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

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,
[email protected] iatrogenic KS (mainly in transplant patients, but also can
& Dirk P. Dittmer be due to chemotherapy and other immune suppressive
[email protected] 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,
 J. W. Schneider, D. P. Dittmer

intravenous drug addicts, and recipients of organ trans- evidence that lytic replication is required for systemic
plants are also affected [4]. Additional clinicopathological persistence, oncogenesis, and disease progression [23].
sub-groups of epidemic KS comprise HIV-associated KS Obviously, viral replication is required for transmission,
on combined antiretroviral therapy (cART), HIV-associ- independent of KS lesion status.
ated KS with no or failing cART, i.e., end-stage AIDS, Transmission of KSHV is chiefly by horizontal trans-
HIV-associated pediatric KS, and KS associated with mission through saliva [2428], though extensive, repeated
immune reconstitution inflammatory syndrome (IRIS) [5]. contact is needed to establish transmission, such as occurs in
Current evidence indicates that pediatric KS, regardless of mother-to-child or sexual interactions. This scenario repre-
the epidemiologic variant, is different from adult KS, with sents an important distinction to EpsteinBarr virus, which is
an increased risk for disseminated and progressive disease present at significantly higher levels in saliva and is readily
[6]. The wide clinicopathological spectrum of KS suggests transmitted, e.g., in college settings, where it leads to
that KS does not represent a single disease. Yet, all forms infectious mononucleosis. For adults, heterosexual trans-
of KS are treated the same: surgery/cryotherapy for mission of KSHV is not considered significant, but sexual
superficial skin lesions and liposomal doxorubicin (Dox- transmission between MSM is important to explain the ele-
ilTM) as first-line therapy for systemic and more extensive vated population prevalence. KSHV seroconversion corre-
forms of KS [7, 8]. Recently, more treatment options have lates with contact number [26]. Here too, saliva is considered
gained acceptance, and newer targeted therapies show to be a major factor. Transmission of KSHV through blood
promise in clinical trials. transfusions is rare, and isolated cases of transmission by
organ transplant have been reported [29], while vertical
routes of transmission appear to be unimportant.
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. The fact that the risk of
(KSHV) [913]. KSHV comprises six major subtypes (A, developing KS is higher in KSHV seropositive HIV-posi-
B, C, D, E, and F). Genetic variability of ORF-K1 gene tive patients than in HIV-negative transplant patients,
sequences correlates to 13 different variants of KSHV [14]. suggests that HIV infection may generate a qualitatively
Limited evidence exists that certain KSHV subtypes may more deleterious immune deficiency than chemical- or
correlate with more aggressive disease or with particular drug-induced T-cell inactivation. This notion is supported
epidemiological types of KS [15, 16]. by results from the Strategic Timing of AntiRetroviral
The molecular biology of KSHV has recently been Treatment (START) trial [30]. Here, fewer patients
reviewed in detail [17]. 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.
set of micro RNAs (miRNAs). The virus is enveloped and Alternatively, HIV viral replication, HIV proteins, 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. The vation. On the one hand, KSHV replication is known to
viral polymerase is sensitive to the drugs ganciclovir and precede KS tumorigenesis, and this may explain the pro-
foscarnet, but not to acyclovir. Like other herpesviruses, phylactic efficacy of ganciclovir [23, 31], a KSHV poly-
KSHV also encodes a large number of genes that help it to merase inhibitor. On the other hand, KSHV replication is
escape immune destruction during primary infection. These not required to maintain existing KS lesions, as these
relate to the inhibition of the interferon (IFN) response, contain KSHV mostly in its latent form, which may explain
serve as anti-apoptosis factors, autophagy inhibitors, and why ganciclovir had no effect on established KS lesions
also oppose natural killer (NK) cell-mediated control of [32, 33].
KSHV infection (reviewed in [18]). 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, including in KS tumor cells. At any given time, KS, but is less so in classic KS, HIV-negative endemic KS
only a low percentage of KS tumor cells replicate the virus, and in KS that develops in HIV-positive individuals on
while the majority of cells only express the viral latent successful therapy, i.e., with near normal CD4 counts and
proteins and viral latent miRNAs [1921]. This gene undetectable HIV viral load. Whether persons that develop
expression pattern suffices to maintain KS lesions. The KS in the absence of massive CD4 cell deficiency suffer
viral latency-associated nuclear antigen (LANA) alone is from more subtle impairments, such as anergy, immune
necessary and sufficient to maintain the viral episome in senescence, and loss of T-cell repertoire [34], or whether
dividing infected cells [22] (Fig. 1); however, there exists there exist tumor triggers that operate entirely
Diagnosis and Treatment of Kaposi Sarcoma

Fig. 1 KS pathology and histology. a Shows an image of gross chromosome. c Shows an image of LANA staining of a KS lesion by
morphology of disseminated KS on the surface of the lung. Note the immunohistochemistry (brown) with hematoxylin counterstain (blue).
