Kaposi's sarcoma pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Haytham Allaham, M.D. [2]

Overview

Kaposi's sarcoma arises from endothelial cells, which are epithelial cells that normally lines the luminal surface of blood vessels and lymphatic vessels. Kaposi's sarcoma is mainly caused by an infection with Human herpes virus 8 (HHV-8), which is also known as Kaposi's sarcoma-associated herpes virus (KSHV). The main gene involved in the pathogensis of Kaposi's sarcoma is ORF73 gene, which encodes the viral latency-associated nuclear antigen (LANA-1). Kaposi's sarcoma is commonly associated with acquired immune deficiency syndrome (AIDS). On gross pathology, reddish, violaceous, or bluish-black macules and patches are characteristic findings of Kaposi's sarcoma. On microscopic histopathological analysis the presence of spindle cells with minimal nuclear atypia are characteristic findings of Kaposi's sarcoma.

Pathogenesis

• Kaposi's sarcoma arises from endothelial cells, which are epithelial cells that normally lines the luminal surface of blood vessels and lymphatic vessels.
• Kaposi's sarcoma is mainly caused by an infection with Human herpes virus 8 (HHV-8), which is also known as Kaposi's sarcoma-associated herpes virus (KSHV).
• HHV-8 is usually transmitted through both saliva and semen via close sexual contact.
• Another minor routes of transmission for HHV-8 are through organ transplantation and blood transfusion.
• A state of immunosuppression facilitates the development of Kaposi's sarcoma among patients infected with the virus.
• Kaposi's sarcoma is a widely disseminated malignancy that may involve the skin, oral cavity, gastrointestinal tract, and respiratory airways.
• Kaposi's sarcoma is characterised by abnormal proliferation of endothelial cells, neoangiogenesis, and inflammation.
• Cutaneous manifestations of Kaposi's sarcoma are due to:

• The high vascularity of the tumor that leads to the leakage of RBC and haemosiderin into the surrounding tissue
• The inflammatory process that surrounds the tumor leads to a mild painful swelling of the area

• The oncogenesis of HHV-8 infection is due to a number of human cellular genes that have been incorporated through molecular piracy into the viral DNA sequence.
• The genes acquired by HHV-8 will augment the cellular proliferation pathways of infected cells through various mediators and DNA synthesis proteins such as:

• Complement-binding protein
• IL-6
• BCL-2
• Cyclin D
• VEGF
• PDGF
• FGF
• TGF β
• Interferon regulatory factor
• Flice inhibitory protein (FLIP)
• Dihydrofolate reductase
• Thymidine kinase
• Thymidylate synthetase
• DNA polymerase

• The augmentation of such cellular proliferation pathways will protect the virus from the immune system and allow a continuous viral replication during the latency period.
• During the latent period, HHV-8 will express a viral latency-associated nuclear antigen (LANA-1) that acts as transcriptional modulator.
• The functions of HHV-8 viral latency-associated nuclear antigen (LANA-1) include:

• A tethering molecule that stabilize the viral DNA to the cellular chromosome
• An inhibitor of p53 tumor suppressor protein
• An inhibitor of retinoblastoma (Rb) tumor suppressor protein
• A suppressor of the viral lytic phase of replication

Genetics

• The main gene involved in the pathogensis of Kaposi's sarcoma is ORF73 gene, which encodes the viral latency-associated nuclear antigen (LANA-1).
• Other viral latent genes involved in the induction of malignant cellular proliferation include:

• vCyclin gene
• vFLIP gene
• ORF K12 gene (kaposins gene)
• KSHV miRNAs

Associated Conditions

• Kaposi's sarcoma is associated with a number of conditions that include:

• Acquired immune deficiency syndrome (AIDS)
• Patients receiving immunosuppressive therapy

Gross Pathology

• On gross pathology, reddish, violaceous, or bluish-black macules and patches are characteristic findings of Kaposi's sarcoma.
• The cutaneous lesions start to develop distally then progressively spread and coalesce to form nodules or plaques.

• 

  Kaposi's sarcoma patient presenting with a redish/violaceous macules

• 

  Kaposi's sarcoma located on the nose

• 

  An HIV-positive patient presented with an intraoral Kaposi’s sarcoma lesion with an overlying candidiasis infection

Microscopic Pathology

• On microscopic histopathological analysis the presence of spindle cells with minimal nuclear atypia are characteristic findings of Kaposi's sarcoma.
• Other findings of Kaposi's sarcoma on light microscopy may include:

• Excessive vascular proliferation
• Abundant red blood cells
• Red blood cell and hemosiderin extravasation
• Abundant lymphocytes and monocytes
• Premonitory sign (a neovascular lesion wrapped around a pre-existing space)
• Intracytoplasmic PAS +ve hyaline globules (pale pink globs that are paler than red blood cells)

• The table below differentiates between the four main lesion stages of development for Kaposi's sarcoma:

Lesion Stage	Histologic Features
Macular stage	Thin vessel wall Angulated vessels throughout the dermis Plasma cell and hemosiderin infiltrates
Patch stage	Angulated lumina that dissect dermal collagen Premonitory sign Spindle cells surround angiomatoid vascular spaces filled with RBC
Tumor stage	Solid nodules The presence of spindle cells and red blood cells in a slit-like lumina Abscence of cellular atypia or mitotic activity
Lymphangioma-like variant	Thin walled, angulated vessels Absence of red blood cells

• On immunohistochemistry Kaposi's sarcoma is characterized by:

• Positive CD31
• Positive CD34
• Positive HHV-8
• Positive D2-40
• Positive Ki-67
• Positive ERG

• Detection of the LANA protein antigen in tumor cells confirms the diagnosis.

Gallery

• Illustrated below is a series of microscopic images demonstrating Kaposi's sarcoma:

• 

  Kaposi sarcoma observed under low magnification

• 

  Kaposi sarcoma observed under high magnification