Guideline

DOI: 10.1111/ddg.14788

S1 Guidelines for the Kaposi Sarcoma

Stefan Esser 1,2, Helmut Schöfer 3, Christian Hoffmann4,5, Johannes

Claßen6, Alexander Kreuter 7, Ulrike Leiter8, Mark Oette9, Jürgen C.
Becker 10,11,12, Mirjana Ziemer 13, Franz Mosthaf 14, Judith Sirokay15,
Selma Ugurel16, Anja Potthoff 17, Doris Helbig18, Erhard Bierhoff 19,
Thomas F. Schulz20, Norbert H. Brockmeyer 17, Stephan Grabbe21
(1) HPSTD Outpatient Clinic, University Hospital of Dermatology Essen, University of
Duisburg-Essen, Essen, Germany
(2) Institute for Translational HIV Research, University Hospital Essen, University of
Duisburg-Essen, Essen, Germany
(3) Helios Dr. Horst Schmidt Kliniken, German Clinic for Diagnostics, Wiesbaden,
Germany
(4) ICH Study Center Hamburg, Hamburg, Germany
(5) Medical Clinic II, University of Schleswig-Holstein, Kiel Campus, Kiel, Germany
(6) Clinic for Radiotherapy, Radiological Oncology and Palliative Medicine, ViDia
Christian Clinics Karlsruhe, Karlsruhe, Germany
(7) Clinic for Dermatology, Venerology and Allergology, HELIOS St.-Elisabeth Hospi-
tal Oberhausen, University of Witten-Herdecke, Germany
(8) Center for Dermatooncology, University Department of Dermatology, University
Hospital Tübingen, Tübingen, Germany
(9) Clinic for General Internal Medicine, Gastroenterology, Infectiology, Augustinian
Sisters Hospital, Cologne, Germany
(10) Translational Skin Cancer Research, German Consortium for Translational Cancer
Research (DKZK), University Medical Center Essen, Essen, Germany
(11) Clinic for Dermatology, University Hospital Essen, Essen, Germany
(12) German Cancer Research Institute (DKFZ), Heidelberg, Germany
(13) Clinic for Dermatology, Venereology and Allergology, University Hospital Leip-
zig, Leipzig, Germany
(14) Joint Practice for Hematology, Oncology and Infectiology Karlsruhe, Karlsruhe,
Germany
(15) Clinic and Polyclinic for Dermatology and Allergology, University Hospital Bonn,
Bonn, Germany
(16) Clinic for Dermatology, Venereology and Allergology, University Hospital Essen,
Essen, Germany
(17) WIR- Walk In Ruhr, Center for Sexual Health and Medicine, Clinic for Dermatology,
Venerology and Allergology, Ruhr- University Bochum, Germany
(18) Clinic and Polyclinic for Dermatology and Venereology, University Hospital
Cologne, Cologne, Germany
(19) Heinz Werner Seifert Institute for Dermatopathology Bonn, Bonn, Germany
(20) Institute of Virology, Hannover Medical School, Hannover, Germany
(21) Department of Dermatology, University Medical Center Mainz, Mainz, Germany

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Guideline S1 Guidelines for the Kaposi Sarcoma

Summary
Kaposi’s sarcoma (KS) is a rare, malignant, multilocular vascular disease originating
from lymphatic endothelial cells that can primarily affect the skin and mucous mem-
branes, but also the lymphatic system and internal organs such as the gastrointestinal
tract, lungs or liver. Five epidemiological subtypes of KS with variable clinical course
and prognosis are distinguished, with increased incidence in specific populations: (1)
Classical KS, (2) Iatrogenic KS in immunosuppression, (3) Endemic (African) lympha-
denopathic KS, (4) Epidemic, HIV-associated KS and KS associated with immune re-
constitution inflammatory syndrome (IRIS), and (5) KS in men who have sex with men
(MSM) without HIV infection. This interdisciplinary guideline summarizes current
practice-relevant recommendations on diangostics and therapy of the different forms
of KS. The recommendations mentioned in this short guideline are elaborated in more
detail in the extended version of the guideline (online format of the JDDG).

1. General information about KS1 1.2 Epidemiology

For more detailed information and literature references,
please refer to the long version of the guideline.
(Chapter 1.1 Epidemiology, Clinic)
1.1 Definition and classification
Kaposi’s sarcoma (KS) is a rare, malignant, multilocular va-
scular disease originating from lymphatic endothelial cells,
which can primarily affect the skin and mucous membranes,
but also the lymphatic system and internal organs such as the
gastrointestinal tract, lungs or liver. The first description of
KS was made in 1872 by the Austro-Hungarian dermatolo-
gist Moritz Kaposi [1]. In 1981, a new aggressive variant was
first described in young HIV-infected men who have sex with
men (MSM) [2]. 95 % of all KS are caused by human herpes
virus 8 (HHV-8), also known as Kaposi’s sarcoma-associated
herpes virus (KSHV) [3].
Recommendation 1.1: Recommendations for the classi-
fication of Kaposi’s sarcoma
– Kaposi’s sarcoma (KS) is a tumor disease of lymphatic
endothelial cells induced by human herpesvirus-8 (HHV-
8)/Kaposi’s sarcoma-associated herpesvirus (KSHV),
which can affect internal organs in addition to skin and
mucous membranes.
– Five subtypes of KS with variable course and prognosis,
which occur more frequently in specific populations, are
distinguished:
– Sporadic, classic KS
– KS in iatrogenic immunosuppression
– Endemic, African KS
– Epidemic, HIV-associated KS
– K S in men who have sex with men (MSM) without
HIV infection
Recommendation 1.2: Epidemiology of Kaposi’s
sarcoma (KS).
– The prevalence of KS correlates with the prevalence of
HHV-8 infection.
– Classic KS occurs predominantly in men of Eastern
European and Mediterranean origin over the age of 50.
– KS occur with increased frequency in patients undergo-
ing long-term iatrogenic immunosuppression, especially
in organ transplant recipients.
– Endemic KS is predominantly prevalent in equartorial
Africa and is clinically subdivided into nodular, florid,
infiltrative, and lymphopathic types, with the latter pre-
dominantly affecting children and aldolescents.
– Since the onset of the HIV pandemic, epidemic HIV-as-
sociated KS has been the most commonly diagnosed
KS subtype. Following the introduction of antiretro-
viral therapy (ART), the incidence and prevalence of
HIV-associated KS has decreased dramatically. However,
HIV-associated KS remains the most common AIDS-defi-
ning neoplasm. New KS may occur, or existing KS may
worsen in the setting of immune reconstitution inflam-
mation syndrome (IRIS) following initiation of ART.
– More recently, another (fifth) type of KS has been increa-
singly reported in HIV-negative men who have sex with
men (MSM). This type of KS has an indolent course and
disease severity correlates with CD4 cell count and CD4/
CD8 ratio.
All five subtypes of KS are associated with human her-
pes virus 8 (HHV-8) infection. Therefore, KS prevalence re-
flects the prevalence of HHV-8 [4]. HHV-8 seroprevalence
varies considerably worldwide. It reaches more than 40 %
in sub-Saharan Africa, 10 %–30 % in Mediterranean coun-
tries (e.g., Sicily or Sardinia), and less than 5 % in Northern
Europe [3, 5, 6].

