Virus-related cancers

RELATED CONDITIONS: Cervical cancer, hepatocarcinoma, Kaposi sarcoma, T-cell lymphomas, B-cell lymphomas

DEFINITION: Cancer is a malignant disease characterized by the uncontrolled growth of anaplastic cells that invade or spread to sites beyond their origin. While many human cancers result from genetic mutations, some result from infection by viruses.

Risk factors: Viruses associated with cancer, such as the human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV), are most commonly spread through sexual relations or contamination of intravenous fluids. The pooling of blood fluids for isolation of the clotting factor VIII during the early years of the acquired immunodeficiency syndrome (AIDS) epidemic was the primary factor in the infection of hemophiliacs with HIV. Unprotected sexual relations with infected partners and intravenous drug use, in which infected users shared contaminated needles, also transmitted HIV and the hepatitis viruses. The human papillomavirus (HPV), the etiological agent for cervical carcinoma, is commonly transmitted by unprotected sexual contact. The Epstein-Barr virus (EBV), a type of herpes virus, is primarily transmitted via saliva. The human herpes virus 8 (HHV-8), also called the Kaposi sarcoma-associated herpes virus (KSHV), is transmitted through sexual contact and blood and saliva. Human T-lymphotropic virus-1 (HTLV-1), a retrovirus, is spread through unprotected sex, intravenous drug use, and maternal transmission. Merkel cell polyomavirus (MCV), discovered in 2008, is thought to be responsible for between 59 and 100 percent of Merkel cell carcinomas.

Etiology and the disease process: Most human cancers do not directly result from microbial infection. However, certain virus groups have long been associated with malignancies in animals, and several members of these groups have been shown to cause certain human cancers. Viruses can cause genetic changes in oncogenes—genes that directly regulate cell division, such as growth factors and their receptors, signal mechanisms, and tumor suppressors and disrupt the regulation of cell growth. However, people can be infected with these viruses and not develop cancer.

More than one hundred types of human papillomaviruses have been identified, of which about half are capable of causing cervical cancer. More than 90 percent of cervical cancer cases are associated with HPV infection. Infection of cervical cells by these virus strains may result in uncontrolled growth and malignancy.

Hepatocellular carcinoma (liver cancer) is among the cancers that cause the most cancer deaths worldwide and usually results from infection with the hepatitis B virus (HBV) and, less commonly, the hepatitis C virus (HCV). Both HBV and HCV are associated with potentially severe forms of liver disease, and a person with a chronic hepatitis infection or a long-term carrier may eventually develop liver cancer.

Kaposi sarcoma is linked to human herpesvirus 8 (HHV-8), which produces gene products that induce cell replication and inhibit tumor suppressor pathways. Classic Kaposi sarcoma, a rare form of the disease not associated with HIV infection, appears to involve both viral and genetic factors.

A variety of B-cell and T-cell lymphomas are also associated with viral infections. The human T-cell lymphotropic virus (HTLV), also known as the human T-cell leukemia virus, is the etiological agent for certain forms of T-cell disease. Between 2 and 5 percent of persons infected by HTLV type 1 will develop adult T-cell lymphoma. The mechanism by which cancer is induced is unclear but appears to involve a disruption of the cell’s signaling mechanism, which regulates cell replication.

A variety of B-cell and T-cell lymphomas are also associated with viral infections. The human T-cell lymphotropic virus (HTLV), also known as the human T-cell leukemia virus, has been shown to be the etiological agent for certain forms of T-cell disease. Between 2 and 5 percent of persons infected by HTLV type 1 will develop adult T-cell lymphoma. The mechanism by which cancer is induced is unclear but appears to involve a disruption of the cell’s signaling mechanism, which regulates cell replication.

There are numerous non-Hodgkin lymphomas (NHLs), some of which are associated with viral infection. The Epstein-Barr virus (EBV), a member of the herpesvirus family, is the etiological agent behind Burkitt lymphoma, an illness in which malaria is a cofactor, and nasopharyngeal carcinoma. The precise mechanism by which EBV infection results in cancer is unclear but appears to involve a translocation event with the cell chromosome, activating a cellular oncogene.

Incidence: Incidence rates for virus-related cancers vary widely by virus and location. Incidence rates for cancers with viral and nonviral causes are generally not broken down by cause.

