Introduction

Kaposi sarcoma (KS) is a soft tissue cancer that forms lesions on the skin, the internal lining of the blood vessels, and the digestive system. The lesions form in the blood and lymph vessels, thus giving them a purplish appearance.¹

KS can extend from the external surface of the skin to the nose, mouth and anus. KS is mostly found on the limbs and groin, and if the lesion swells, it can become painful. Additionally, KS can present in the internal organs, such as the lungs, liver, and abdomen. When KS develops in the lungs, it causes breathing difficulties.¹

 Human herpesvirus 8 (HHV-8) is known as the Kaposi sarcoma-associated herpesvirus (KSHV). HHV-8 is the major cause of KS in patients with a suppressed immunity and those suffering from AIDs.²

Patients suffering from HIV infection with a CD4 lymphocyte count of less than 200 cells/mm³ are most likely to develop KS. Hence, KS is known as AIDs defining illness (illnesses that indicate advanced HIV diseases).²

Every individual who gets KS has HHV-8 present in their blood.³ In this article, we will explore the link between this virus and KS, and how it leads to the formation of a soft tissue tumour in the body.

What is human herpesvirus 8 (HHV-8)?

Human herpesvirus 8 (HHV-8) is part of the Herpesviridae family. HHV-8 and human herpesvirus 4 (HHV-4), also known as Epstein-Barr virus (EBV), are the only two types of herpes viruses that cause cancers in humans. HHV-4 causes Burkitt lymphoma, and HHV-8 causes KS.⁴

HHV-8 is a lymphotropic virus (a virus that infects lymphocyte cells). These viruses undergo a pathway called lytic replication within the infected human cells; this means that the virus replicates and reproduces within the host cells and causes ‘lysis’, meaning death of the host cell. HHV-8 virus is capable of being dormant (latent) within the host cell. The virus can remain present in the body, albeit in an inactive state, for the lifetime of the host.⁴

Some factors that contribute to the HHV-8 activation and KS are:⁴

• A weak immune system in HIV/ AIDs patients
• A solid organ transplant patient is on immunosuppressive drugs
• Malnutrition
• Older people assigned male at birth (AMAB)

Transmission methods of HHV-8 are:⁴

• Sexual transmission 
• Body fluids, such as saliva
• Blood transfusion
• Intravenous drug use

Overview of Kaposi sarcoma

Kaposi sarcoma was first discovered in European men by a dermatologist called Moritz Kaposi in 1872.³

Types of Kaposi sarcoma

The four types of Kaposi sarcoma are:³

• Classic KS is present in elderly people AMAB of Mediterranean and Eastern Europe. The lesions are found on the lower limbs
• Endemic KS is present in Africa, where besides people AMAB, people assigned female at birth (AFAB), and children can commonly have it
• Epidemic KS is present in HIV infected individuals with AIDs who are not taking their highly active antiretroviral therapy (HAART). It involves the skin and the internal organs of the affected individual
• Iatrogenic KS is present in people with a weak immune system, particularly after an organ transplant. It involves the skin and the internal organs

HHV-8 can be found in all of the above types.

What are the clinical features of Kaposi sarcoma?

KS is a vascular tumour and presents itself on the skin as pink, red, purple or brown lesions. These lesions are painless and involve the external surface of the skin and the internal lining of the vessels (blood and lymph) and organs. However, the lesions could swell and become painful if there is inflammation. The lesions present themselves in 3 different stages on the skin.³

These are:

• Patch
• Plaque
• Nodule 

Additionally, KS can transform into ulcers and involve other tissues of the body. When the lungs develop KS, it is usually life-threatening.³

How HHV-8 causes tumour formation

HHV-8 infects the lining of the blood vessels (endothelial), lymph nodes, skin (epithelial), and internal organs (mesenchymal). HHV-8 is found in the tumour spindle cells (SC), which serve as a histological (structural) identification of the cancer.⁵

HHV-8 has two phases:⁵

• Latent (inactive)
• Lytic (active)