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Guideline S1 Guidelines for the Kaposi Sarcoma
1.2.1 Classic (sporadic) Kaposi’s sarcoma
Classic KS occurs predominantly in men (male:female ratio
2:1 to 17:1) of Eastern European and Mediterranean origin
[7, 8]. The first manifestation usually occurs at an age of
more than 60 years. Risk factors for the development of clas-
sical subtype KS primarily include previous HHV-8 infection
and increased age [9]. According to current knowledge, mor-
tality is not significantly increased in patients with classic KS
compared to the overall population [10–12].
1.2.2 African endemic Kaposi’s sarcoma
Endemic KS not associated with HIV infection is also pre-
valent in equatorial Africa, particularly among children and
adolescent males. Based on the pattern of spread and aggres-
siveness, four clinical courses are distinguished:
 Benign course: slowly and less aggressively progressing
nodular KS lesions of the skin, similar to those seen in
classic KS; predominantly seen in middle-aged men.
 Locally aggressive course: Cutaneous KS lesions with
aggressive infiltration into soft tissue and bone; usually
fatal outcome within five to seven years.
 Diffusely aggressive course: Diffuse mucocutaneous and
visceral involvement; unfavorable prognosis.
 Fulminant course: predominantly lymphadenopathy and
involvement of visceral organs, rarely skin involvement;
fulminantly aggressive course of disease; predominantly
in young children.
Endemic KS was 9 % of all cancers in Central Africa
[13, 14] until the outbreak of the HIV pandemic dramatically
increased the incidence of HIV-associated KS, especially in
sub-Saharan Africa [13, 15].
1.2.3 Kaposi’s sarcoma in iatrogenic immunosuppression
Iatrogenic KS may develop under long-term immunosup-
pression and may regress after discontinuation, reduction, or
conversion of immunosuppressive therapy. Kaposi’s sarcoma
occurred in more than 5 % of organ transplant patients who
subsequently developed malignancy [16]. The risk of develo-
ping KS is increased 50- to 500-fold in organ transplant pati-
ents compared to the normal population [17].
1.2.4 HIV-associated epidemic Kaposi’s sarcoma
Epidemic HIV-associated KS is the most common AIDS-de-
fining neoplasm and, since the onset of the HIV pandemic,
the most common clinical subtype of KS. The course is
highly variable, ranging from single lesions that are statio-
nary for years to foudroyant and fatal courses [18]. Parti-
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cularly HIV-infected patients in advanced stages with severe
immunodeficiency who are not or not sufficiently treated
with antiretroviral therapy develop HIV-associated KS. Af-
ter initiation of antiretroviral therapy (ART), HIV-associa-
ted KS often regresses without additional treatment, whereas
unexpectedly severe courses and/or new-onset KS have been
described in the context of immune reconstitution inflamma-
tion syndrome (IRIS) [19, 20–32].
Despite wide use of effective ART regimens, new KS or
KS recurrences also occur with good immune status, such
that the risk of developing KS is 30–80 times higher for PLH
than in the general population [33–35]. The progressive
aging of the HIV population due to improved life expectancy
with ART is associated with immunosenescence, which may
favor the development of KS [33]. Mortality of HIV-associa-
ted KS is inverselyassociated with CD4 cell count as well as
consistent ART use [36, 37].
1.2.5 Kaposi’s sarcoma in MSM without HIV infection
For several years, KS has been increasingly reported in youn-
ger HIV-negative MSM from geographic regions with a low
HHV-8 seroprevalence (e.g. France, England or Germany)
[38–41]. Similar to classic KS, the course is rather indolent,
skin lesions occur on the entire integument, and visceral
involvement or organ involvement is very rare. Apparently,
CD4 cell count and CD4/CD8 ratio correlate inversely with
disease severity. Because of these features and differences
from the four previously recognized subtypes of KS, this
form is newly classified as an additional (fifth) epidemiologic
subtype [3, 38].
1.3 Pathogenesis
Recommendation 1.3: Pathogenesis of Kaposi’s sarcoma
– KS is characterized by abnormal neoangiogenesis,
inflammation, and proliferation of lymphoendothelial
tumor cells as a result of multistep toncogenesis.
– More than 95 % of all KS are caused by HHV-8 infections.
– Immunosuppression and immunodeficiency favor the
development of KS.
All five subtypes of KS are associated with human her-
pesvirus 8 (HHV-8) infection [3, 38, 42–48].
1.4 Virology
HHV-8 from the DNA virus family belongs to the gam-
ma-herpesviruses [42]. HHV-8 can cause other diseases and
malignancies besides KS [18, 46, 49, 50].
HHV-8 prevalence is estimated to be 5 %–50 % wor-
ldwide, with regional variation. HHV-8 is endemic in

