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Am J Clin Dermatol

DOI 10.1007/s40257-017-0270-4

REVIEW ARTICLE

Diagnosis and Treatment of Kaposi Sarcoma
Johann W. Schneider1 • Dirk P. Dittmer2

Ó Springer International Publishing Switzerland 2017

Abstract Kaposi sarcoma (KS) is the most common neo-
plasm of people living with HIV today. In Sub-Saharan Key Points
Africa, KS is among the most common cancers in men,
overall. Not only HIV-positive individuals present with Kaposi sarcoma continues to be among the most
KS; any immune compromised person infected with KS- common causes of morbidity and mortality in people
associated herpesvirus (KSHV) or human herpesvirus 8 is living with HIV worldwide.
at risk: the elderly, children in KSHV-endemic areas, and
There is evidence for multiple types of Kaposi
transplant recipients. KS diagnosis is based on detection of
sarcoma, dependent on clinical presentation,
the viral protein latency-associated nuclear antigen
cofactors and viral gene expression.
(LANA) in the biopsy, but not all cases of KS are the same
or will respond to the same therapy. Standard KS therapy New approaches to treat Kaposi sarcoma are under
has not changed in 20 years, but newer modalities are on development.
the horizon and will be discussed.

1 Introduction

It is somewhat disheartening, but after 20 years of intense
research, the cell of origin of Kaposi sarcoma (KS) remains
elusive. KS displays broad clinicopathological variation
depending on (1) the location of KS lesions (lymph node,
internal, or cutaneous), (2) the clinical stage (patch, plaque,
nodular), and (3) the epidemiological classification. The
latter includes classic KS in elderly men, African (en-
& Johann W. Schneider demic) KS in younger African men, women, and children,
jws2@sun.ac.za iatrogenic KS (mainly in transplant patients, but also can
& Dirk P. Dittmer be due to chemotherapy and other immune suppressive
ddittmer@med.unc.edu therapy), and epidemic HIV/AIDS-associated KS [1].
1
National Health Laboratory Service, Division of Anatomical Endemic KS includes a nodular clinically indolent form, an
Pathology, Faculty of Medicine and Health Sciences, aggressive variant with large invasive cutaneous tumors
Tygerberg Hospital, Stellenbosch University, PO Box 241, with involvement of underlying soft tissue and bone, and
Cape Town 8000, South Africa an endemic-pediatric variant that presents as lym-
2
Department of Microbiology and Immunology, Lineberger phadenopathy in young children [2, 3]. The overwhelming
Comprehensive Cancer Center, University of North Carolina majority of epidemic HIV-associated KS occurs in men
at Chapel Hill, CB#7295, 450 West Dr., Chapel Hill,
NC 27517, USA who have sex with men (MSM), but women, children,

