]
The cutaneous lesions can be appeared in different
colors and characteristics depending on subtype and
stage. The lesions may be seen clinically in the form of pink patches, purplish, blue, or black nodules/plaques
or polyps.[] The dermoscopy can be used to differentiate
vascular tumors.[] The lesions may be accompanied
by pain, bleeding, pruritus, lymphedema, or superinfection.[] The punch biopsy (or rarely excisional
biopsy) is required for definitive diagnosis.[]
Regardless of the clinical subtype, cutaneous lesions
usually consist of three stages: Patch, plague, and nodular
stage.[] In the patch phase, endothelial cell proliferation
is observed in the reticular dermis. Inflammatory
changes are present, plasma cells and lymphocytic cells
infiltration may occur. The morphological changes can
be observed in dermal vessels and adnexal structures.
In the plaque stage, there is proliferation of spindle
cells in the dermis (sometimes in the subcutaneous
area) irregular dermal collagen increases. Erythrocyte suffiextravasation
and hemosiderin-laden macrophages
can be seen and neo-angiogenesis occurs. In the nodular
phase, the spindle cells have mild and moderate
atypia; chronic inflammatory reaction predominates.
Lymphocyte, plasma cell, and dendritic cell infiltration
can be observed. There is no relationship between the
pathological evaluation and prognosis; however, prognosis
is adversely affected only in the presence of high
atypia/anaplastic cells.[]
KS is not only cutaneous but also mucosal, visceral,
and nodal involvement may develop at first admission
or during the disease. The visceral involvement rate is
more than 50% in HIV-related type. The gastrointestinal
system (GIS) involvement is most observed. It is
manifested by symptoms such as weight loss, abdominal
pain, and diarrhea regardless of skin involvement.
The pulmonary extension is the second most common
extra-cutaneous KS involvement after GIS. The patient
may present with cough, dyspnea, and hemoptysis.[]
The human herpesvirus (HHV) 8, HIV, immunosuppression;
genetic factors; antimalarial therapies,
and the use of angiotensin-converting enzyme inhibitors
may play a role as risk factors.[,]
Kaposi's Sarcoma-The Clinical Subgroups
Classic KS (CKS)
It is the form described by Moritz Kaposi in 1872. It
is common in males (Males/Females;=10-15/1) of advanced
age (60<) of Mediterranean, Eastern Europe,
Jewish, and South American origin.[] Advanced
age and HHV-8 are the main risk factors.[] The initial
complaints are often patchy pigmented lesions in
the lower extremities. Although not frequent, mucosal
(<5%), visceral (<10%), and LN (<10%) involvement
may occur.[,,] It is usually not aggressive, manifests
as chronic skin lesions, progresses slowly, rarely
fatal, and does not increase the risk of secondary malignancy.
The median overall survey (OS) is 9.4 years;
advanced age and immunosuppression are negative
prognostic.[] The localized lesions can be treated with
surgery, radiotherapy (RT), and follow-up; systemic
therapies are indicated in the presence of diffuse lesions
or visceral involvement.[]
Endemic KS (EnKS)
EnKS was first detected in children living in Central and
Eastern Africa in the 1960s.[-] The male/female ratio
is 2-3/1. It is generally diagnosed in HIV-negative
men aged 25-30 years and reported in the pediatric endemic group and the median age in this group is 3 years.
[] The patients were HIV negative, and the EnKS was
associated with HHV-8 positivity. Unlike other forms,
LN involvement is more common than skin lesions.
Afterward, endemic HIV was detected in the region. In
the last two to three decades, KS observed at a young age
showed a shift toward HIV-related type.[] The prognosis
varies widely from indolent skin lesion to aggressive
fatal systemic disease.[] Depending on the course of
the disease, local or systemic therapies are preferred.
Iatrogenic KS (IKS)
It is frequently observed after solid organ transplantation
(OT). IKS was first described in patients who used
long-term immunosuppressive drugs after OT in the
1970s.[] In addition to OT, KS may also develop due
to long-term use of corticosteroids and other malignancies/
treatments where immunosuppression is observed.