single, raised, nodular lesion in the upper left, as compared to the flat Note all LANA staining is nuclear and the appearance of darker spots
lesions. b Shows a computer-enhanced image of immunofluorescence or dots within the nuclear staining. d Shows an H&E stain of a KS
in a KSHV recombinant virus that also expressed green fluorescent lesion. Note the spindle-shaped nature of the cells, which are of
protein (gfp) in a PEL cell line. LANA staining is in red, nuclear endothelial cell lineage. Slit-like spaces in between the cells contain
DNA staining in blue, and gfp (to indicate infected cells) in green. extravasated red blood cells. KS Kaposi sarcoma, KSHV KS-
This analysis clearly shows the presence of discrete LANA dots, associated herpesvirus, H&E hematoxylin and eosin, 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. endothelial cells (LEC) or blood-vessel endothelial cells
(BEC)] [3537, 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.
endothelial lineage [35, 36], though they also have features
of smooth muscles cells and pericytes [3739]. There is
evidence that KS is a mixture of tumor cells. Even though 4 Update on KS Epidemiology: Classic and AIDS
spindle cells comprise the bulk of the lesion and the pro- KS
liferating fraction, they may not be the driver population.
Other stromal components, such as pericytes or even The epidemiology of KS in the USA, i.e., an area of low
macrophages, may be necessary to sustain the lesion and KSHV and HIV seroprevalence and primarily adult trans-
may secrete essential, lesion-driving paracrine factors [40]. mission in high-risk groups, is driven by AIDS KS between
If so, then targeting these cell populations, even though MSM and classic KS in the elderly. Figure 2 summarizes
they are in a minority, may lead to advances in KS therapy. the most recent data as collected in the SEER database.
Finally, tumor stem cells in KS could perpetuate the tumor Since only 6% of cases were female, only male cases are
and spawn the highly proliferative spindle cells. Endothe- included. Firstly, KS incidence rates are stratified by age
lial stem cells would be de-differentiated or trans- group (\65 and 65?) as a crude surrogate to separate
 J. W. Schneider, D. P. Dittmer

1997, the KS incidence has remained level at *1/100,000.

Today, we see as many cases developing in younger males
as in older males. The incidence of AIDS KS no longer
declines after the year 2000 as both KSHV and HIV are
now established in the US population. Dermatologists and
oncologists will continue to see and treat KS lesions.
These SEER data indicate a significant race/ethnicity
disparity with respect to KS incidence and response to
treatment. The HIV epidemic hit the black communities
in the USA somewhat delayed, but has continued at a
higher level up to today [42]. This is reflected in a sig-
nificantly higher rate of KS even in the most recent years
(Fig. 2, panel b). The 5-year survival for black KS patients
is significantly worse than for white KS patients (Fig. 2,
panel c). All of the KS cases in blacks are in younger men
(044 years old). In that age bracket, the survival disparity
continues to this day. In the 19901992 calendar period,
the 5-year survival for whites was 19.2% compared to
15.1% for black KS patients. In the most recent 20062012
calendar period, the 5-year survival for whites was 75.3%
compared to 59.4% for black KS patients. The reason for
this discrepancy is unclear, 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, i.e., an area of high KSHV and substantial HIV
seroprevalence is driven by AIDS KS and endemic KS in
the elderly and children. Here, transmission is seen in the
pediatric population (mother-to-child) as well as in the
adult population, and KSHV seroprevalence was substan-
tial prior to the emergence of HIV. High-quality incidence
data are difficult to obtain, but the World Health Organi-
zations (WHOs) Global Burden of Cancer Study (GLO-
BOCAN) [43, 44] and several other studies indicate that
Fig. 2 Review of KS incidence rates based on US SEER data (10-15-
KS continues to comprise a significant percentage of total
2016). Data and graphs were obtained using the SEER data website cancer burden in Sub-Saharan Africa, with 24% in
(http://seer.cancer.gov/explorer/). For a and b the calendar year is Mozambique, 27% in Uganda, and 35% in Zimbabwe
shown on the horizontal axis and incidence rate per 100,000 on the [4552]. The introduction of ART has significantly reduced
vertical axis. a Stratifies data by age (orange circle \65 and gray
the incidence of KS in HIV-infected patients, as eloquently
triangle [65). b Stratifies data by race/ethnicity (red circle African
American and blue triangle white). c Shows 5-year survival by cal- illustrated by Bohlius et al. [53], 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). AA Age adjusted, KS by 80% in a cohort of HIV-infected South African patients.