Guideline S1 Guidelines for the Kaposi Sarcoma
sub-Saharan Africa. Overall, men and especially MSM are
infected more often than women. HHV-8 is transmitted
primarily via saliva, but also sexually, vertically (from mo-
ther to child), and via blood products [50].
Serologically, various tests can detect HHV-8 antibo-
dies. Using PCR-based methods, highly sensitive and speci-
fic viral HHV-8 sequences can be detected and quantified in
KS lesions and blood plasma. Immunohistochemically, mo-
noclonal antibodies against LANA (latency-associated nuc-
lear antigen) are routinely used for specific HHV-8 detection.
1.5 Clinical appearance, differential diagnosis
and histology of KS
For details on the clinical appearance, differential diagnosis,
and histology, please refer to the long version of the guideline
[51–61].
1.6 Prognosis
Recommendation 14: Prognosis of Kaposi’s sarcoma
– KS shows an extraordinarily variable clinical appearance,
ranging from acutely foudroyant to years of low-aggres-
sive, stable courses.
– In classic KS, there is usually oligolocular limb invol-
vement with years of less aggressive, stable or slowly
progressive courses.
– Acutely foudroyant courses are most common in
HIV-associated KS, some African endemic KS subtypes,
and KS under severe iatrogenic immunosuppression.
– The prognosis of KS depends on several factors in additi-
on to age and immune status:
– KS subtype:
 Classic, endemic, iatrogenic (immunosuppressed),
epidemic HIV-associated and IRIS-associated, KS in
HIV-negative MSM.
– Spread:
 Skin lesions, mucosal involvement, lymph node
involvement, visceral involvement.
 Local, disseminated; isolated, numerous (solitary,
olilocular, multiple)
– Growth:
 Extensive, nodular, hyperkeratotic, infiltrating,
ulcerated
– Symptoms:
 Edema, hemorrhage, functional impairment
– Course:
 Stable, slow growing or rapidly progressive
 Isolated or numerous new lesions
Prognosis differs among the five KS subtypes.
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1.6.1 Prognosis of classic Kaposi’s sarcoma
Classic Kaposi’s sarcoma is considered a low-malignancy,
slowly progressive tumor mostly confined to the skin [62–72].
In the current European consensus-based interdiscipli-
nary KS guideline published in 2019 [73], immunosuppres-
sion and older age are rated as prognostic factors with high
evidence.
1.6.2 Prognosis of iatrogenic Kaposi’s sarcoma
Aggressive courses are rare but possible in Kaposi’s sarcoma
under iatrogenic immunosuppression. Spontaneous tumor
regression may occur after cessation of immunosuppression,
especially in early, non-aggressive stages [74]. In contrast,
progressive tumors usually do not regress spontaneously
after discontinuation of immunosuppressive drugs without
additional treatment of KS. So far, there is no staging for
iatrogenic KS, since the intensity of immunosuppressive the-
rapy against the previous disease is rather decisive for the
course.
1.6.3 Prognosis of African endemic Kaposi’s sarcoma
African endemic Kaposi’s sarcoma shows both low-ma-
lignant courses that are comparable to classical KS, and
aggressive (especially as a lymphadenopathic form in
children) courses rapidly leading to death [75, 76] (see
Chapter 1.2.2).
1.6.4 Prognosis of HIV-associated epidemic Kaposi’s
sarcoma and immune reconstitution inflammatory
syndrome (IRIS)-associated Kaposi’s sarcoma
HIV-associated Kaposi’s sarcoma shows variable courses. In
addition to lesions that can remain chronically stationary for
several years, rapidly progressive courses with dissemination
involving lymph nodes and internal organs can be found. In
untreated PLH, aggressive and infiltrative tumor growth can
lead to death within a few weeks [77]. With the introduction
of ART, the incidence and prevalence of HIV-associated KS
decreased, and prognosis improved [78–80]. New manifesta-
tions of KS under effective ART are rare but can occur even
with good CD4 cell counts.
Acute exacerbation of preexisting or emergence of new
KS within the first months of treatment after initiation
of ART in the setting of IRIS sometimes shows foudroy-
ant courses. Risk factors for IRIS-associated KS include
HIV RNA > 5 log10 copies/ml prior to ART initiation,
detection of HHV-8 in plasma, and ART initiation wi-
thout concomitant systemic chemotherapy [23]. Aggressive
courses with rapid tumor progression, usually with mas-
sive pulmonary involvement, occur especially in patients
895

Guideline S1 Guidelines for the Kaposi Sarcoma
with initially low CD4 cell counts and concomitant edema.
Early chemotherapy can stop this potentially lethal course
[20, 21].
According to the current European KS guidelines, prog-
nostically significant indicators of poor outcome for HIV-as-
sociated KS are age ≥ 50 years, a weakened immune status,
detectable HHV-8 viremia, the occurrence of systemic symp-
toms, other AIDS-related illnesses during the course, and KS
manifestation concurrently with other AIDS-related illnesses
[73]. Sustained reduction of HIV viral load below the limit of
detection through reliable use of effective ART is essential to
improve the prognosis.
1.6.5 Prognosis of Kaposi’s sarcoma in HIV-negative
MSM
Although little valid data on the prognosis of this KS subty-
pe are available to date, the course in the majority of cases
appears to be similar to that of classic KS. In the largest co-
hort to date on this KS subtype, only 5 % of cases showed
lymph node involvement and visceral involvement was never
seen, but genital involvement was significantly more common
(20 %). In addition, affected patients were younger than in
other forms of KS and showed significantly less concomitant
lymphedema [38].
1.7 Staging
Recommendation 1.5: Staging of Kaposi’s sarcoma
– There is no universally accepted staging for any of the
five KS subtypes.
– Investigations, staging, and management of the va-
rious KS subtypes should be individualized based on
symptoms, course, and involvement.
Currently, no generally accepted KS staging exists, even
for individual subtypes. In addition to the staging according
to Mitsuyasu and Groopman [81] and the ACTG TIS staging
of epidemic HIV-associated Kaposi’s sarcoma [82–86], the
European KS guidelines contain a KS classification into ma-
nagement-relevant situations [73]. Here, it is recommended
that the investigations and staging of the different KS subty-
pes be individualized on the basis of symptoms, course, and
involvement, with three situations being distinguished for the
management of KS patients:
– Local non-aggressive KS,
– local aggressive KS,
– disseminated KS.
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2 Diagnostics and staging
Recommendation 2.1: Confirmation of the diagnosis of
Kaposi’s sarcoma (Table 1).
– At least one deep biopsy should always be performed
to histologically confirm the clinical KS diagnosis, at the
latest before initiating specific therapy.
– All KS patients without known HIV infection should be
offered HIV testing at initial KS diagnosis.
– In HIV-associated and iatrogenic KS, cellular immune
status should be determined.
– Qualitative or quantitative determinations of HHV-
8 PCR and assays for HHV-8 antibodies are reserved
for specific questions and are not required in routine
clinical practice.
Recommendation 2.2: Assessment of KS dissemination
(Table 1).
– In addition to the medical history, a complete inspecti-
on including the visible mucous membranes as well as
palpation of the lymph nodes and the abdomen with
recording of all lesions and symptoms are part of the
(initial) examination in all types of KS.
– Further investigation should be individualized based
on disease dissemination, symptoms, course, and KS
subtype.
– In the case of (suspected) visceral KS involvement,
a whole-body computed tomography (CT: thorax,
abdomen/pelvis) should be performed. If necessary,
esophagogastro-duodenoscopy, colonoscopy, and
bronchoscopy may also be performed.
Apart from the examinations mentioned in recommen-
dations 2.1 and 2.2, which are advocated in all guidelines
and by experts [87], additional examinations and further
diagnostics to assess disease dissemination have so far
been performed on an individualized basis at the discreti-
on of the respective physician in charge. The prognostic fac-
tors mentioned in recommendation 1.4 form the basis for
decision-making.
2.1 Advanced blood tests: Cellular immunogram,
HHV-8 PCR, HHV-8 serology
In iatrogenic KS, in KS in HIV-negative MSM, and especially
in HIV-associated KS, a cellular immunogram with determi-
nation of the CD4 cell count and the CD4/CD8 ratio is part
of the diagnostic workup. A serologic KS tumor marker is not
available, but PCR detection of HHV-8 DNA and detection
of HHV-8 antibodies in blood precedes tumor development
[88, 89]. By far not all patients in whom HHV-8 has been
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Guideline S1 Guidelines for the Kaposi Sarcoma

