Cáceres, Cinthia Veronica Bardalez Lopez de; Vargas, Pablo Agustin; Sánchez-Romero, Celeste; Bunn, Belinda K; Heerden, Willie F. P. van; Fonseca, Felipe Paiva

doi:10.1590/0103-6440201902599

Cinthia Veronica Bardalez Lopez de Cáceres

Department of Oral Diagnosis, UNICAMP - Universidade de Campinas, Piracicaba, SP, Brazil

https://orcid.org/0000-0002-9032-2067

Pablo Agustin Vargas

Department of Oral Diagnosis, UNICAMP - Universidade de Campinas, Piracicaba, SP, Brazil

Department of Oral Pathology and Oral Biology, School of Dentistry, Faculty of Health Sciences, University of Pretoria, Pretoria, South Africa

https://orcid.org/0000-0003-1840-4911

Celeste Sánchez-Romero

Department of Oral Diagnosis, UNICAMP - Universidade de Campinas, Piracicaba, SP, Brazil

https://orcid.org/0000-0001-5365-2692

Belinda K Bunn

Department of Oral Pathology and Oral Biology, School of Dentistry, Faculty of Health Sciences, University of Pretoria, Pretoria, South Africa

https://orcid.org/0000-0001-5699-4997

Willie F. P. van Heerden

Department of Oral Pathology and Oral Biology, School of Dentistry, Faculty of Health Sciences, University of Pretoria, Pretoria, South Africa

https://orcid.org/0000-0003-2494-667X

Felipe Paiva Fonseca

Department of Oral Diagnosis, UNICAMP - Universidade de Campinas, Piracicaba, SP, Brazil

Department of Oral Surgery and Patholog, School of Dentistry, UFMG, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil

https://orcid.org/0000-0002-6657-4547

Figuras (3)
Tabelas (2)

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Figure 1
Microscopic and immunohistochemical aspects of oral Kaposi’s sarcoma. A) All cases included in this study were categorized as solid Kaposi’s sarcoma and exhibited a spindle cell component with irregular blood vessels with different shapes and sizes (H&E; 50X). B) Higher magnification demonstrating the spindle cell component of Kaposi’s sarcomas (H&E; 100X). C) All cases were positive for the vascular marker CD34 (DAB; 200×) and D) were confirmed to be associated with HHV-8 infection, demonstrated as a nucler staining in the neoplastic cells (DAB; 200×).

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Figure 2
Immunohistochemical reactivity against CD207 in the epithelium and stroma of oral Kaposi’s sarcoma and of highly vascular oral lesions. A) CD207 stained immature LC in the overlying epithelium of oral Kaposis’s sarcoma, revealing the dendritic characteristic of these cells (DAB; 200×). B) In the stroma of Kaposi’s sarcomas, CD207+ IDC were very scarce and were observed as round cells without dendritic prolongations (DAB; 100×). C) A significantly higher count of CD207+ immature LC were observed in the epithelium of HIV-negative highly vascular oral lesions (DAB; 200×), D) whereas a lower count of CD207+ IDC was obtained inside the highly vascular oral lesions (DAB; 200×).

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Figure 3
Immunohistochemical reactivity against CD207 and CD83 in the epithelium and stroma of oral Kaposi’s sarcoma and of highly vascular oral lesions A) CD83 stained mature LC, few cells were observed in the epithelium of AIDS-associated oral Kaposi’s sarcomas (DAB; 100X). B) In the stroma of Kaposi’s sarcomas, whereas a higher number of CD83+ IDC (DAB; 100X). C) In highly vascular oral lesions, the number of CD83+ LC was lower than in Kaposi’s sarcoma (DAB; 200?)., and G) a significantly lower number of CD83+ IDC was observed in highly vascular oral lesions (DAB; 200×).

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Table 1
Distribution of LC and IDC in different compartments (epithelium and stroma of the lesions) of oral Kaposi’s sarcoma and in highly vascular oral lesions (hemangioma and pyogenic granuloma)

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Table 2
Summary of the available studies that investigated the importance of different dendritic cells in the pathogenesis of Kaposi’s sarcoma

Lesions	CD83
	Epithelium		Stroma		Epithelium		Stroma
	Mean (±SD)	Median (range)	Mean (±SD)	Median (range)	Mean (±SD)	Median (range)	Mean (±SD)	Median (range)
Kaposi’s sarcoma	44.2† (37.1)	35 (0 - 142)	17.9 (15.3)†	13 (0 - 62)	8.31 (8.0)	6 (0 - 37)	37.2 (20.9)†	35 (0 - 100)
Highly vascular oral lesions *	65.7 (26.4)	63 (18 - 109)	4.2 (2.4)	4 (1 - 11)	6.9 (6.9)	4 (0 - 21)	17.6 (11.0)	16.0 (4 - 46)