Kaposi sarcoma, KSHV KS-associated herpesvirus
KS continues to increase in South African pediatric
patients [54]. The HIV epidemic on the African continent
classic and HIV-associated KS in a low KSHV sero- is most severe in South Africa, and in 2015, approximately
prevalence region. Secondly, KS incidence rates are strat- 7 million South Africans lived with HIV. Despite the
ified by race. The peak of the US KS epidemic between introduction of ART and actions to fight HIV infection, an
1981 and 1997 is clearly evident (Fig. 2, panel a). Since estimated 380,000 new infections occurred in South Africa
Diagnosis and Treatment of Kaposi Sarcoma

and 180,000 patients died from AIDS-related illnesses in disease, primary effusion lymphoma, and lymphoma aris-
2015 (UNAIDS gap report as cited in http://www.avert. ing in KSHV-associated multicentric Castlemans disease
org). In 2015, HIV prevalence in South Africa varied [70]. LANA expression is therefore not confined to KS
between regions from 18 to 40% amongst adults, despite lesions [65, 71, 72]. 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.who.int/hiv/pub/arv/global- induction or with progressive KS, but is undetectable in
aids-update-2016-pub/en/). KS will therefore continue to almost all patients on ART and those with regression of KS
be a major cancer burden. [19, 73].
LANA staining, however, is variable. It depends to some
degree on the clinical progression stage of the disease,
6 Diagnosis and Pathology particularly in skin lesions. 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]. In patients with multiple lesions,
clinical setting, recent studies confirmed the limited pre- there can be a tendency to biopsy milder lesions to mini-
dictive value of clinical diagnosis alone [55]. Histopatho- mize bleeding, and these tend to have fewer spindle cells
logical confirmation of a diagnosis of KS remains the gold and, among those, fewer LANA positive cells. The variable
standard, but the diagnosis is often not straight forward, staining pattern for LANA in KS cells does not relate to
especially if pathologists are not familiar with the spectrum patient age, gender, clinical subtype of KS, the distribution
of histopathological features of KS. Histopathological or extent of KS lesions, or CD4 count [75, 76]. 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]. Well-established clinical lesions of KS, however, cells, the factors that influence the level of LANA
typically, but not always, display characteristic expression remain unknown [76].
histopathological features that can be accurately diagnosed The absence of detectable LANA expression on
by a trained histopathologist [5760]. immunohistochemistry may be due to technical reasons or
The wide morphological spectrum of KS may mimic very low viral copy numbers within KS cells. Failure to
numerous unrelated non-neoplastic and neoplastic condi- demonstrate LANA does not necessarily rule out KS in an
tions, presenting a diagnostic pitfall to the pathologist. appropriate clinicopathological setting [77]. In such cases,
Pathologists should be aware of recognized variants of KS, LANA-stained sections should be carefully reassessed for
including anaplastic, telangiectatic, lymphangioma-like, subtle granular staining in KS cell nuclei [76]. Polymerase
cavernous hemangioma-like, pyogenic granuloma-like, chain reaction (PCR) has been shown to reliably detect
intravascular, bullous, ecchymotic, hyperkeratotic, keloi- KSHV in KS lesions even in the absence of LANA
dal, micronodular, glomeruloid, solid, keloidal, desmo- expression [77, 78]. However, recent studies highlighted
plastic, KS with myoid nodules, KS with sarcoid-like potential contamination of KS biopsies with subsequent
granulomas, and pigmented KS [5761]. Spindle-shaped false positive PCR results for KSHV [79]. Negative LANA
cells are present in all forms of KS [62]. They represent a expression should therefore always prompt very careful
unifying feature, form the basis of diagnosis, and constitute reconsideration of all clinicopathological features, 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. differential diagnosis.