Table 1 Recommended tests to assess disease dissemination for the different KS types.

Initial examination Classic KS Endemic KS Iatrogenic KS HIV-associated KS KS in HIV-

negative MSM
Inspection/alpation +++ +++ +++ +++ +++
Specimen biopsy/histology +++ +++ +++ +++ +++
HIV Serology +++ +++ +++ +++ +++
Standard blood test +++ +++ +++ +++ +++
CD4 cell count + + ++ +++ ++
HHV-8 viremia – – – – –
Locoregional LK sonography ±* ±* ±* ±* ±*
Abdominal sonography ±* ±* ±* ±* ±*
X-ray thorax ±* ±* ±* ±* ±*
Cross-sectional imaging (CT/MRI, ± ± ± ± ±
if necessary PET-CT)
– Abdomen ±** ±** ±** ±** ±**
– Thorax ±** ±** ±** ±** ±**
– Full body (neck, thorax, ± ± ± ± ±
abdomen, pelvis)
EGD/Coloscopy ± ± ± ± ±
Bronchoscopy ± ± ± ± ±
+++ mandatory; ++ required; + optional; ± symptom- and findings-dependent individual indication, – not recommended in
routine; *less informative alternative to CT examinations, **only if no whole-body CT is indicated.

detected develop KS or other HHV-8 associated disease.
Determination of HHV-8 viremia is not recommended as
a routine test because the result has no further consequen-
ce [47, 90]. HHV-8 DNA or antigen can also be detected
in tumor tissue (e.g., PCR, immunohistochemistry). Becau-
se, for example, multicentric Castleman’s disease is also an
HHV-8-positive disease, detection of HHV-8 DNA is not
conclusive for KS diagnosis.
2.2 Further apparative and invasive tests to assess
disease dissemination: sonography, thoracic
X-ray, computed tomography, endoscopy
The European guidelines do not recommend sonographic ex-
aminations (lymph nodes, abdomen) at baseline or follow-up,
although whole-body computed tomography (CT) is stan-
dard at baseline and symptom-based during follow-up for
HIV-associated and iatrogenic KS. For the diagnosis of di-
sease spread, CT scans have been shown to be more informa-
tive for many malignancies as compared with sonographies
and chest X-rays, while the latter are more readily available
and less invasive.
In some cases, endoscopy of the upper and lower gast-
rointestinal tract and bronchoscopy are required. The con-
sensus guidelines of the British HIV professional society
recommend the latter examinations only in symptomatic
patients, since visceral involvement, for example, is found
in only about 14 % of HIV-infected KS patients and does
not lead to a worsening of prognosis [87]. This assessment
is challenged by a study of young KS patients in which vi-
sceral involvement significantly worsened prognosis [91].
Kaposi’s sarcoma of the upper gastrointestinal tract may
remain asymptomatic for a long time [92]. Therefore, the
indication for esophagogastroduodenoscopy (EGD) and co-
lonoscopy should be generous. In some centers, because of
the increased risk of visceral involvement in cases of oral
mucosal involvement, the diagnosis is always extended by
esophagogastroduodenoscopy/colonoscopy and bronchos-
copy. The latter should be performed especially when diffe-
rential diagnosis of other relevant diseases such as lung car-
cinoma or pulmonary manifesting opportunistic infections
must be excluded. Bronchoscopy is usually indicated only in
the presence of pathologic abnormalities on chest X-ray/CT
or hemoptysis.