Authors	Country	KS clinical subtype	Sample source	No. cases	KS location	HIV status	DC investigated	Lab technique	Markers used	Main results	Lab technique	Markers used	Main results
Current study, 2017.	Brazil/South Africa	HIV-associated KS	Tissue	51 cases of KS ; 10 cases of pyogenic granuloma ; 10 cases of hemangioma	Oral mucosa	100% positive	Langerhans cells	IHC	CD83 + ; CD207 +	KS revealed a significantly lower CD207+ immature LC count and an increased CD207+ IDC than benign vascular oral lesions. Moreover, KS also showed an increased number of mature CD83+ IDC than benign vascular lesions.	IHC	CD83 + ; CD207 +	KS revealed a significantly lower CD207+ immature LC count and an increased CD207+ IDC than benign vascular oral lesions. Moreover, KS also showed an increased number of mature CD83+ IDC than benign vascular lesions.
Rappocciolo et al., 2017	USA	NA	Neonatal cord blood	-	NA	NA	Langerhans cells, Interstitial Dermal Dentritic cell, monocyte-derived dendritic cells.	Flow Cytometry; Cell culture; Immunofluorescence; PCR	HLA-DR CD1a CD11b CD14 CD91 CD80; CD86 CD83 ; CD209 CD207	HHV-8 can target both LC and iDDC for productive infection via different receptors and alter their function, supporting their potential role in HHV-8 pathogenesis and KS	Flow Cytometry; Cell culture; Immunofluorescence; PCR	HLA-DR CD1a CD11b CD14 CD91 CD80; CD86 CD83 ; CD209 CD207	HHV-8 can target both LC and iDDC for productive infection via different receptors and alter their function, supporting their potential role in HHV-8 pathogenesis and KS
Jivan et al., 2016	South Africa	HIV-associated KS	Tissue	Study groups: 15 cases of KS without Candida albicans co-infection ; 17 cases of KS with Candida albicans co-infection; Control groups: 23 cases of non-candida and non-HIV infected mucosa overlying pleomorphic adenomas ; 19 cases of oral candidosis from healthy patients	Oral mucosa	100% positive	Langerhans cells	IHC	CD1a +	Significant lower count of LC in non-Candida infected KS than in uninfected normal mucosa.	IHC	CD1a +	Significant lower count of LC in non-Candida infected KS than in uninfected normal mucosa.
Karouni et al., 2016	Lebanon	Classic KS	Tissue	20 cases of KS ; 20 cases of mollusccum contagiosun	Cutaneous	100% negative	Plasmacytoid DC	IHC	BDCA-2 + ; MxA + (to evaluate interferon production)	pDCs are recruited into the skin lesions of classic KS, but there is a significantly lower plasmacytoid cells and lower interferon production in cKS than in mollusccum cases.	IHC	BDCA-2 + ; MxA + (to evaluate interferon production)	pDCs are recruited into the skin lesions of classic KS, but there is a significantly lower plasmacytoid cells and lower interferon production in cKS than in mollusccum cases.
Ramdial et al., 2011	UK/South Africa	HIV-associated KS	Tissue	9 cases of anaplastic KS	Cutaneous	100% positive	Langerhans cells	IHC	S100+ ; CD1a+ ; CD207+	Presence of an extensive amount of intratumoral Langerhans cells.	IHC	S100+ ; CD1a+ ; CD207+	Presence of an extensive amount of intratumoral Langerhans cells.
West et al., 2011	USA	NA	Peripheral blood	Health subjects ; Laboratorial HHV8 infected DC cells	NA	NA	Plasmacytoid DC	Flow cytometry; Cell culture	BCDA4+ ; BDCA2+ ; CD303+ ; CD123+ ; CD83-/+ ; CD86-/+	KSHV can infect and activate human pDCs, as measured by upregulation of CD83 and CD86, and by IFN-α secretion. Induction of IFN-α occurs through activation of TLR9 signaling.	Flow cytometry; Cell culture	BCDA4+ ; BDCA2+ ; CD303+ ; CD123+ ; CD83-/+ ; CD86-/+	KSHV can infect and activate human pDCs, as measured by upregulation of CD83 and CD86, and by IFN-α secretion. Induction of IFN-α occurs through activation of TLR9 signaling.