which may explain serve as anti-apoptosis factors. This scenario repre- the epidemiologic variant. a KSHV poly- KSHV also encodes a large number of genes that help it to merase inhibitor. HIV proteins. developing KS is higher in KSHV seropositive HIV-posi- B. all forms infectious mononucleosis. This gene undetectable HIV viral load. fewer patients reviewed in detail [17]. KSHV seroconversion corre- forms of KS [7. contact is needed to establish transmission. 1). Additional clinicopathological persistence. sub-groups of epidemic KS comprise HIV-associated KS Obviously.e. D. P. J. On the other hand. i.e. evidence that lytic replication is required for systemic plants are also affected [4]. in college settings.. Here too. and KS associated with mission through saliva [24–28]. On the one hand. suggests that HIV infection may generate a qualitatively Limited evidence exists that certain KSHV subtypes may more deleterious immune deficiency than chemical. and this may explain the pro- foscarnet. autophagy inhibitors. For the purpose of this article it is developed KS if antiretroviral therapy (ART) was started important to recall that KSHV is a double-strand DNA immediately at 500 CD4 cells/mm3 compared to deferred virus that encodes more than 80 proteins and an extensive therapy initiation at still a respectable 350 CD4 cells/mm3.g. For adults. KS. ated KS with no or failing cART. heterosexual trans- of KS are treated the same: surgery/cryotherapy for mission of KSHV is not considered significant. and why ganciclovir had no effect on established KS lesions also oppose natural killer (NK) cell-mediated control of [32. 16]. KSHV replication is escape immune destruction during primary infection. The wide clinicopathological spectrum of KS suggests transmitted. end-stage AIDS. sequences correlates to 13 different variants of KSHV [14]. which is an increased risk for disseminated and progressive disease present at significantly higher levels in saliva and is readily [6]. oncogenesis. 33]. as these relate to the inhibition of the interferon (IFN) response. or HIV- uses a virus-encoded DNA-dependent DNA polymerase associated immune activation may result in KSHV reacti- (orf9) for genome replication during the lytic phase. i. E. such as occurs in Current evidence indicates that pediatric KS. regardless of mother-to-child or sexual interactions. independent of KS lesion status. D. 2 Kaposi Sarcoma (KS)-Associated Herpesvirus The fact that KS develops in HIV-negative transplant patients as well as in AIDS patients suggests that HIV in All variants of KS are caused by KS-associated herpesvirus itself is not required for KS. phylactic efficacy of ganciclovir [23. however. Transmission of KSHV is chiefly by horizontal trans- HIV-associated pediatric KS. The KS in the absence of massive CD4 cell deficiency suffer viral latency-associated nuclear antigen (LANA) alone is from more subtle impairments. 31]. HIV-associ. At any given time. viral replication is required for transmission. Yet.. These not required to maintain existing KS lesions. KSHV replication is known to viral polymerase is sensitive to the drugs ganciclovir and precede KS tumorigenesis. The virus is enveloped and Alternatively. but is less so in classic KS. set of micro RNAs (miRNAs). but sexual superficial skin lesions and liposomal doxorubicin (Dox. 8]. Schneider. with sents an important distinction to Epstein–Barr virus. Genetic variability of ORF-K1 gene tive patients than in HIV-negative transplant patients. or whether dividing infected cells [22] (Fig. on combined antiretroviral therapy (cART). and disease progression [23]. and F). KSHV infection (reviewed in [18]). Recently. though extensive. The vation. This notion is supported epidemiological types of KS [15. with near normal CD4 counts and proteins and viral latent miRNAs [19–21]. The fact that the risk of (KSHV) [9–13]. Like other herpesviruses. contain KSHV mostly in its latent form. saliva is considered gained acceptance. immune necessary and sufficient to maintain the viral episome in senescence. T-cell specific immunosuppression is a well-recognized KSHV like all herpesviruses establishes molecular cofactor in late-stage AIDS KS and in transplant-associated latency. HIV-negative endemic KS only a low percentage of KS tumor cells replicate the virus. Dittmer intravenous drug addicts. there exists there exist tumor triggers that operate entirely . e. repeated immune reconstitution inflammatory syndrome (IRIS) [5]. but not to acyclovir. and in KS that develops in HIV-positive individuals on while the majority of cells only express the viral latent successful therapy. is different from adult KS. KSHV comprises six major subtypes (A. and isolated cases of transmission by organ transplant have been reported [29]. Here. Whether persons that develop expression pattern suffices to maintain KS lesions. Transmission of KSHV through blood promise in clinical trials. and recipients of organ trans. HIV viral replication. and loss of T-cell repertoire [34].. where it leads to that KS does not represent a single disease. more treatment options have lates with contact number [26]. including in KS tumor cells. and newer targeted therapies show to be a major factor. transmission between MSM is important to explain the ele- ilTM) as first-line therapy for systemic and more extensive vated population prevalence. W. C. by results from the Strategic Timing of AntiRetroviral The molecular biology of KSHV has recently been Treatment (START) trial [30]. such as anergy. while vertical routes of transmission appear to be unimportant.or correlate with more aggressive disease or with particular drug-induced T-cell inactivation. transfusions is rare.