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Guideline S1 Guidelines for the Kaposi Sarcoma
3 Therapy
Recommendation 31: Aims of KS treatment
– 
The goal of KS treatment is usually to induce regression
of the lesions, to achieve control over the course of the
disease, and to reduce symptoms while maintaining
quality of life and life expectancy.
– 
To date, there is no universally accepted “standard the-
rapy regimen” for the treatment of KS.
– 
Both local and systemic treatments with different me-
chanisms of action are available for the therapy of KS.
– 
The indication for and selection of appropriate treatments
should be based on prognostic factors, as well as on the
individual performance status and patient preferences and
should take into account the proportionality of treatment
measures in the context of a mostly incurable disease.
3.1 General therapeutical recommendations
3.1.1 Therapy Goal
Since a cure is usually not possible, the goal of KS treatment is
to control the course of the disease and reduce symptoms while
maintaining quality of life and life expectancy. Patients should
be informed about the likelihood of recurrence regardless of
the chosen KS therapy regimen and, in the case of local thera-
pies, about the possibility of new lesions occurring outside the
treatment field even during therapy. The expected cosmetical
outcome (hyperpigmentation, edema) should also be discussed
with the patient before starting therapy. Therapy indications
and general treatment recommendations for the different KS
types [93–99] are described in more detail in the long version
of the guideline and summarized in recommendation 3.2.
Recommendation 3.2: Indication for KS therapy
– 
Immediate treatment is not always required after a con-
firmed diagnosis of KS if the prognostic indicators are
favorable, and the patient is symptom-free. However,
appropriate follow-up is always recommended.
– 
Various local treatment options are available for indi-
vidual KS lesions that are symptomatic or aesthetically
discomforting.
– 
In cases of mucosal lesions, lymph node involvement,
and visceral involvement, systemic treatment should be
considered promptly regardless of KS type.
– 
In case of rapidly progressive or aggressive course, the
appearance of symptoms and/or functional impair-
ment, targeted treatment should be initiated immedia-
tely, regardless of the type of KS.
– 
In cases of HIV infection not yet treated or not effecti-
vely treated with antiretroviral therapy, ART should be
initiated or optimized immediately.
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3.2 Local therapy of Kaposi’s sarcoma
Recommendation 3.3: Indications for local KS treatment
– Local KS treatment options primarily apply to individu-
al cutaneous lesions, especially if they are symptomatic,
aesthetically disturbing, or lead to functional impair-
ment, and to patients who cannot tolerate systemic
therapy because of side effects and/or comorbidities.
– Numerous local treatment options are available for the
treatment of individual cutaneous KS lesions, ranging
from camouflage, excision, cryotherapy, radiotherapy
or intralesional injections of chemotherapeutic agents,
to topical therapies with various externals, which can
also be used in combination.
– In KS-associated lymphedema, in addition to the initiati-
on of specific KS treatment, early compression therapy,
lymphatic drainage, and physical therapy are required
as adjunct measures to prevent further complications.
Local therapies have been investigated in clinical trials,
especially for classical KS and HIV-associated KS. They may
have advantages over systemic therapies, because they (1) are
feasible with fewer side effects, (2) have few interactions with
other drugs (e.g., antiretrovirals, immunosuppressants).
The main disadvantage of local therapy is the lack of
effect on tumors outside the treated area.
Kaposi’s sarcoma lesions on the face, hands and forearms
are often particularly distressing for those affected, especi-
ally as they have a high recognition value even for medical
laypersons. Such marker lesions of HIV infection should be
eliminated as soon as possible [100] in order to reduce patient
discomfort.
The choice of therapy methods depends on the size, mor-
phology, and localization of the tumors (Table 2). In a syste-
matic review of local therapies for classical KS, Régnier-Ro-
sencher et al. 2013 [101] found that all therapy trials were of
rather poor structural quality, thus providing little overall
evidence for therapeutic recommendations.
3.2.1 Surgical therapy
Since KS is a multilocular systemic disease, surgical therapy
is limited to initial excisional biopsies to confirm the diag-
nosis and palliative removal of small tumors in cosmetically
conspicuous or functionally disruptive locations, with recur-
rences in loco to be expected postoperatively [102–104].
3.2.2 Local chemotherapy and electrochemotherapy
Local chemotherapy and immunotherapy have the advantage
over systemic applications of lower systemic side effects [105].
High, directly antiproliferative drug concentrations can be

Guideline S1 Guidelines for the Kaposi Sarcoma
Table 2 Local treatment options for Kaposi’s sarcoma: methods depending on tumor size and morphology (macular/
edematous/infiltrative to nodular/ulcerative).
Small area, ≤ 1cm2 (macular, nodular):
Medium sized area, 1–4 cm in diameter
(macular, nodular):
Large area, > 4 cm in diameter (nodular,
infiltrating, oral):
All predominantly macular KS
Intraoral KS
KS on the extremities (especially with
pronounced lymphedema)
achieved in the tumor. In tumors of the oral mucosa, locally
injected 3 % sodium tetradecyl sulfate and intrafocal vinblas-
tine provide comparable success rates [106]. The introducti-
on of electrochemotherapy (ECT) has significantly increased
the local effectiveness of chemotherapies. Intratumoral drug
concentrations are high [107], while systemic drug doses can
be kept low [108]. Thus, ECT treatment of 23 KS patients
with bleomycin showed complete remission in 65 % of tre-
ated lesions. During the 18-month follow-up, 70 % of lesi-
ons remained free of recurrence, and another 17 % remained
stable with multiple ECT [109]. Other research groups also
confirmed these results for electrochemotherapy [110, 111].
3.2.3 Local immunotherapy
The first local immunotherapies of KS used intralesional in-
terferons [117], but these showed only a low response rate. In
case reports [123] and small studies [115, 124], local respon-
ses were seen after 3 x weekly topical application of imiqui-
mod cream under occlusion. Complete remissions occurred
in only 12 % of treated classic KS, while another 35 % of
patients had partial remissions [115].
3.2.4 Cryotherapy
Especially for small, flat KS in the macular and early tumor
stage (< 0.5 cm diameter), cryotherapy is a simple and
repeatedly applicable treatment that places little burden on
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– Cryotherapy [100, 125]
– In individual cases excision
– Vincristine intralesional [100, 105]
– Vinblastine intralesional [106, 120, 129]
– Alitretinoin gel, 0.1 % retinoic acid [112, 113, 126, 133]
– Imiquimod [101, 115, 116, 123]
– Interferons intralesional [117]
– Nicotine patch [118]
– Cauterization with silver nitrate [119]
– Vinca alkaloids intralesional [100]
– Electrochemotherapy [109, 110, 130]
– Fast electrons, photon irradiation [100, 131, 132]
– Fast electrons, photon irradiation [134, 135]
– lower leg: additional compression treatment
– Camouflage [100, 136]
– Vinblastine intralesional, 3 % sodium tetradecyl sulfate intralesional [106, 120–122]
– Photon irradiation [137]
– Compression therapy, lymphatic drainage [93, 94, 138]
the patient [100, 125]. Using the contact method (with absor-
bent cotton carriers), it can also be applied to difficult loca-
tions such as eyelids and tip of the nose. Kutlubay et al. 2013
[125] were able to achieve complete healing in 19/30 (63 %)
KS patients with multiple cryotherapy treatments each. Ho-
wever, patients should be informed about possible blistering
and subsequent scarring as potential side effects.
3.2.5 Other local therapies
In Germany, Alitretinoin (9-cis-retinoic acid) is available in
the form of a gel for topical therapy of KS. After initial 2 x
daily application, treatment frequency can be increased to 4 x/
daily, if tolerated. The duration of application is up to twelve
weeks. Partial, even complete remissions of KS are described
after 8–12 weeks [112, 113]. Adverse local reactions are espe-
cially erythematous, partly erosive to ulcerative reactions and
postinflammatory hypo- to depigmentation [112, 126].
Intralesional injections with bevacizumab in HIV-positi-
ve KS patients whose intraoral, pharyngeal, and laryngeal KS
did not respond to ART showed no therapeutic efficacy [114].
The use of high-frequency ultrasound for the therapy of
cutaneous tumors, including KS, is new [127]. This procedu-
re is still in an experimental phase and needs to be verified by
further studies, as also for the application of the long-pulsed
Nd:YAG laser in classical KS [128].
Camouflage can be applied at any stage of cutaneous KS
[100].
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Guideline S1 Guidelines for the Kaposi Sarcoma

