Introduction
Kaposi sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus 8 (HHV8), is an enveloped double-stranded DNA gamma-2 herpesvirus (rhadinovirus) that was first identified in humans in 1994 in association with acquired immunodeficiency syndrome (AIDS) and cancer. The overall prevalence of KSHV antibodies in the U. S. general population is approximately 7%. KSHV prevalence rates are much higher in certain geographical areas (e.g., 50% in some sub-Saharan African populations). KSHV is thought to be transmitted primarily via saliva, but transmission has also been reported in injection drug users, in transfusion recipients, and from organ-transplant donors to recipients, all of which suggest it can also be spread via blood.
Methods
The National Toxicology Program (NTP) conducted a cancer hazard evaluation of KSHV infection and several types of cancer for possible listing in the Report on Carcinogens. The evaluation included the findings from studies reported in the IARC monograph in Volume 100B and from human cancer studies and mechanistic reviews published after the IARC monograph. For each cancer site, the evidence from human and mechanistic studies was integrated considering the following guidelines: Hill’s characteristics of causality, multicausality epidemiology considerations, guidance from the IARC 100B working group, and concepts of direct and indirect carcinogenesis proposed several virus experts.
Results and discussion
NTP concluded there was sufficient evidence of carcinogenicity for KSHV from studies in humans for the following three types of human cancer:
Kaposi sarcoma
This cancer of the cells that line blood or lymph vessels is associated with KSHV infection based on consistent findings of increased risk (some very high, ranging from 10- to 100-fold) in many prospective cohort and case-control studies in different populations for all four subtypes of Kaposi sarcoma and on the presence of an exposure-response relationship between the degree of viral infection and the cancer. KSHV is found in >90% of Kaposi sarcoma tumors in biopsies from Kaposi sarcoma case series. Many, but not all, patients infected with KSHV who develop Kaposi sarcoma have immune systems compromised either by HIV-1 infection or as a result of drug treatments after organ or tissue transplants. KSHV codes for viral proteins that transform cells into cancer cells, promote tumor growth, and evade and alter the immune system.
Primary effusion lymphoma (PEL)
This rare B-cell non-Hodgkin lymphoma is associated with KSHV infection based on its detection in tumors from 95% of 115 KSHV-infected patients (reported in case reports, several small case series, and a case-comparison study), together with molecular studies of the tumors’ specific morphological and immunological features. Molecular studies show that PEL tumors are monoclonal for the virus, contain high levels of KSHV DNA, and express proteins similar to Kaposi sarcoma. KSHV infection is a diagnostic criterion.
Multicentric Castleman disease (plasmablastic variant)
This is a second type of rare B-cell non-Hodgkin lymphoma linked with KSHV infection based on nine case-series studies and four case-comparison studies supporting an association between KSHV infection and all types of multicentric Castleman disease and molecular studies. The latter found that KSHV DNA was detected in all tumors co-infected with HIV and KSHV and 50% infected with only KSHV. Molecular analysis of tumor tissue confirmed the association between KSHV infection and multicentric Castleman disease and demonstrated that the plasmablastic variant has a unique molecular profile and produces a distinctive monotypic form of immunoglobulin M that is not found in KSHV-negative multicentric Castleman disease.
NTP cancer hazard conclusion and significance
The conclusion of the cancer hazard evaluation was that KSHV should be listed as known to be a human carcinogen in the RoC. The Secretary of Health and Human Services approved the listing of KSHV in the 14th RoC. The rationale for the listing was sufficient evidence from studies in humans (human cancer and mechanistic) for three types of cancer. Globally, KSHV is estimated to be responsible for approximately 44,000 cancers per year.
National Toxicology Program (NTP). 2016. Report on Carcinogens monograph on Kaposi sarcoma-associated herpesvirus. Research Triangle Park, NC: National Toxicology Program. RoC Monograph 10. https://doi.org/10.22427/ROC-MGRAPH-10