virologic response in a time-dependent fashion (Alanio C. personal communication) and could contribute to the occurrence of cancers.

This issue of a link between chronic HCV infection and the risk of non-liver malignancies needs to be investigated further. In addition to hepatic and extra-hepatic factors , comorbidities such as diabetes, cardiovascular and renal disease , life style, the effect of antiviral treatment need to be taken into account. We need prospective data which could quantify any increased risk of extra-hepatic cancers in HCV-infected patients, especially taking into account confounders such as the use of alcohol and smoking. In this era of HCV treatment we need to know what is the « normalized » risk of cancers as well as the extra-hepatic overall mortality in those patients achieving a sustained virologic response (Lee MH. J Infect Dis 2012 ; 206 : 469-477).

Pr Stanislas Pol, Hôpital Cochin, Paris