Approximately 650,000 cases of cervical cancer are reported annually worldwide. In the United States, cervical cancer accounts for over four thousand deaths each year. The annual incidence of cervical cancer in the United States is about 7.7 per 100,000 women. The majority of cervical cancer cases are in women who have never had a Pap test. In developed countries, the rate of squamous cell carcinoma of the cervix has been decreasing due to improved screening and increasing rates of HPV vaccination.

Liver cancer is one of the leading causes of cancer deaths worldwide, resulting in over 700,000 deaths annually. Globally, chronic HBV or HCV infection causes around 80 percent of all primary liver cancers. Persons chronically infected with HBV are one hundred times more likely to develop liver cancer than uninfected persons. Hepatitis B vaccination is available to all age groups to prevent HBV infection.

An increasing number of cases of Kaposi sarcoma began to appear in the late 1980s as a result of the AIDS epidemic. Incidence rates grew to 9.5 per 100,000 men in 1989 and fell to 1.3 in 2005. Between 1980 and 2007, there were more than eighty thousand cases of Kaposi sarcoma reported among persons with HIV infection in the United States. Incidence rates by the 2020s reached about .39 per 100,000 people. Risk factors for Kaposi sarcoma include infection with HIV or human herpesvirus 8.

Non-Hodgkin lymphomas (all types) account for about 4 percent of cancers in the United States. About one in forty-two men and one in fifty-two women develop lymphoma.

Symptoms: Symptoms of virus-related cancers vary depending on the site affected. For cervical cancer, the early stages are generally asymptomatic, and as the disease progresses, women may experience unusual vaginal bleeding or pain.

For liver cancer, the symptoms include abdominal pain, unexplained weight loss, and a sudden onset of jaundice. A physician performing a physical examination usually finds an enlarged and tender liver and can hear turbulent blood flow through the liver because it has an extensive vascular system. Blood tests may reveal an elevation of certain liver proteins, such as alpha-fetoprotein.

The first symptoms of Kaposi sarcoma are generally purplish lesions or nodules on or under the skin or mucous membranes.

Symptoms of lymphomas are general, usually manifesting as swollen lymph nodes, fever, or unexplained weight loss.

Screening and diagnosis: A standard screening test exists for cervical cancer, but other virus-related cancers do not have routine screening procedures.

Early diagnosis of cervical cancer results from the observation of abnormal cervical cells following a Pap test. Although not all abnormal-appearing cells are cancerous, their presence may indicate a precancerous state. A colposcopy, the visual observation of the cervix, may help the physician in deciding whether to perform a biopsy. As with most cancers, the extent of the disease is the basis for staging.

If a patient’s symptoms suggest liver cancer, the physician will investigate furthe, using a variety of imaging scans. Ultrasound is generally the first choice because it is noninvasive and easily performed. This may be followed up with a computed tomography (CT) scan or (MRI). Ultimately, a biopsy is necessary to confirm the cancer. Staging of liver cancer is based on the size of the tumor and the extent of its spread.

Kaposi sarcoma is diagnosed by taking the patient’s history and examining the skin for the lesions typical of the disease. Biopsies are performed to confirm the disease, and imaging tests are used to find lesions in the stomach or lungs.

Non-Hodgkin lymphoma is commonly diagnosed by biopsy of an enlarged lymph node that does not respond to antibiotic treatment. If cancer is found in the sample, imaging tests such as X-ray, CT scans, MRI, and positron emission tomography (PET) scans can help determine how much the cancer has spread. Staging for non-Hodgkin lymphoma used the Ann Arbor system for many years based on the degree of spread. The Lugano classification system, an adaptation of the Ann Arbor system, is more commonly used in modern medicine. Additionally, two prognostic systems have been developed, one for slow-growing and one for fast-growing lymphomas. These systems attempt to describe a patient’s risk of dying and help physicians select appropriate courses of treatment.

Treatment and therapy: Treatment for virus-related cancers varies depending on the site but generally involves surgery, radiation therapy, chemotherapy, or a combination of therapies.

Treatment of cervical cancer generally starts with surgery to remove as much cancerous tissue as safely possible. Additional treatments depend on the stage of the disease. Radiation therapy may be external or internal using a radioactive implant. Chemotherapy, usually intravenous, is recommended if metastasis has occurred.

