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==Overview==
==Overview==
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). 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 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.
Kaposi's sarcoma arises from endothelial cells, which are epithelial cells that normally lines the interior surface of blood vessels and lymphatic vessels.<ref name="pmid23806158">{{cite journal| author=Ruocco E, Ruocco V, Tornesello ML, Gambardella A, Wolf R, Buonaguro FM| title=Kaposi's sarcoma: etiology and pathogenesis, inducing factors, causal associations, and treatments: facts and controversies. | journal=Clin Dermatol | year= 2013 | volume= 31 | issue= 4 | pages= 413-22 | pmid=23806158 | doi=10.1016/j.clindermatol.2013.01.008 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23806158  }} </ref><ref name="patho2"> Kaposi's Sarcoma. PathologyOutlines (2015) http://www.pathologyoutlines.com/topic/skintumornonmelanocytickaposisarcoma.html Accessed on January, 19 2015</ref><ref name="wiki">Kaposi's sarcoma. Wikipedia (2015)  https://en.wikipedia.org/wiki/Kaposi's_sarcoma Accessed on January, 17 2015</ref> 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).<ref name="pmid23698402">{{cite journal| author=Toth Z, Brulois K, Jung JU| title=The chromatin landscape of Kaposi's sarcoma-associated herpesvirus. | journal=Viruses | year= 2013 | volume= 5 | issue= 5 | pages= 1346-73 | pmid=23698402 | doi=10.3390/v5051346 | pmc=PMC3712311 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23698402  }} </ref> Kaposi's sarcoma is commonly associated 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.<ref name="pmid25375885">{{cite journal| author=Rossetto CC, Pari GS| title=PAN's Labyrinth: Molecular biology of Kaposi's sarcoma-associated herpesvirus (KSHV) PAN RNA, a multifunctional long noncoding RNA. | journal=Viruses | year= 2014 | volume= 6 | issue= 11 | pages= 4212-26 | pmid=25375885 | doi=10.3390/v6114212 | pmc=PMC4246217 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25375885  }} </ref><ref name="pmid23685018">{{cite journal| author=Cancian L, Hansen A, Boshoff C| title=Cellular origin of Kaposi's sarcoma and Kaposi's sarcoma-associated herpesvirus-induced cell reprogramming. | journal=Trends Cell Biol | year= 2013 | volume= 23 | issue= 9 | pages= 421-32 | pmid=23685018 | doi=10.1016/j.tcb.2013.04.001 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23685018  }} </ref><ref name="pmid25068226">{{cite journal| author=Zattra E Coati I, Alaibac M, Piaserico S| title=Kaposi's sarcoma and other rare skin cancers in organ transplant patients. | journal=G Ital Dermatol Venereol | year= 2014 | volume= 149 | issue= 4 | pages= 395-400 | pmid=25068226 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25068226  }} </ref><ref name="radio"> Kaposi's Sarcoma. Radiopaedia (2015) http://radiopaedia.org/articles/kaposi-sarcoma Accessed on January, 19 2016</ref>


==Pathogenesis==
==Pathogenesis==
Line 47: Line 47:
:* vFLIP gene<ref name="pmid16809323">{{cite journal| author=Grossmann C, Podgrabinska S, Skobe M, Ganem D| title=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. | journal=J Virol | year= 2006 | volume= 80 | issue= 14 | pages= 7179-85 | pmid=16809323 | doi=10.1128/JVI.01603-05 | pmc=PMC1489050 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16809323  }} </ref>
:* vFLIP gene<ref name="pmid16809323">{{cite journal| author=Grossmann C, Podgrabinska S, Skobe M, Ganem D| title=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. | journal=J Virol | year= 2006 | volume= 80 | issue= 14 | pages= 7179-85 | pmid=16809323 | doi=10.1128/JVI.01603-05 | pmc=PMC1489050 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16809323  }} </ref>
:* ORF K12 gene (kaposins gene)<ref name="pmid10738139">{{cite journal| author=Muralidhar S, Veytsmann G, Chandran B, Ablashi D, Doniger J, Rosenthal LJ| title=Characterization of the human herpesvirus 8 (Kaposi's sarcoma-associated herpesvirus) oncogene, kaposin (ORF K12). | journal=J Clin Virol | year= 2000 | volume= 16 | issue= 3 | pages= 203-13 | pmid=10738139 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10738139  }} </ref>
:* ORF K12 gene (kaposins gene)<ref name="pmid10738139">{{cite journal| author=Muralidhar S, Veytsmann G, Chandran B, Ablashi D, Doniger J, Rosenthal LJ| title=Characterization of the human herpesvirus 8 (Kaposi's sarcoma-associated herpesvirus) oncogene, kaposin (ORF K12). | journal=J Clin Virol | year= 2000 | volume= 16 | issue= 3 | pages= 203-13 | pmid=10738139 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10738139  }} </ref>
:* KSHV miRNAs<ref name="pmid25341664">{{cite journal| author=Plaisance-Bonstaff K, Choi HS, Beals T, Krueger BJ, Boss IW, Gay LA et al.| title=KSHV miRNAs decrease expression of lytic genes in latently infected PEL and endothelial cells by targeting host transcription factors. | journal=Viruses | year= 2014 | volume= 6 | issue= 10 | pages= 4005-23 | pmid=25341664 | doi=10.3390/v6104005 | pmc=PMC4213575 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25341664  }} </ref>
:* KSHV miRNAs<ref name="pmid25341664">{{cite journal| author=Plaisance-Bonstaff K, Choi HS, Beals T, Krueger BJ, Boss IW, Gay LA et al.| title=KSHV miRNAs decrease expression of lytic genes in latently infected PEL and endothelial cells by targeting host transcription factors. | journal=Viruses | year= 2014 | volume= 6 | issue= 10 | pages= 4005-23 | pmid=25341664 | doi=10.3390/v6104005 | pmc=PMC4213575 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25341664  }} </ref><ref name="patho">Libre Pathology. Kaposi's sarcoma (2015) http://librepathology.org/wiki/index.php/File:Kaposi_sarcoma_low_intermed_mag.jpg Accessed on January, 19 2016</ref>


==Associated Conditions==
==Associated Conditions==
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:* Premonitory sign (a neovascular lesion wrapped around a pre-existing space with abnormal protrusions)
:* 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)
:* 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:
* The table below differentiates between the four main lesion stages of development for Kaposi's sarcoma:<ref name="patho2"> Kaposi's Sarcoma. PathologyOutlines (2015) http://www.pathologyoutlines.com/topic/skintumornonmelanocytickaposisarcoma.html Accessed on January, 19 2015</ref>
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Revision as of 18:52, 19 January 2016

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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 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

  • 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).[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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