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]

Pathogenesis

• Kaposi's sarcoma arises from endothelial cells, which are epithelial cells that normally lines the interior surface of blood vessels and lymphatic vessels.
• Kaposi's sarcoma is mainly caused by an infection with Human herpes virus 8 (HHV8), which is also known as Kaposi's sarcoma-associated herpes virus (KSHV).
• HHV8 is usually transmitted through both saliva and semen via close sexual contact.
• Another minor route of transmission for HHV8 is through organ transplantation.
• A state of immunosuppression facilitates the development of Kaposi's sarcoma among patients infected with 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 is due to:

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

• The oncogenesis of HHV8 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 HHV8 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
• βFGF
• TGFβ
• 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, HHV8 will express a viral latency-associated nuclear antigen (LANA-1) that acts as transcriptional modulator.
• The functions of HHV8 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 distally and 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 with abnormal protrusions)
• Intracytoplasmic PAS +ve hyaline globules (pale pink globs that are paler than red blood cells)

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

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

References

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