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 interior surface of blood vessels and lymphatic vessels.[1][2][3] 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). The main gene involved in the pathogensis of Kaposi's sarcoma is ORF73 gene, which encodes the viral latency-associated nuclear antigen (LANA-1).[4] 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.[5][6][7][8]

Pathogenesis

  • 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 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
  • 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, 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).[6][9]
  • Other viral latent genes involved in the induction of malignant cellular proliferation include:
  • vcyclin gene
  • vFLIP gene[10]
  • ORF K12 gene (kaposins gene)[11]
  • KSHV miRNAs[12][13]

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 patient presenting with a redish/violaceous macules

  • Kaposi's sarcoma located on the nose

    Kaposi's sarcoma located on the nose

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

    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 lesion stages of development for Kaposi's sarcoma:[2]
Lesion Stage Histologic Features

Macular stage

  • Thin vessel wall
  • Angulated vessels throughout 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

Gallery

  • Illustrated below is a series of microscopic images demonstrating Kaposi's sarcoma:[13]
  • Kaposi sarcoma observed under low magnification[13]

    Kaposi sarcoma observed under low magnification[13]

  • Kaposi sarcoma observed under high magnification[13]

    Kaposi sarcoma observed under high magnification[13]

References

  1. ↑ Ruocco E, Ruocco V, Tornesello ML, Gambardella A, Wolf R, Buonaguro FM (2013). "Kaposi's sarcoma: etiology and pathogenesis, inducing factors, causal associations, and treatments: facts and controversies". Clin Dermatol. 31 (4): 413–22. doi:10.1016/j.clindermatol.2013.01.008. PMID 23806158.
  2. ↑ 2.0 2.1 Kaposi's Sarcoma. PathologyOutlines (2015) http://www.pathologyoutlines.com/topic/skintumornonmelanocytickaposisarcoma.html Accessed on January, 19 2015
  3. ↑ Kaposi's sarcoma. Wikipedia (2015) https://en.wikipedia.org/wiki/Kaposi's_sarcoma Accessed on January, 17 2015
  4. ↑ Toth Z, Brulois K, Jung JU (2013). "The chromatin landscape of Kaposi's sarcoma-associated herpesvirus". Viruses. 5 (5): 1346–73. doi:10.3390/v5051346. PMC 3712311. PMID 23698402.
  5. ↑ Rossetto CC, Pari GS (2014). "PAN's Labyrinth: Molecular biology of Kaposi's sarcoma-associated herpesvirus (KSHV) PAN RNA, a multifunctional long noncoding RNA". Viruses. 6 (11): 4212–26. doi:10.3390/v6114212. PMC 4246217. PMID 25375885.
  6. ↑ 6.0 6.1 Cancian L, Hansen A, Boshoff C (2013). "Cellular origin of Kaposi's sarcoma and Kaposi's sarcoma-associated herpesvirus-induced cell reprogramming". Trends Cell Biol. 23 (9): 421–32. doi:10.1016/j.tcb.2013.04.001. PMID 23685018.
  7. ↑ Zattra E Coati I, Alaibac M, Piaserico S (2014). "Kaposi's sarcoma and other rare skin cancers in organ transplant patients". G Ital Dermatol Venereol. 149 (4): 395–400. PMID 25068226.
  8. ↑ Kaposi's Sarcoma. Radiopaedia (2015) http://radiopaedia.org/articles/kaposi-sarcoma Accessed on January, 19 2016
  9. ↑ LANA. Wikipedia (2015) https://en.wikipedia.org/wiki/LANA Accessed January, 19 2015
  10. ↑ Grossmann C, Podgrabinska S, Skobe M, Ganem D (2006). "Activation of NF-kappaB by the latent vFLIP gene of Kaposi's sarcoma-associated herpesvirus is required for the spindle shape of virus-infected endothelial cells and contributes to their proinflammatory phenotype". J Virol. 80 (14): 7179–85. doi:10.1128/JVI.01603-05. PMC 1489050. PMID 16809323.
  11. ↑ Muralidhar S, Veytsmann G, Chandran B, Ablashi D, Doniger J, Rosenthal LJ (2000). "Characterization of the human herpesvirus 8 (Kaposi's sarcoma-associated herpesvirus) oncogene, kaposin (ORF K12)". J Clin Virol. 16 (3): 203–13. PMID 10738139.
  12. ↑ Plaisance-Bonstaff K, Choi HS, Beals T, Krueger BJ, Boss IW, Gay LA; et al. (2014). "KSHV miRNAs decrease expression of lytic genes in latently infected PEL and endothelial cells by targeting host transcription factors". Viruses. 6 (10): 4005–23. doi:10.3390/v6104005. PMC 4213575. PMID 25341664.
  13. ↑ 13.0 13.1 13.2 13.3 Libre Pathology. Kaposi's sarcoma (2015) http://librepathology.org/wiki/index.php/File:Kaposi_sarcoma_low_intermed_mag.jpg Accessed on January, 19 2016


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