Even though 4 Update on KS Epidemiology: Classic and AIDS spindle cells comprise the bulk of the lesion and the pro. KS Kaposi sarcoma. may be necessary to sustain the lesion and KSHV and HIV seroprevalence and primarily adult trans- may secrete essential. single. There is evidence that KS is a mixture of tumor cells. nodular lesion in the upper left.. b Shows a computer-enhanced image of immunofluorescence or dots within the nuclear staining.e. Figure 2 summarizes they are in a minority. Other stromal components. only male cases are and spawn the highly proliferative spindle cells. Slit-like spaces in between the cells contain DNA staining in blue. tumor stem cells in KS could perpetuate the tumor Since only 6% of cases were female. KS incidence rates are stratified by age lial stem cells would be de-differentiated or trans. 1 KS pathology and histology. included. Finally. H&E hematoxylin and eosin. 36]. and gfp (to indicate infected cells) in green. a Shows an image of gross chromosome. may lead to advances in KS therapy. extravasated red blood cells. an area of low macrophages. is driven by AIDS KS between If so. group (\65 and 65?) as a crude surrogate to separate . endothelial cells (LEC) or blood-vessel endothelial cells (BEC)] [35–37. i. LANA staining is in red. c Shows an image of LANA staining of a KS lesion by morphology of disseminated KS on the surface of the lung. they may not be the driver population. lesion-driving paracrine factors [40]. though they also have features of smooth muscles cells and pericytes [37–39]. such as pericytes or even The epidemiology of KS in the USA. raised. then targeting these cell populations. the most recent data as collected in the SEER database. Note the spindle-shaped nature of the cells. mission in high-risk groups.’’ associated herpesvirus. d Shows an H&E stain of a KS in a KSHV recombinant virus that also expressed green fluorescent lesion. Note the immunohistochemistry (brown) with hematoxylin counterstain (blue). as compared to the flat Note all LANA staining is nuclear and the appearance of darker spots lesions. endothelial lineage [35. KS liferating fraction. Endothe. even though MSM and classic KS in the elderly. nuclear endothelial cell lineage. 41] that acquire traits of ‘‘stemness’’ (shared molecular pathways that underpin the fundamental 3 Cell Lineage/Origin and Differentiation in KS stem cell properties of self-renewal and specific cellular differentiation). as defined by loss of differentiation The spindle-shaped cells in KS lesions are believed to be of markers or gain of stemness markers.Diagnosis and Treatment of Kaposi Sarcoma Fig. KSHV KS- This analysis clearly shows the presence of discrete ‘‘LANA dots. LANA latency- each indicating a place where the viral genome is tethered to the host associated nuclear antigen independently of immune surveillance is the subject of differentiated lineage-specific endothelial cells [lymphatic ongoing scientific inquiries. which are of protein (gfp) in a PEL cell line. Firstly.