In almost all KS biopsies, spindle-shaped cells are
infected by KSHV [63]. KSHV is necessary for KS
development [26, 64]. All KSHV-infected cells transcribe 7 Update on Treatment Approaches
so-called latent messenger RNAs and a minimal set of viral
proteins [19, 21, 65]. The KSHV LANA has become the The Food and Drug Administration (FDA)-approved
deciding diagnostic marker for KS. LANA-specific mon- treatment modalities for KS have not changed in 20 years.
oclonal antibodies are robust and are commercially avail- This may seem disappointing at first glance, but it also
able for automated immunohistochemical staining systems. 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. As KS manifests in many forms,
the center of the protein: EQEQE. A positive LANA stain therapies should also be divided into multiple application
unequivocally confirms a diagnosis of KS in the appro- scenarios.
priate clinicopathological context [6669]. However, AIDS KS responds to immune reconstitution and HIV
LANA expression may also be present in other KSHV- suppression. Depending on geographic location and
associated conditions, including multicentric Castlemans severity of presentation, 50% of AIDS KS responds to
 J. W. Schneider, D. P. Dittmer

cART [8085]. State of the art cART and monitoring of its mechanism of action is the subject of investigation. One
efficacy are essential in the treatment of AIDS KS and difference between cyclosporine A and sirolimus is that
often suffice. The goal is to reconstitute the immune system cyclophillin, the target of cyclosporine, is only expressed in
and suppress HIV replication, either in the context of T cells, whereas mTOR, the target of rapamycin, is
treatment-naive patients, where KS lesions are the first expressed in T cells, B cells, endothelial cells, and in most
indication of HIV infection, or in the context of AIDS, KS tumors. Even established KS lesions respond to rapa-
where KS lesions indicate HIV cART failure. 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. This phenomenon has [103], though rapamycin primarily stalls tumor growth,
been termed KS immune reconstitution inflammatory leading to stable disease rather than inducing tumor
syndrome (KS-IRIS) [8688]. It is seen in as many as 10% regression outright.
of patients exposed to cART for the first time, particularly Cytotoxic chemotherapy represents the standard of care
in Africa. The cause of this manifestation of KS is unclear. for KS [104], including in children [105]. DNA-damaging
Clearly withdrawing cART is not an option, but concurrent agents, such as doxorubicin, are effective in 6080% of KS
chemotherapy and perhaps immune-modulating adjuvants in the USA, which conversely implies that state of the art
may be beneficial in the short term [89]. Importantly therapy fails in up to a third of KS patients (Fig. 2). The
though, 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, 91]. If and how other modulators of inflammation and than optimal access to HIV and cancer care. Liposomal
immunoactivation would work is unknown. formulations of doxorubicin or daunorubicin minimize
There are several studies that suggest that HIV protease systemic toxicity [106, 107]. In addition, paclitaxel also
inhibitors and, in particular, nelfinavir have direct anti-KS shows clinical efficacy against KS [108111]. It is often
activity in addition to their anti-retroviral activity considered as second-line therapy or is used in situations
[88, 9294]. There are also reports that failed to see a clinical where doxorubicin is not available.
benefit in KS comparing non-protease inhibitor-containing Vascular endothelial growth factor (VEGF) is essential
regimen to protease inhibitor-containing regimen [95]. Pre- 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. Thus far,
solid tumors are encouraging, but it is difficult to judge how however, clinical trials of single-agent VEGF-neutralizing
these would translate into clinical practice. Several trials of antibodies or VEGF receptor (VEGFR) inhibitors (beva-
nelfinavir against KS and other solid cancers are ongoing, but cizumab, imatinib) have been ambiguous [112115]. Anti-
no outcomes are available. In this regard, it is noteworthy that VEGF therapy worked in some patients, but not others.
many modern cART regimens no longer contain protease These variable results may be due to inadequacy of drug
inhibitors. For instance, Gilead uses cobicistat in its non- delivery to the KS lesion, the overall performance status of
nucleoside reverse transcriptase inhibitor (NNRTI)-based the patients, and redundancy in angiogenic factor signaling,
medication: elvitegravir/cobicistat/emtricitabine/tenofovir as VEGF, basic fibroblast growth factor (bFGF), and pla-
disoproxil. Cobicistat like the protease inhibitor ritonavir telet-derived growth factor (PDGF) all contribute to KS
boosts drug concentrations by inhibiting P450 metabolism, growth [116, 117]. In other solid tumor indications,
but has no protease inhibitory activity. angiogenesis inhibitors such as bevacizumab are used in
A third of AIDS KS in the USA now develops in the the adjuvant setting, and we speculate that this would have
context of successful cART, i.e., in patients with unde- utility in KS as well. Further downstream acting drugs,
tectable HIV viral load and near normal CD4 counts such as the mTOR inhibitor sirolimus have shown clinical
[96, 97]. We know that even these patients experience HIV efficacy in transplant KS, and it may be interesting to
disease, either in the form of unspecific, systemic immune explore more potent VEGFR/c-kit inhibitors such as
activation or as a result of incomplete CD4 T-cell receptor cabozantinib, pan-kinase inhibitors such as sorafenib, or
reconstitution after symptomatic HIV disease [98]. anti-VEGF antibodies with different pharmacokinetics or
Transplant KS responds to immune reconstitution, intralesional applications.