A small liver tumor can be removed surgically. Historically, a liver transplant had been recommended for most forms of liver cancer, though later, scientists determined that such a radical approach might not be necessary in the absence of extensive involvement. Extensive liver cancer may require chemotherapy, though other approaches have also been shown to be useful. Transarterial chemoembolization (TACE), the embolization of tumor blood vessels using a gel or coil; radiofrequency ablation (RFA), the insertion of an electrical probe directly into the tumor, followed by ablation of the tissue; and proton beam therapy have all been shown to be useful in reducing the size of localized tumors.

Treatment of Kaposi sarcoma depends on the extent of the tumor and can involve either surgical removal or radiation therapy and chemotherapy.

Non-Hodgkin lymphoma in HIV-infected patients is complicated by the patients’ low blood cell counts, although the use of highly active antiretroviral therapy has made it easier for patients to complete chemotherapy.

Prognosis, prevention, and outcomes: Prognosis and prevention of virus-related cancers varies depending on the specific cancer and virus. Prevention generally involves attempting to avoid the spread of viruses that cause cancers. Screening donated blood has reduced the risk of viral infection through transfusion. Safe sex practices (especially condom use) help prevent the spread of sexually transmitted viruses such as HPV, HIV, HBV, and HCV. Efforts to educate intravenous drug users about the dangers of sharing needles and thereby spreading viruses are critical in controlling the spread of dangerous viruses. Vaccines for HBV and HPV prevent most infections from this virus. Since 80 percent of liver cancer cases are associated with the hepatitis B virus, immunization should reduce the incidence rate. In 2006, a vaccine for HPV, Gardasil, was approved by the US Food and Drug Administration; a second HPV vaccine, Cervarix, received FDA approval in 2009. In the five years following the introduction of the first HPV vaccine in the United States, HPV prevalence dropped by 56 percent among female adolescents.

The prognosis for patients with cervical cancer depends on the stage of the disease and its response to therapy. Early diagnosis can result in the elimination of the disease, while once metastasis has taken place, the outcome becomes increasingly poor.

Liver cancer is curable if caught early and the tumor removed. None of the techniques used to treat advanced cancer is effective long-term, and the prognosis for patients with advanced liver cancer remains poor, with death generally resulting within a year of diagnosis.

The prognosis for those with HIV-related Kaposi sarcoma is improving because of better treatments for persons with HIV. If detected early, the five-year survival rate can reach 90 percent. However, if the disease has reached the lungs, the survival rate drops to 30 percent. Similarly, the outlook for HIV-infected patients with lymphoma depends largely on how well their HIV infection is controlled.

Bibliography

Bezeljak, Urban. "Cancer Gene Therapy Goes Viral: Viral Vector Platforms Come of Age." Radiology and Oncology, vol. 56., no. 1, 2022, pp. 1-13. doi.org/10.2478/raon-2022-0002.

Brenner, Malcolm K., and Mien-Chie Hung, eds. Cancer Gene Therapy by Viral and Non-Viral Vectors. Wiley, 2014.

Kandeel, M. "Oncogenic Viruses-Encoded microRNAs and Their Role in the Progression of Cancer: Emerging Targets for Antiviral and Anticancer Therapies." Pharmaceuticals, vol. 16, no. 485, 2023. doi.org/10.3390/ph16040485.

Kantarjian, Hagop. The MD Anderson Manual of Medical Oncology. 4th ed., McGraw Hill Education, 2022.

MacLennan, Signe A., and Marco A. Marra. “Oncogenic Viruses and the Epigenome: How Viruses Hijack Epigenetic Mechanisms to Drive Cancer.” International Journal of Molecular Sciences, vol. 24, no. 11, 31 May. 2023, doi:10.3390/ijms24119543.

Robertson, Erle S., ed. Cancer Associated Viruses. Springer, 2012.

Tannock, Ian, et al. The Basic Science of Oncology. 6th ed., McGraw-Hill, 2021.

Tognon, Mauro G., et al. "Recent Advances in Diagnosis, Prognosis, and Therapy of Oncogenic Virus-driven Tumors." Frontiers in Oncology, vol. 14, 2024, doi.org/10.3389/fonc.2024.1402877.

Wu, T.-C., Mei-Hwei Chang, and Kuan-Teh Jeang. Viruses and Human Cancer: From Basic Science to Clinical Prevention. 2nd ed., Springer, 2021.