2 Review of KS incidence rates based on US SEER data (10-15- KS continues to comprise a significant percentage of total 2016). Since estimated 380. High-quality incidence data are difficult to obtain.000 new infections occurred in South Africa .. the 5-year survival for whites was 75. c Shows 5-year survival by cal. The incidence of AIDS KS no longer declines after the year 2000 as both KSHV and HIV are now established in the US population. but may point to a need for increased screening and education in addition to better treatment and overall health resources. 5 Update on KS epidemiology: Endemic and AIDS KS The epidemiology of KS in Sub-Saharan Africa and South Africa. [53]. Secondly. In the most recent 2006–2012 calendar period. 2. and KSHV seroprevalence was substan- tial prior to the emergence of HIV. illustrated by Bohlius et al. an 1981 and 1997 is clearly evident (Fig. approximately prevalence region. panel b). Dermatologists and oncologists will continue to see and treat KS lesions.2% compared to 15. is most severe in South Africa. In that age bracket. P. W. and 35% in Zimbabwe shown on the horizontal axis and incidence rate per 100. panel c). In the 1990–1992 calendar period. 2.e. Kaposi sarcoma. 44] and several other studies indicate that Fig. The HIV epidemic on the African continent classic and HIV-associated KS in a low KSHV sero. Dittmer 1997.4% for black KS patients. an area of high KSHV and substantial HIV seroprevalence is driven by AIDS KS and endemic KS in the elderly and children. who found that the early endar interval and also stratifies data by race/ethnicity (red circle introduction of ART decreased the risk of developing KS African American and blue triangle white). Here. The peak of the US KS epidemic between introduction of ART and actions to fight HIV infection. with 24% in (http://seer. Data and graphs were obtained using the SEER data website cancer burden in Sub-Saharan Africa. but has continued at a higher level up to today [42]. KS incidence rates are strat.000.gov/explorer/). This is reflected in a sig- nificantly higher rate of KS even in the most recent years (Fig. and in 2015. The 5-year survival for black KS patients is significantly worse than for white KS patients (Fig. The reason for this discrepancy is unclear. the 5-year survival for whites was 19. we see as many cases developing in younger males as in older males. 27% in Uganda. KSHV KS-associated herpesvirus KS continues to increase in South African pediatric patients [54]. The HIV epidemic ‘‘hit’’ the black communities in the USA somewhat delayed. KS by 80% in a cohort of HIV-infected South African patients. AA Age adjusted. a Stratifies data by age (orange circle \65 and gray the incidence of KS in HIV-infected patients. J. These SEER data indicate a significant race/ethnicity disparity with respect to KS incidence and response to treatment. Today.000 on the [45–52]. the survival disparity continues to this day. The introduction of ART has significantly reduced vertical axis. b Stratifies data by race/ethnicity (red circle African American and blue triangle white). but the World Health Organi- zation’s (WHO’s) Global Burden of Cancer Study (GLO- BOCAN) [43. For a and b the calendar year is Mozambique. Schneider. the KS incidence has remained level at *1/100. Despite the ified by race.3% compared to 59. panel a).cancer.1% for black KS patients. All of the KS cases in blacks are in younger men (0–44 years old). 2. 7 million South Africans lived with HIV. D. transmission is seen in the pediatric population (mother-to-child) as well as in the adult population. i. as eloquently triangle [65).