Bella et al., 2006.	Italy	Classic KS	Peripheral blood	76 KS ; 72 controls	NA	100% negative	Myeloid cell ; Plasmacytoid cell ; Monocytes (DC precursor)	Flow cytometry; Cell culture	HLA-DR + ; CD3 - ; CD19 - ; CD20 - ; CD16 - ; CD14 - ; CD11c + ; CD123 + ; CD80 -/+ ; CD83 -/+ ; CD86 -/+ ; CD49c -/+ ; CD91 -/+ ; CD34 -/+ ; CD14 -/+ ; CD1a + ; CD40+ ; ILT2, 3, 4 +	PBDC (both myeloid, plasmacytoid and monocytes) in cKS patients were significantly lower than controls, and was more severe in more advanced cases. PBDC expressing the HHV8 receptor CD49c was higher in cKS patients than in healthy control;	Flow cytometry; Cell culture	HLA-DR + ; CD3 - ; CD19 - ; CD20 - ; CD16 - ; CD14 - ; CD11c + ; CD123 + ; CD80 -/+ ; CD83 -/+ ; CD86 -/+ ; CD49c -/+ ; CD91 -/+ ; CD34 -/+ ; CD14 -/+ ; CD1a + ; CD40+ ; ILT2, 3, 4 +	PBDC (both myeloid, plasmacytoid and monocytes) in cKS patients were significantly lower than controls, and was more severe in more advanced cases. PBDC expressing the HHV8 receptor CD49c was higher in cKS patients than in healthy control;
Stebbing et al., 2003.	UK	HIV-associated KS	Peripheral blood	12 cases of HIV-positive ; KS patients; 6 cases of HIV-positive patients ; without KS	NA	100% positive	Myeloid cell ; Plasmacytoid cell ; Monocytes (DC precursor)	Flow cytometry; Cell culture	CD3 - ; CD14 - ; CD16 - ; CD19 - ; HLA-DR + ; CD11c -/+ ; CD1a ; CD80 ; CD83 ; CD40 ; CD91	Despite the impaired functional capacity of DC in patients with KS, they retained the ability of activating and stimulating CD8 cytotoxic T cells. Plasmacytoid DCs were depleted in KS-positive compared with KS-negative HIV-1-infected patients.	Flow cytometry; Cell culture	CD3 - ; CD14 - ; CD16 - ; CD19 - ; HLA-DR + ; CD11c -/+ ; CD1a ; CD80 ; CD83 ; CD40 ; CD91	Despite the impaired functional capacity of DC in patients with KS, they retained the ability of activating and stimulating CD8 cytotoxic T cells. Plasmacytoid DCs were depleted in KS-positive compared with KS-negative HIV-1-infected patients.
Simonart et al., 2000	Belgium	Iatrogenic, sporadic and HIV-associated KS	Cell cultures derived from tissue	4 KS patients	Cutaneous	50% positive	Dendritic cell	IHC ; Flow cytometry ; Cell culture	CD1a	Less than 1% of the spindle cells cultured were positive for CD1a. Spindle cell cultures have nearly always given rise to cells with fibroblastic and/or smooth muscle cell differentiation. KS spindle cells lack endothelial and/or leucocyte markers.	IHC ; Flow cytometry ; Cell culture	CD1a	Less than 1% of the spindle cells cultured were positive for CD1a. Spindle cell cultures have nearly always given rise to cells with fibroblastic and/or smooth muscle cell differentiation. KS spindle cells lack endothelial and/or leucocyte markers.
Tabata et al., 1993	Germany/Japan	HIV-associated KS	Tissue	15 cases of HIV+ KS 19 cases of oral mucosa of HIV+ patients 22 cases of oral mucosa of HIV- patients	Oral mucosa	100% positive	Dendritic cells	IHC	HLA-DR +	The number of HLA-DR+ cells was increased in patch-like and nodular KS compared to HIV+ and HIV- normal mucosa.	IHC	HLA-DR +	The number of HLA-DR+ cells was increased in patch-like and nodular KS compared to HIV+ and HIV- normal mucosa.
Kanitakis et al., 1992	France	Classic KS Immunossupression-associated KS	Tissue	13 classic KS ;16 Immunes KS	Cutaneous	13 HIV+ patients	Dermal dendrocytes	IHC	Factor XIIIa + ; Antigen H -	Dermal dendrocytes density tended to be decreased in immunosuppression-associated Kaposi’s sarcoma when compared with classical form. The results do not support dermal dendrocytes as being the cells of origin of Kaposi’s sarcoma. Decreased density of dermal dendrocytes could be related with a more aggressive clinical course.	IHC	Factor XIIIa + ; Antigen H -	Dermal dendrocytes density tended to be decreased in immunosuppression-associated Kaposi’s sarcoma when compared with classical form. The results do not support dermal dendrocytes as being the cells of origin of Kaposi’s sarcoma. Decreased density of dermal dendrocytes could be related with a more aggressive clinical course.

[TFN1] *Hemangioma and pyogenic granuloma. †Statistically significant differences.

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Distribution of Dendritic Cells in AIDS-Associated Oral Kaposi’s Sarcoma

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