Kaposi’s sarcoma of the extremities, which is often asso-
ciated with edema, benefits from compression therapy with
compression bandages or fitted compression stockings (com-
pression class II). As a result, lesions flatten and become less
visible. In addition, regular lymphatic drainage and physio-
therapy are recommended.
See Table 2 for local treatment options for Kaposi’s sarcoma.
3.3 Radiotherapy
When defining the target volume, care must be taken to
maintain a sufficient safety distance from the visible tumor
margins and, in the case of electron irradiation, to obser-
ve the dose fall-off at the visible field edge (approximately
5 mm). Side effects such as erythema and hyperpigmentation
are rarely seen, as well as telangiectasias, fibrosis, and atro-
phy of the skin. Induction of secondary tumors such as squa-
mous cell carcinoma and basal cell carcinoma is a rare risk,
but should be considered in young patients.

Due to the high radiosensitivity of KS, radiotherapy is among 3.4 Systemic therapy
the most effective local treatments for all KS subtypes. Local
control rates of 80–90 % are achieved [75, 132] in classic and Recommendation 3.4: Indication for systemic KS therapy
in KS with iatrogenic immunosuppression [139]. In addition
– In cases of HIV infection not yet treated or not effecti-
to typical dermal findings, radiotherapy is also suitable for
vely treated with antiretroviral therapy, ART should be
the treatment of deeper processes or mucosal findings [137].
initiated or optimized immediately.
Relatively low radiation doses are necessary for effective
– When iatrogenic KS occurs, consideration should be
treatment, so that radiation can also be performed on acral
given to discontinuing, reducing, or reversing immuno-
areas or at the face with few side effects and good cosmetic
suppressive therapy.
results. Depending on the indication, performance status of
– In case of new onset or exacerbation of KS while on
the patient, size and extent of the lesion, different fractionati-
effective ART (IRIS-associated KS), careful follow-up and
on schemes are available with 1 x 8 Gy, 5 x 4 Gy or 12–20 x
early chemotherapy should be initiated.
2 Gy. As a general rule, small lesions can be treated with hy-
– Indications for systemic KS treatment are:
pofractionated doses, whereas more extensive lesions should
– rapid growth of multiple tumors
be irradiated more frequently with lower fractionation doses.
– infiltrative growth or ulceration
Superficial macular and plaque KS can be treated with
– accompanying symptoms such as significant edema,
single doses of 4–5 Gy (total dose 20–30 Gy fractionated 3 x/
hemorrhage, severe aesthetic and functional
week [100, 131, 134, 140, 141]). The previously used X-ray
impairment
therapy regimen has been replaced by fast electrons, photons
– extensive mucosal lesions
or by superficial brachytherapy techniques [142–145].
– systemic involvement with clinical relevance
Large-area KS with edematous swelling and/or lymph
– For systemic therapy of KS, chemotherapy with pegyla-
node involvement should be treated with conventional fracti-
ted liposomal doxorubicin should be the first choice.
onation (5 x 2 Gy per week) up to a total target volume dose
– Local and systemic KS therapies can be combined.
of 40 Gy whenever possible [135].

Table 3 Recommendations for systemic treatment of HIV-associated KS, always in combination with antiretroviral therapy.

Therapeutic Dosage Draw rate Side effects

Pegylated liposomal 20 mg/m i.v. at two-week in-
2
60–80 % Neutropenia, anemia
doxorubicine tervals Rarely: Heat sensation, dyspnea, back pain,
palmoplantar erythrodysaesthesia
Liposomal daunorubicine 40 mg/m2 i.v. at two-week ≈ 60 % Neutropenia, anemia
intervals Rarely: Heat sensation, dyspnea,
palmoplantar erythrodysaesthesia
Paclitaxel 100 mg/m2 i.v. at two-week inter- ≈ 50–60 % Neutropenia, peripheral neuropathy,
vals or 135 mg/m2 every 3 weeks. allergic skin reactions, alopecia.
Rarely: Hypotension, ECG changes
IFN-α (2a,b) 3–6 x 106 I.U. s.c. 3 x/week (dose 40–50 % Fever, myoarthralgia, depressive moods
escalation possible depending (including suicide risk!)
on tolerability)

