Kaposi's sarcoma pathophysiology: Difference between revisions

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Latest revision as of 21:15, 10 October 2019

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

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 pathogenesis 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.

Pathophysiology

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).^[1]^[2]
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.^[1]
Kaposi's sarcoma is a widely disseminated malignancy that may involve the skin, oral cavity, gastrointestinal tract, and respiratory airways.
Kaposi's sarcoma is characterized by abnormal proliferation of endothelial cells, neoangiogenesis, and inflammation.^[3]^[4]
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
vcyclin ^[5]
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.^[6]
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 pathogenesis of Kaposi's sarcoma is ORF73 gene^[7], which encodes the viral latency-associated nuclear antigen (LANA-1).^[3]
Other viral latent genes involved in the induction of malignant cellular proliferation include:

vCyclin gene^[5]
vFLIP gene^[8]
ORF K12 gene (kaposins gene)^[9]
KSHV miRNAs^[10]^[11]

Associated Conditions

Kaposi's sarcoma is associated with a number of conditions that include:^[1]

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.^[11]
The cutaneous lesions start to develop distally then progressively spread and coalesce to form nodules or plaques.

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:^[11]

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:^[2]


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:^[11]

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

The following images show the different gross pathological findings and different sites:

Intraoral lesion depicting Kaposi Sarcoma. Source: Wikimedia Commons ^[12]
Violaceous lesions on the nose of Kaposi sarcoma. Source: Wikimedia Commons^[13]
Pulmonary lesion of Kaposi sarcoma. Source: Wikimedia Commons ^[14]
Lesion in a foot. Source: Wikimedia Commons.^[15]
Kaposi sarcoma lesion Source: Wikimedia Commons.^[16]
Kaposi sarcoma lesion Source: Wikimedia Commons.^[17]

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

Kaposi sarcoma observed under low magnification^[11]
Kaposi sarcoma observed under high magnification^[11]

References

↑ ^1.0 ^1.1 ^1.2 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.
↑ ^2.0 ^2.1 Kaposi's Sarcoma. PathologyOutlines (2015) http://www.pathologyoutlines.com/topic/skintumornonmelanocytickaposisarcoma.html Accessed on January, 19 2015
↑ ^3.0 ^3.1 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.
↑ 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.
↑ ^5.0 ^5.1 Burbelo PD, Leahy HP, Groot S, Bishop LR, Miley W, Iadarola MJ, Whitby D, Kovacs JA (May 2009). "Four-antigen mixture containing v-cyclin for serological screening of human herpesvirus 8 infection". Clin. Vaccine Immunol. 16 (5): 621–7. doi:10.1128/CVI.00474-08. PMC 2681582. PMID 19261774.
↑ De Leo A, Deng Z, Vladimirova O, Chen HS, Dheekollu J, Calderon A, Myers KA, Hayden J, Keeney F, Kaufer BB, Yuan Y, Robertson E, Lieberman PM (January 2019). "LANA oligomeric architecture is essential for KSHV nuclear body formation and viral genome maintenance during latency". PLoS Pathog. 15 (1): e1007489. doi:10.1371/journal.ppat.1007489. PMID 30682185.
↑ Zhu L, Wang R, Sweat A, Goldstein E, Horvat R, Chandran B (April 1999). "Comparison of human sera reactivities in immunoblots with recombinant human herpesvirus (HHV)-8 proteins associated with the latent (ORF73) and lytic (ORFs 65, K8.1A, and K8.1B) replicative cycles and in immunofluorescence assays with HHV-8-infected BCBL-1 cells". Virology. 256 (2): 381–92. doi:10.1006/viro.1999.9674. PMID 10191203.
↑ 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.
↑ 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.
↑ 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.
↑ ^11.0 ^11.1 ^11.2 ^11.3 ^11.4 ^11.5 Libre Pathology. Kaposi's sarcoma (2015) http://librepathology.org/wiki/index.php/File:Kaposi_sarcoma_low_intermed_mag.jpg Accessed on January, 19 2016
↑ Photo Credit: Sol Silverman, Jr., D.D.S.Content Providers: CDC/ Sol Silverman, Jr., D.D.S., University of California, San Francisco [Public domain], https://upload.wikimedia.org/wikipedia/commons/d/d5/Kaposi%E2%80%99s_sarcoma_intraoral_AIDS_072_lores.jpg
↑ Photo courtesy: Michael Sand, Daniel Sand, Christina Thrandorf, Volker Paech, Peter Altmeyer, Falk G Bechara [CC BY 2.5https://creativecommons.org/licenses/by/2.5)],https://commons.wikimedia.org/wiki/File:Kaposi%27sSarcoma.jpg
↑ Photo courtesy: Yale Rosen from USA [CC BY-SA 2.0 https://creativecommons.org/licenses/by-sa/2.0)],https://commons.wikimedia.org/wiki/File:Kaposi_sarcoma_(3944996124).jpg
↑ Photo courtesy:Mohammad2018 [CC BY-SA 4.0 (https://creativecommons.org/licenses/by-sa/4.0)]https://commons.wikimedia.org/wiki/File:Kaposi_sarcoma_new_photo_to_help_in_diagnosis.jpg
↑ Photo Credit:Content Providers: CDC/ Dr. Steve Kraus [Public domain]https://commons.wikimedia.org/wiki/File:Kaposi%27s_sarcoma_lesion.jpg
↑ Photo Credit:OpenStax College [CC BY 3.0(https://creativecommons.org/licenses/by/3.0)]https://commons.wikimedia.org/wiki/File:Kaposis_Sarcoma_Lesions.jpg