During the infection, HHV-8 releases viral genes that disturb the normal functions of a protein called p53, also known as the tumour suppressor protein. The p53 is involved in the regulation of the cell DNA repair, cell cycle, and programmed cell death (apoptosis). HHV-8 interferes with p53 in several ways.⁶

Key viral proteins involved in the activation and formation of KS are:

• Latency-associated nuclear antigen (LANA-1) is encoded by the viral gene ORF73 and directly inhibits p53's ability to cause apoptosis⁶
• Viral interferon regulatory factor 4 (vlRF4) reduces levels of p53⁶
• Viral interleukin-6 (vIL-6) activates cytokines, promotes angiogenesis (abnormal increase in blood vessel formation), and cell proliferation (growth)⁶
• Viral G protein-coupled receptor (vGPCR) drives cell proliferation, cell signalling, and the development of KS⁷
• MIR1 and MIR2 help the virus escape the immune system by downregulating the surface MHC-I receptors (important for the immune system to identify foreign cells and attack them) and promoting endocytosis and lysosomal degradation of MHC-I⁷
• Rta is a viral protein that activates the lytic cycle from the latent viral gene when the disease is dormant⁸
• K1 and K15 proteins cause abnormal blood vessel proliferation and the development of neoplasm⁹

Immunosuppression and viral reactivation

All of these viral proteins suppress the natural immune response of the body, promote abnormal cell growth, and contribute to tumour formation. Therefore, people with decreased immunity, such as solid organ transplant patients (e.g, heart, kidney, liver, or lung) and HIV/AIDs patients, are more likely to develop KS.^6,7,8,9

Diagnosis of HHV-8 and KS

KS is diagnosed through biopsy. A small piece of the lesion is cut and sent for microscopic examination. The presence of spindle cells (SC) confirms the diagnosis in the biopsy. When the lesion is taken from a patch, an increased number of abnormal endothelial cells are seen in the lining of the blood vessel, and signs of inflammation are present. When the lesion is taken in a plaque stage, then the spindle cells confirm the diagnosis.¹⁰

A monoclonal antibody against LANA-1 confirms the diagnosis of KS in a process called immunohistochemistry. Serological tests and polymerase chain reaction (PCR) are done for further diagnosis. In PCR, the DNA sequence of HHV-8 is identified.¹⁰

Treatment of HHV-8 and KS

Treatment of KS depends on the type of cancer and the stage of the skin lesion. Additionally, your doctor will check your history to attempt to identify the exact cause of KS. The treatment option for HIV/AIDs patients is antiretroviral therapy, which includes the combination of different antiviral drugs. Ultimately, the goal is to limit the HIV infection.¹¹

In solid organ transplant patients, the immunosuppressants are checked and controlled to increase the immunity in these individuals and limit KS. In children suffering from KS, cytotoxic chemotherapy is performed to target the spindle cells of KS.¹¹

FAQs

What is the survival rate of Kaposi sarcoma?

The combined survival rate for all types of Kaposi sarcoma is 74%.

Does a Kaposi sarcoma lesion feel painful to touch?

No, it is painless and often presents like a bruise on the skin.

How do doctors treat a Kaposi sarcoma lesion on the skin?

A doctor first injects a local anaesthetic and numbs the skin. Then, an instrument called a curette is used to scrape off the lesion, and electrocautery (applying electricity with a probe) is completed to stop the bleeding.

What is the new treatment for Kaposi sarcoma?

Pomalidomide is used for treating HIV/AIDs patients who have not responded to highly active antiretroviral therapy (HAART). Additionally, pomalidomide is used to treat patients with KS who are HIV- negative. 

Summary

HHV-8 causes KS and affects people from Mediterranean, African, and European origins, with older people AMAB more prone to develop the disease. HIV patients and organ transplant patients are required to monitor their CD4 cell levels to prevent the development of KS. If someone suspects symptoms and the appearance of lesions on their body, they should immediately consult a doctor. The treatment of KS is possible, and new treatment options are under research.