expression [77. however. fewer LANA positive cells. In 2015. the factors that influence the level of LANA typically. 76]. staining pattern for LANA in KS cells does not relate to especially if pathologists are not familiar with the spectrum patient age. The KSHV LANA has become the The Food and Drug Administration (FDA)-approved deciding diagnostic marker for KS. and lymphoma aris- 2015 (UNAIDS gap report as cited in http://www. and the bulk of the proliferating cell fraction as ascertained by potential alternative conditions should be considered in the Ki-67 stain or by other molecular markers of proliferation. recent studies highlighted plastic. treatment modalities for KS have not changed in 20 years. 50% of AIDS KS responds to . immunohistochemistry may be due to technical reasons or The wide morphological spectrum of KS may mimic very low viral copy numbers within KS cells. induction or with progressive KS. However. mize bleeding. LANA staining. LANA-specific mon. oclonal antibodies are robust and are commercially avail. chain reaction (PCR) has been shown to reliably detect intravascular. histopathological features that can be accurately diagnosed The absence of detectable LANA expression on by a trained histopathologist [57–60]. and these tend to have fewer spindle cells logical confirmation of a diagnosis of KS remains the gold and. subtle granular staining in KS cell nuclei [76]. clinical setting.avert. It depends to some degree on the clinical progression stage of the disease. The variable standard. hyperkeratotic. demonstrate LANA does not necessarily rule out KS in an tions. but not always. Superficial lesions or lesions that develop in patients on stable cART may have very few Although KS can be strongly suspected in an appropriate LANA-positive cells [74]. however. micronodular. LANA-stained sections should be carefully reassessed for including anaplastic. They represent a expression should therefore always prompt very careful unifying feature. Well-established clinical lesions of KS.who. scenarios. Histopatho. including multicentric Castleman’s severity of presentation. KSHV DNAemia is commonly present the fact that the South African ART program is the largest in HIV-positive patients with KS at the time of ART one in the world (http://www. 71. lymphangioma-like. As KS manifests in many forms. solid. All KSHV-infected cells transcribe 7 Update on Treatment Approaches so-called latent messenger RNAs and a minimal set of viral proteins [19. HIV prevalence in South Africa varied [70]. but the diagnosis is often not straight forward.000 patients died from AIDS-related illnesses in disease. the center of the protein: EQEQE. presenting a diagnostic pitfall to the pathologist. LANA expression is therefore not confined to KS between regions from 18 to 40% amongst adults. Depending on geographic location and associated conditions. In almost all KS biopsies. 65]. 6 Diagnosis and Pathology particularly in skin lesions. desmo. 64]. recent studies confirmed the limited pre. bullous. primary effusion lymphoma. A positive LANA stain therapies should also be divided into multiple application unequivocally confirms a diagnosis of KS in the appro. [19. KSHV in KS lesions even in the absence of LANA dal. and pigmented KS [57–61]. KS will therefore continue to almost all patients on ART and those with regression of KS be a major cancer burden. This may seem disappointing at first glance. differential diagnosis. In such cases. 73]. is variable.Diagnosis and Treatment of Kaposi Sarcoma and 180. Polymerase cavernous hemangioma-like. Failure to numerous unrelated non-neoplastic and neoplastic condi. suppression. AIDS KS responds to immune reconstitution and HIV LANA expression may also be present in other KSHV. despite lesions [65. spindle-shaped cells are infected by KSHV [63]. display characteristic expression remain unknown [76]. 72]. ecchymotic. 21. and constitute reconsideration of all clinicopathological features. clinical subtype of KS. Spindle-shaped false positive PCR results for KSHV [79]. pyogenic granuloma-like. the distribution of histopathological features of KS. implies that we have 20 years of experience with the cur- They are directed against a highly antigenic repeat motif in rent standard of care. Histopathological or extent of KS lesions. Although diagnosis of early stage KS depends on the detection of stage of KS and the immunohistochemical method have subtle clues that can be easily missed by the pathologist been shown to influence variable staining for LANA in KS [56]. keloidal. keloi. gender. priate clinicopathological context [66–69]. Negative LANA cells are present in all forms of KS [62].int/hiv/pub/arv/global. Pathologists should be aware of recognized variants of KS. cells. but it also able for automated immunohistochemical staining systems. among those. ing in KSHV-associated multicentric Castleman’s disease org). appropriate clinicopathological setting [77]. but is undetectable in aids-update-2016-pub/en/). 78]. telangiectatic. or CD4 count [75. However. KS with sarcoid-like potential contamination of KS biopsies with subsequent granulomas. KSHV is necessary for KS development [26. form the basis of diagnosis. glomeruloid. In patients with multiple lesions. there can be a tendency to biopsy milder lesions to mini- dictive value of clinical diagnosis alone [55]. KS with myoid nodules.