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Guideline S1 Guidelines for the Kaposi Sarcoma
3.4.1 Chemotherapy
For classical KS, systemic chemotherapy is only considered
in individual cases with extensive tumors, severe pain, and/
or visceral involvement [146, 147]. The therapeutic regimens
used [148] are similar to the treatment of HIV-associated KS
(see below). Randomized, controlled, prospective therapy
studies are not available due to the rarity of the tumor [149].
In HIV-associated KS, chemotherapy-induced bone
marrow suppression should be considered, especially in ad-
vanced immunodeficiency. The indication for initiation of
prophylaxis against opportunistic infections, such as admi-
nistration of cotrimoxazole, should be generous. However,
therapy with liposomal anthracyclines does not appear to
significantly increase the risk of opportunistic infections. All
therapies should be combined with ART in HIV-associated
KS according to currently valid guidelines [98].
3.4.1.1 Liposomal anthracyclines
Liposomal anthracyclines show the highest remission rates in
KS and are classified by the U.S. Food and Drug Administ-
ration (FDA) together with ART as first-line therapy for ad-
vanced KS in HIV-infected patients. In particular, pegylated
doxorubicine is generally better tolerated and less myelotoxic
than the previously used ABV regimen (adriamycin, bleomy-
cin, and vincristine) [150].
Pegylated liposomal doxorubicine at a dose of 20 mg/m 2
body surface area i.v. every 2–3 weeks can achieve partial re-
missions in up to 60–80 % of treated patients [151–153]. Af-
ter 50 months of follow-up, the relapse rate was 13 % [154].
Infusions can be performed on an outpatient basis and are
usually well tolerated. Myelotoxicity and cardiotoxicity of
doxorubicine should be noted. Although the latter is rare and
occurs only above cumulative doses of 450 mg, transthoracic
echocardiograms are recommended before initiation of the-
rapy and after every six infusions. In cases of severe cardiac
disease, heart failure, or markedly reduced ejection fraction,
therapy with doxorubicin should be considered with care.
Another possible side effect of doxorubicine is palmoplantar
erythrodysesthesia (hand-foot syndrome), which manifests
as painful macular erythema on the hands and feet [155].
The duration of therapy depends on the initial findings
and the response. In most cases, a profound partial remission
is achieved after about 3-6 infusions, whereas some patients
require more infusions to achieve a response. Often, therapy
with pegylated liposomal doxorubicine continues to have an
effect for some time after completion of the last infusion, so
that further clinical improvement may still occur. If relapse
occurs some time after the end of treatment, the reapplicati-
on of doxorubicine is usually successful again.
An alternative for doxorubicine is liposomal daunorubi-
cine, which is probably somewhat less effective. In a small,
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underpowered but double-blind randomized trial, response
rates were 63 %, compared with 80 % with doxorubicine
[156–158]. Liposomal daunorubicine (DaunoXome®) is given
at a dose of 40 mg/m 2 KO i.v. every two weeks.
3.4.1.2 Taxanes: Paclitaxel
Paclitaxel is effective in KS and achieves remission in appro-
ximately 60 % [159, 160]. The recommended dose is 100 mg/
m 2 i.v. over 3–4 hours every two weeks. In a small rando-
mized trial, response rates were comparable with those of
liposomal doxorubicine [161]. Paclitaxel, however, is more
myelotoxic and often results in alopecia, occasionally even
after the first dose. Further side effects include bone marrow
(neutropenia), nervous system (peripheral neuropathy), and
skin (allergic reactions; onycholysis) toxicity. Less common-
ly, arthralgias, myalgias, and chronic fatigue syndrome may
occur. Paclitaxel therapy may also be beneficial in patients
who have been progressive on prior chemotherapy [160, 162].
Paclitaxel should therefore be used as second-line therapy
when KS is progressive on anthracycline therapy. However,
interactions should be considered, and plasma concentra-
tions may increase significantly upon concomitant protease
inhibitor administration [163, 164]. In addition to paclitaxel,
docetaxel also appears to be effective, according to uncont-
rolled studies [165, 166].
3.4.1.3 Other chemotherapeutic agents
As a salvage treatment after anthracycline or paclitaxel the-
rapy, oral etoposide [167], irinotecan [168], the previously
used ABV regimen (adriamycin or doxorubicin with bleomy-
cin and vincristine) [169] as well as Gemcitabine [170] may
also be considered.
3.4.2 Immunomodulatory therapies: Interferons, PD-1
inhibitors
The pathogenesis of KS involves a balance between immu-
ne activating and suppressive mechanisms that allow latent
HHV-8 infection to persist throughout the life of the infected
host. For example, HHV-8 infection induces increased PD-
L1 expression in monocytes, contributing to immune evasion
[3]. Thus, the general therapeutic approach for immunode-
ficient KS patients is to reconstitute the immune system by
treating HIV patients with ART, reducing the extent of ia-
trogenic immunosuppression, or administering immunomo-
dulatory therapies.
3.4.2.1 Interferon Therapy
In addition to the known immunomodulatory effect, interfe-
rons also have the ability to induce apoptosis in tumor cells
and have further antiproliferative properties via inhibition
of angiogenesis by inhibiting β-FGF expression. Classical KS
901