Template:WH Template:WS

[pmid23806158-1] 1.0 ^1.1 ^1.2 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.

[patho2-2] 2.0 ^2.1 Kaposi's Sarcoma. PathologyOutlines (2015) http://www.pathologyoutlines.com/topic/skintumornonmelanocytickaposisarcoma.html Accessed on January, 19 2015

[pmid23685018-3] 3.0 ^3.1 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.

[pmid25068226-4] 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.

[pmid19261774-5] 5.0 ^5.1 Burbelo PD, Leahy HP, Groot S, Bishop LR, Miley W, Iadarola MJ, Whitby D, Kovacs JA (May 2009). "Four-antigen mixture containing v-cyclin for serological screening of human herpesvirus 8 infection". Clin. Vaccine Immunol. 16 (5): 621–7. doi:10.1128/CVI.00474-08. PMC 2681582. PMID 19261774.

[pmid30682185-6] De Leo A, Deng Z, Vladimirova O, Chen HS, Dheekollu J, Calderon A, Myers KA, Hayden J, Keeney F, Kaufer BB, Yuan Y, Robertson E, Lieberman PM (January 2019). "LANA oligomeric architecture is essential for KSHV nuclear body formation and viral genome maintenance during latency". PLoS Pathog. 15 (1): e1007489. doi:10.1371/journal.ppat.1007489. PMID 30682185.

[pmid10191203-7] Zhu L, Wang R, Sweat A, Goldstein E, Horvat R, Chandran B (April 1999). "Comparison of human sera reactivities in immunoblots with recombinant human herpesvirus (HHV)-8 proteins associated with the latent (ORF73) and lytic (ORFs 65, K8.1A, and K8.1B) replicative cycles and in immunofluorescence assays with HHV-8-infected BCBL-1 cells". Virology. 256 (2): 381–92. doi:10.1006/viro.1999.9674. PMID 10191203.

[pmid16809323-8] 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.

[pmid10738139-9] 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.

[pmid25341664-10] 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.

[patho-11] 11.0 ^11.1 ^11.2 ^11.3 ^11.4 ^11.5 Libre Pathology. Kaposi's sarcoma (2015) http://librepathology.org/wiki/index.php/File:Kaposi_sarcoma_low_intermed_mag.jpg Accessed on January, 19 2016

[12] Photo Credit: Sol Silverman, Jr., D.D.S.Content Providers: CDC/ Sol Silverman, Jr., D.D.S., University of California, San Francisco [Public domain], https://upload.wikimedia.org/wikipedia/commons/d/d5/Kaposi%E2%80%99s_sarcoma_intraoral_AIDS_072_lores.jpg

[13] Photo courtesy: Michael Sand, Daniel Sand, Christina Thrandorf, Volker Paech, Peter Altmeyer, Falk G Bechara [CC BY 2.5https://creativecommons.org/licenses/by/2.5)],https://commons.wikimedia.org/wiki/File:Kaposi%27sSarcoma.jpg

[14] Photo courtesy: Yale Rosen from USA [CC BY-SA 2.0 https://creativecommons.org/licenses/by-sa/2.0)],https://commons.wikimedia.org/wiki/File:Kaposi_sarcoma_(3944996124).jpg

[15] Photo courtesy:Mohammad2018 [CC BY-SA 4.0 (https://creativecommons.org/licenses/by-sa/4.0)]https://commons.wikimedia.org/wiki/File:Kaposi_sarcoma_new_photo_to_help_in_diagnosis.jpg

[16] Photo Credit:Content Providers: CDC/ Dr. Steve Kraus [Public domain]https://commons.wikimedia.org/wiki/File:Kaposi%27s_sarcoma_lesion.jpg

[17] Photo Credit:OpenStax College [CC BY 3.0(https://creativecommons.org/licenses/by/3.0)]https://commons.wikimedia.org/wiki/File:Kaposis_Sarcoma_Lesions.jpg

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 ==Overview==