either in the context of T cells. olimus often leads to KS regression [101. 2). but not others. however. 99. 102]. If and how other modulators of inflammation and than optimal access to HIV and cancer care. Schneider. The goal is to reconstitute the immune system cyclophillin. Gilead uses cobicistat in its non. P. benefit in KS comparing non-protease inhibitor-containing Vascular endothelial growth factor (VEGF) is essential regimen to protease inhibitor-containing regimen [95]. mycin directly and independently of immune reconstitution A fraction of AIDS KS responds to introduction of in AIDS KS [74] and immunodeficient preclinical models cART with disease progression. Even established KS lesions respond to rapa- where KS lesions indicate HIV cART failure. including in children [105]. In addition. W. but concurrent agents. systemic immune explore more potent VEGFR/c-kit inhibitors such as activation or as a result of incomplete CD4 T-cell receptor cabozantinib. endothelial cells. it is noteworthy that VEGF therapy worked in some patients. It is noteworthy. B cells. many modern cART regimens no longer contain protease These variable results may be due to inadequacy of drug inhibitors. pan-kinase inhibitors such as sorafenib. 91]. or through the transplant [4. clinical trials of single-agent VEGF-neutralizing these would translate into clinical practice. The cause of this manifestation of KS is unclear. tectable HIV viral load and near normal CD4 counts such as the mTOR inhibitor sirolimus have shown clinical [96. There are also reports that failed to see a clinical where doxorubicin is not available. human evidence for the extreme immune reactivity of KS. Doxorubicin has now largely Switching the chemical immune suppressive regimen from replaced IFN-a. but has no protease inhibitory activity. Thus far. either in the form of unspecific. for endothelial proliferation. and inhibition of VEGF con- clinical data on the efficacy of nelfinavir against KS and other stitutes a rational therapeutic approach for KS. 117]. is only expressed in and suppress HIV replication. 107]. The It has since been observed in the context of other immune . i. both KS disease stabilization as well as disease median survival in response to cytotoxic chemotherapy is acceleration have been reported in response to steroids worse in resource-limited settings and populations with less [90. The though. basic fibroblast growth factor (bFGF). D. formulations of doxorubicin or daunorubicin minimize There are several studies that suggest that HIV protease systemic toxicity [106. some success in the early days of the AIDS epidemic and after transplant. or in the context of AIDS. solid tumors are encouraging. Further downstream acting drugs. 100]. and we speculate that this would have context of successful cART. which conversely implies that state of the art may be beneficial in the short term [89]. been termed KS immune reconstitution inflammatory leading to stable disease rather than inducing tumor syndrome (KS-IRIS) [86–88]. medication: elvitegravir/cobicistat/emtricitabine/tenofovir as VEGF. and in most indication of HIV infection. Here KSHV can be acquired before transplant. the overall performance status of nucleoside reverse transcriptase inhibitor (NNRTI)-based the patients. and pla- disoproxil. DNA-damaging Clearly withdrawing cART is not an option. J. of patients exposed to cART for the first time. imatinib) have been ambiguous [112–115]. Pre. We know that even these patients experience HIV efficacy in transplant KS. angiogenesis inhibitors such as bevacizumab are used in A third of AIDS KS in the USA now develops in the the adjuvant setting. 97]. Anti- no outcomes are available. Several trials of antibodies or VEGF receptor (VEGFR) inhibitors (beva- nelfinavir against KS and other solid cancers are ongoing. One efficacy are essential in the treatment of AIDS KS and difference between cyclosporine A and sirolimus is that often suffice. and it may be interesting to disease. are effective in 60–80% of KS chemotherapy and perhaps immune-modulating adjuvants in the USA. State of the art cART and monitoring of its mechanism of action is the subject of investigation. KS tumors. where KS lesions are the first expressed in T cells. in particular. but it is difficult to judge how however. 92–94]. paclitaxel also inhibitors and. anti-VEGF antibodies with different pharmacokinetics or Transplant KS responds to immune reconstitution. It is often activity in addition to their anti-retroviral activity considered as second-line therapy or is used in situations [88. Dittmer cART [80–85]. particularly Cytotoxic chemotherapy represents the standard of care in Africa. intralesional applications. Importantly therapy fails in up to a third of KS patients (Fig. 29. in that the cyclosporine A/FK506 to mammalian target of rapamycin clinical success of pegylated IFN-a provided the first-in- (mTOR) inhibitors such as rapamycin/sirolimus/ever. though lowering the immunosuppressive dose risks graft IFN-a and its pegylated derivatives have been used with rejection. delivery to the KS lesion. Liposomal immunoactivation would work is unknown. the target of cyclosporine. the target of rapamycin. This phenomenon has [103]. and redundancy in angiogenic factor signaling. such as doxorubicin. in patients with unde. or reconstitution after symptomatic HIV disease [98]. For instance. Cobicistat like the protease inhibitor ritonavir telet-derived growth factor (PDGF) all contribute to KS boosts drug concentrations by inhibiting P450 metabolism. for KS [104]. In other solid tumor indications. It is seen in as many as 10% regression outright. is treatment-naive patients.. In this regard. though rapamycin primarily stalls tumor growth. growth [116. nelfinavir have direct anti-KS shows clinical efficacy against KS [108–111]. but cizumab. against classic KS [118–121].e. utility in KS as well. whereas mTOR.