though lowering the immunosuppressive dose risks graft IFN-a and its pegylated derivatives have been used with
rejection. Here KSHV can be acquired before transplant, some success in the early days of the AIDS epidemic and
after transplant, or through the transplant [4, 29, 99, 100]. against classic KS [118121]. Doxorubicin has now largely
Switching the chemical immune suppressive regimen from replaced IFN-a. It is noteworthy, however, 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- human evidence for the extreme immune reactivity of KS.
olimus often leads to KS regression [101, 102]. The It has since been observed in the context of other immune
Diagnosis and Treatment of Kaposi Sarcoma

modulatory drugs [122]. A fraction of KS, like a fraction of co-infected with HIV and KSHV are at risk of developing
melanoma (reviewed in [123]), will spontaneously regress. KS even if HIV is controlled by cART, and this risk will
Many, though not all, transplant KS lesions as well as increase as a person ages. The histopathological diagnosis
AIDS KS lesions will regress upon immune reconstitution of KS is not trivial, but is greatly improved by the detection
alone. The molecular mechanisms of these seemingly of LANA in biopsies of KS lesions. Detection of KSHV
spontaneous regression events are unclear, but support DNA or RNA is not yet developed to the same standard of
further explorations in this area. accuracy. Doxorubicin and paclitaxel are efficacious
Imiquimod is a TLR7 agonist with non-specific activity against KS, but are also associated with significant toxicity.
against a variety of conditions. It is FDA approved as a Newer approaches such as sirolimus, VEGF/VEGFR inhi-
topical formulation for the treatment of actinic keratosis bitors and immune modulatory agents show promise, but we
and superficial basal cell carcinoma. Since 2015, generic do not yet know which types of KS and which kind of
forms of imiquimod have been available. TLR7/8 agonists patients will benefit the most from these new agents. In the
reactivate KSHV [124], but imiquimod was one of the early days of the AIDS epidemic, skin KS was extensive
weaker stimulants in this experimental system. If this and often accompanied by systemic KS, requiring systemic
reactivation leads to virus release, this in turn may stimu- drug delivery. In the era of concurrent cART and complete
late tissue and tumor-resident antigen-presenting cells HIV suppression, many HIV-positive KS patients present
[125]. At this point, several cases of skin KS responding to with only localized lesions and may benefit from intrale-
topical treatment with imiquimod have been published, as sional therapy alone or newer agents with more limited
have reports of treatment failures [126128]. A systemic toxicity than standard dose chemotherapy.
clinical trial has not been conducted.
Another group of agents with promising clinical expe- Acknowledgements We would like to thank our colleagues B.
Damania, Marcia Sanders, Anthony Eason for critical reading and
riences [129132] includes thalidomide and its more active insightful discussions.
derivatives pomalidomide and lenalidomide. These agents
have broad immunomodulatory, anti-angiogenesis proper- Compliance with Ethical Standards
ties, targeting nuclear factor-jB (NF-jB) among others,
Funding This work is supported by Public Health Service (PHS)
and are the subject of ongoing clinical studies. Like other
Grants DE018304 and CA190152 to DPD and CA192744 to JWS and
immunomodulatory agents, one could speculate that their DPD. The authors are members of the AIDS Malignancy Consortium
benefit will be most pronounced in the setting of limited (AMC), which is supported by PHS Grant CA121947, and JWS is a
KS, classic KS, or as adjuvant to chemotherapy. member of the AIDS Cancer Specimen Resource (ACSR), which is
supported by PHS Grant CA181255.
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, including melanoma and poly- consulting agreement related to KS with Delenex AG and Navidea
omavirus-associated Merkel cell carcinoma [133136]. It is Inc. This did not influence the opinions expressed in this review. JWS
likely that these agents will be also active against KS, although has no conflicts of interest to declare.
clinical evidence has not been formally reported. Nivolumab
is a humanized monoclonal antibody directed against PD-1,
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