Guideline S1 Guidelines for the Kaposi Sarcoma
shows remission rates of 60-70 % on class I interferons (IFN-
α2a, 2b; IFN-β) at doses of 3–9 million I.U. 3 x/week s.c.
However, a standardized treatment regimen does not exist.
In KS of organ transplanted patients occurring under iatroge-
nic immunosuppression, low-dose interferon treatment (e.g.
3 million I.U./week s.c.) can be given under control of renal
function. High doses of interferon should be avoided because
graft rejection may be induced [173].
Clinical experience in the therapy of HIV-associated KS
has been gained mainly with the systemic application of IFN-
α. However, most studies with relevant patient numbers were
conducted before the introduction of ART. Studies on the joint
application of interferons and ART are not yet available. If KS
recurs despite efficient ART or if existing KS does not show
regression, low doses of IFN-α are usually sufficient to treat
KS. Initially, in combination with ART, 3–9 million IU IFN-α
are applied daily, later 3–5 x/week, s.c. Complete remissions
can be achieved after at least 6–8 weeks of treatment (often
much later). Good remission rates are also achieved with in-
terferon in HIV-associated KS, although these are lower than
with liposomal doxorubicine [174]. There is an association
between the efficacy of interferon and immune status. Thus,
remission rates were about 45 % when CD4 T lymphocytes/μl
were greater than 400, and only 7 % below 200 CD4 T lym-
phocytes/μl. Interferon should therefore only be considered in
KS patients with more than 200 CD4 cells/μl.
The production of non-pegylated interferons for inde-
pendent use by patients has been discontinued. Pegylated
interferons (weekly administration possible) are not appro-
ved for KS and the optimal dose is not known. To date, only
case reports exist on the administration of pegylated IFN-
α in HIV-associated [175, 176] and classical KS [172, 177],
which, as in other indications, e.g., the treatment of chronic
hepatitis C in the pre-DAA (direct-acting antivirals) era, sug-
gest better tolerability and efficacy of pegylated versus non-
pegylated interferons. Contraindications such as autoimmu-
ne disease should be ruled out before initiating therapy.
IFN-γ leads to tumor progression in KS and is conside-
red contraindicated [178].
New immunotherapeutic approaches that have not yet
been adequately evaluated are listed in the long version of the
guideline [179–183].
3.4.3 KS treatment and antiretroviral therapy in patients
with HIV infection
In all ART-naive HIV patients, the immediate initiation of
ART is the first priority, and in the case of pretreatment and
viremia, the optimization of ART by switching or inten-
sifying it after resistance testing according to the recommen-
dations of the guidelines of the German [98] and the Europe-
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an AIDS Society [184]. Especially in the case of only mild KS
infestation, additional specific KS therapy is rarely required
in addition to ART. With a decrease of the HI viral load and
the onset of immune reconstitution, most lesions stabilize or
even heal completely. In 213 early-stage patients, 5-year sur-
vival with ART alone was 95 % and a total of 77 % remained
without further progression [82, 87]. ART improves the hu-
moral response against HHV-8 [185] and rapidly decreases
HHV-8 viremia [99].
ART pauses should be avoided as KS may re-exacerbate
[186]. Early ART even with still normal CD4 cells is pro-
tective against the occurrence of KS [187, 188]. Under ART,
the risk of KS is highest in the first months, decreasing to
less than one-tenth after 5–8 years. While low CD4 cells are
the most important risk factor in the beginning, later it is a
detectable HI viral load independent of CD4 cell count [188].
Other independent risk factors for the occurrence of KS in
effectively treated HIV-infected individuals are a low CD4/
CD8 ratio and an increased CD8 cell count [33, 189].
Whether certain ART regimens are preferable to others
has not been conclusively determined [190–196]. In a syste-
matic review, the data remained too weak to demonstrate
differential effects of different antiretroviral therapies [197].
If ART and local therapies are not sufficiently effective,
additional systemic KS therapy is indicated.
3.4.4 Switching immunosuppressive therapy in
transplant recipients
The type and degree of immunosuppression play an import-
ant role in the development of posttransplant KS. Patients
treated with calcineurin inhibitor-based immunosuppressi-
ve therapies are at particularly high risk of developing ag-
gressive KS. Reducing the intensity of immunosuppression
or switching immunosuppressants to mTOR inhibitors,
such as sirolimus or everolimus, are cornerstones of treat-
ment [198].
Regression of KS has been reported after switching from
calcineurin inhibitors to sirolimus by restoring effector and
memory T-cell immune activity against HHV-8 [199, 200].
In organ transplant patients with KS who do not respond to
a change in immunosuppression, KS is treated similarly to
classic KS. Individual lesions can also be treated locally (see
Chapter 3.2) [201].
Systemic chemotherapy should be considered in patients
with visceral involvement, extensive lymph node involvement,
or progressive mucocutaneous involvement. Doxorubicine
(pegylated, liposomal) is most commonly used.
The use of interferon alfa is generally not recommended
after organ transplantation because its use is associated with
a higher risk of rejection [73].
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Guideline S1 Guidelines for the Kaposi Sarcoma

3.5 Criteria for treatment response and cessation 3.5 Rehabilitation and supportive therapy
of KS therapy
Recommendation 5: Rehabilitation and supportive
Recommendation 3.5: Criteria for treatment response therapy
and cessation of KS therapy. – Patients with Kaposi’s sarcoma are eligible for oncologi-
– The goal of treatment is disease control. cal follow-up programs and rehabilitation.
– Treatment response is assessed by clinical examination – This also applies to supportive or palliative treatment
of the lesions. In addition to subjective parameters, the options.
size, thickness and coloration of the tumors as well as
Clinical studies on rehabilitative measures and supporti-
the presence of edema serve as criteria.
ve therapy specifically concerning Kaposi’s sarcoma are rare
– In cases of visceral involvement and/or lymph node
or single case reports.
involvement, follow-up by cross-sectional imaging is re-
For general supportive measures, please refer to corre-
quired and should be supplemented by esophagogast-
sponding guidelines on supportive oncological treatment
roduodenoscopy, colonoscopy, and/or bronchoscopy, if
options [206]. This also applies to palliative medicine, for
appropriate.
which guidelines exists [207].
– After almost all treatments of cutaneous KS, postinflam-
matory hyperpigmentation and hemosiderin deposition
remain, which generally does not respond to continua- 6 Literature
tion or further intensification of KS therapy.
Reference list is available online only in the long version of
– Termination of KS therapy must be determined indivi-
the guideline.
dually and should consider patient preferences.

The goal of treatment is disease control [73] or accepta- 7 Guideline specifications

ble palliation [202]. Complete regression of the disease is the
exception, as residual lesions are to be expected even with
effective therapy.
As an individualized procedure is already recommended
for assessment of the different KS subtypes, neither compre-
hensive response criteria nor a uniform follow-up program
exist yet [203–205]. Thus, the decision to terminate therapy
must be based on the goals set at initiation of therapy that
were agreed between physician and patient (see section 22).
If regression is sufficient, if clinical improvement is sufficient,
or if an acceptable quality of life is restored, the continuation
of treatment should be critically reviewed in each case.
4 Follow-up
Recommendation 4: Follow-up after termination of KS
treatment
AWMF register number: 032-025
Validity of the guideline: This guideline is valid until
30.09.2026.
Participating professional societies: Working Group
Dermatologic Oncology (ADO) for the German Cancer So-
ciety (DKG), German AIDS Society (DAIG), German Der-
matologic Society (DDG), German STI Society (DSTIG),
German Society for Infectiology (DGI), German Society
for Radiation Oncology (DEGRO), German Society for He-
matology and Medical Oncology (DGHO), German Soci-
ety for Gastroenterology, Digestive and Metabolic Diseases
(DGVS), Society for Virology (GfV).
Acknowledgment
Open access funding enabled and organized by Projekt DEAL.

– Follow-up is based on the KS disease pattern and pro-

Correspondence to
gression rate.
– Follow-up is performed by clinical assessment of skin
Stefan Esser, MD
lesions and visible mucosa or by assessment of disease
University of Duisburg-Essen. Essen University Hospital
progression via cross-sectional imaging and should be
Clinic for Dermatology, HPSTD Outpatient Clinic
symptom oriented.
– Follow-up intervals depend on the individual KS disease Hufelandstrasse 55
pattern and progression rate. 45147 Essen, Germany

Studies on the relevance of tumor follow-up for cure rates E-mail: stefan.esser@uk-essen.de
or tumor control are not yet available. Follow-up should be ba-
sed on the individual extent of KS and disease progression rate.

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