this in turn may stimu. At this point. People 2005. This did not influence the opinions expressed in this review. Funding This work is supported by Public Health Service (PHS) and are the subject of ongoing clinical studies.61(3):165–73. Immune checkpoint inhibitors have gained notoriety because of their overwhelming efficacy in a select group of Conflict of interest DPD has received reagents from and was in a immunoreactive cancers. et al. though not all. the expression of the T-cell inhibitory 2. Pathogenesis and Treatment. clinical evidence has not been formally reported. against a variety of conditions.11(4):e0153335. Another group of agents with promising clinical expe.90(7):2826–9. Newsom-Davis in people living with HIV/AIDS. 1997. Strazzulla LC. 4. Blood. Parravicini C. Small studies suggest that KS tumor Kaposi’s Sarcoma: Epidemiology.23(22):5224–8. but support DNA or RNA is not yet developed to the same standard of further explorations in this area. 2015. Clinical factors associated with long-term molecule PD-L1 is variable and needs to be explored further complete remission versus poor response to chemotherapy in [138. as sional therapy alone or newer agents with more limited have reports of treatment failures [126–128]. In sum. KS even if HIV is controlled by cART. anti-angiogenesis proper. Olsen SJ. El-Mallawany NK. Compliance with Ethical Standards ties. A fraction of KS. Since 2015. These agents have broad immunomodulatory. JWS likely that these agents will be also active against KS. Risk of Kaposi’s sarcoma-associated herpes virus trans- mission from donor allografts among Italian posttransplant Kaposi’s sarcoma patients. References which is a negative co-receptor that is expressed on activated T cells. If this and often accompanied by systemic KS. but imiquimod was one of the early days of the AIDS epidemic. Young AM. Kamiyango W. A systemic toxicity than standard dose chemotherapy. and JWS is a KS. but we and superficial basal cell carcinoma. KS will continue to be seen at elevated frequencies 5. Poli F. which is supported by PHS Grant CA181255. The molecular mechanisms of these seemingly of LANA in biopsies of KS lesions. 139]. but is greatly improved by the detection alone. tional study. Sirchia G. targeting nuclear factor-jB (NF-jB) among others. et al. Thirlwell C. PLoS ONE. Gao SJ. including melanoma and poly. transplant KS lesions as well as increase as a person ages. Capra M. cells do not express the T-cell co-stimulatory molecules CD80 Dermatol Ther (Heidelb). classic KS. Acknowledgements We would like to thank our colleagues B. J Trop Pediatr. will spontaneously regress. generic do not yet know which types of KS and which kind of forms of imiquimod have been available. At present. clinical trial has not been conducted. accuracy. Damania. or as adjuvant to chemotherapy. . In the era of concurrent cART and complete late tissue and tumor-resident antigen-presenting cells HIV suppression. now experience substantial co-infection with HIV. Mandalia S. Nelson M. Curtiss P. It is Inc. Nivolumab is a humanized monoclonal antibody directed against PD-1. Anthony Eason for critical reading and riences [129–132] includes thalidomide and its more active insightful discussions. and this risk will Many.6(4):465–70. Slone JS. the AIDS Malignancies Consortium HIV-infected children and adolescents with Kaposi sarcoma (AMC) is conducting a phase I/II trial of nivolumab alone or in receiving bleomycin and vincristine: a retrospective observa- combination with ipilimumab in KS (NCT02408861). An Update on directed against CTL4. TLR7/8 agonists patients will benefit the most from these new agents. Like other Grants DE018304 and CA190152 to DPD and CA192744 to JWS and immunomodulatory agents. Ipilimumab is a humanized monoclonal antibody 1. J Clin Oncol. which is supported by PHS Grant CA121947. consulting agreement related to KS with Delenex AG and Navidea omavirus-associated Merkel cell carcinoma [133–136]. although has no conflicts of interest to declare. drug delivery. Villiera J. Bower M. Marcia Sanders. VEGF/VEGFR inhi- topical formulation for the treatment of actinic keratosis bitors and immune modulatory agents show promise. requiring systemic reactivation leads to virus release. Detection of KSHV spontaneous regression events are unclear. like a fraction of co-infected with HIV and KSHV are at risk of developing melanoma (reviewed in [123]). several cases of skin KS responding to with only localized lesions and may benefit from intrale- topical treatment with imiquimod have been published. Stefan DC. Cox CM. Patterns of distribution of childhood cancer in Africa. It is FDA approved as a Newer approaches such as sirolimus. Doxorubicin and paclitaxel are efficacious Imiquimod is a TLR7 agonist with non-specific activity against KS. Immune reconstitution inflammatory syn- common cancer in regions that were endemic for KSHV and drome associated with Kaposi’s sarcoma. 3. 8 Summary and Outlook et al. Kovarik CL. one could speculate that their DPD. and CD86 [137]. member of the AIDS Cancer Specimen Resource (ACSR). 2016. many HIV-positive KS patients present [125]. In the reactivate KSHV [124]. derivatives pomalidomide and lenalidomide. 2016. Friedman-Kien AE.Diagnosis and Treatment of Kaposi Sarcoma modulatory drugs [122]. skin KS was extensive weaker stimulants in this experimental system. but are also associated with significant toxicity. The histopathological diagnosis AIDS KS lesions will regress upon immune reconstitution of KS is not trivial. It remains the most T. The authors are members of the AIDS Malignancy Consortium benefit will be most pronounced in the setting of limited (AMC).

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