The skin lesions are predominating, mucosal
involvement is 20%, visceral involvement is 20-50%,
and LN involvement is 20-40%. The incidence of KS
in cases with OT is 8.8/100.000.[] The median time
to development of KS after OT is 13 months, but the
interval may range from a few weeks to 18 years.[] It is
rarely aggressive.[] In a recent French study, 5 years
and 10 years OS were reported as 85% and 75%.[]
There are insufficient data on prognostic factors.[]
Epidemic KS (EpKS)
It is the HIV-related subtype that is commonly seen in
homosexual men and it is usually aggressive. EpKS was
first described in the USA in the early 1980s.[] In
addition to cutaneous lesions, mucosal involvement is
observed in 30-40%, visceral involvement is observed
in 20-40%, and LN involvement is observed in 25%
cases. Visceral involvement is also dominant in GIS
and systemic symptoms (fever, weight loss, etc.) are initial
symptoms. KS is the most common malignancy in
HIV-positive patients. The lower CD4 cells increase the
risk of developing KS.[] EpKS may show an indolent
or aggressive course. The patients need antiretroviral
drugs and systemic chemotherapy (CT). Especially after
use the effective combined antiretroviral therapies
in HIV treatment, the incidence of KS decreased after
1995. The mortality of EpKS is also reduced with effective
treatments. The median OS in Western countries
is around 2 years. The presence of other concomitant
HIV-related diseases, age 50 and older, HHV-8 viremia,
and CD4 low are negative prognostic factors.[] Combined
antiretroviral therapies for HIV have a positive
impact on the prognosis of EpKS but may not be sufficient, especially in advanced diseases. In this case, liposomal
anthracycline-based CT and targeted agents are
thought to be more widely used in the future.[,,]
Treatment of Kaposi's Sarcoma
Surgery, RT, topical, intralesional therapies, CT, and
electro-CT can be preferred in the treatment of local
KS. No controlled randomized trials are comparing
for local treatments.[] Surgery may be tried in cases
with good margins and cosmetically acceptable, but
it has high recurrence rates. The CO2-laser and superficial
cryotherapy can be applied in superficial lesions
and have a response rate of 80-90%, but it causes hypopigmentation
in some cases. Intralesional CTs are
another treatment option and have a response rate
of around 70%. Brambilla et al.[] applied intralesional
vincristine to 151 KS patients, and a response
rate of 98.7% was achieved. Electrochemotherapy is
a new and interesting treatment and it is aimed to
increase intratumoral CT uptake with the help of
electropolarization. The most used CT is bleomycin.
In current prospective studies, 65-89% complete response
(CR) was obtained with electrochemotherapy.
[-] RT is one of the effective treatments that will
be discussed in detail.
In the presence of systemic disease, anthracyclinebased
CT and immunotherapy are applied. Furthermore,
antiviral may be administered in case of infection
such as HIV.[] Treatment preference is determined
by clinical subtype and patient's complaints. In systemic
therapies, the aim is not to cure but to improve
disease control and quality of life. Pegylated liposomal
doxorubicin, paclitaxel interferon alfa-2a or 2b, and
antiangiogenic agents (pomalidomide/lenalidomide/
bevacizumab) can be applied for this purpose.[]
Literature Search
A broad search was conducted between November
2019 and December 2019 on PubMed (National Library
of Medicine) using all fields and entering "Kaposi
Sarcoma, Radiotherapy," "Kaposi-Sarkom, Strahlentherapie,"
and "Kaposi Sarkom, Radyoterapi." Studies
that including at least 5 patients, published after 1990,
written in English, German, or Turkish, and detailed
RT dose technical and outcome details were included
in the study. Studies with fewer than 5 patients, written
language was not English, German, or Turkish, published
before 1990, without RT detail was excluded from the study. The 36 original articles were found to
meet our criteria and RT techniques, treatment outcome,
and side effect data are summarized in Table 1.
Table 1: Review of the literature
Table 1: Cont.
Table 1: Cont.
Table 1: Cont.
Table 1: Cont.
Role of RT in Kaposi's Sarcoma Treatment
RT has been used safely in the local treatment of KS for
many years. The most com mon indications for cutaneous
lesions are pain, bleeding, pruritus, and edema.
[] RT is an effective treatment option not only in cutaneous
lesions but also in mucosal lesions, especially
in the oral cavity. Although oral cavity lesions are seen
in all subtypes, it is the most common in epidemic
type. Oral lesions are most commonly localized in
hard palate, gingival, and dorsal tongue. Lesions may
cause complaints such as pain, bleeding, and chewing
difficulties due to local detrusion.[] In this case, RT is
indicated for palliative purposes. Besides, RT may be
applied for eyelid, conjunctiva, genital area, and visceral
organ involvement.[26,27]
KS is a radiosensitive tumor and a response rate of
70-90% is obtained in both cutaneous and extracutaneous
lesions (Table 1).[] In the study by Donato et
al.,[] who evaluated 18 KS patients, 83.3% CR was
obtained in patients.
Akmansu et al.[] reported in their study (2011),
CR rates were 86.7% at 6-month control and 93.3% at
12-month control. In Teke et al.[] study, 45.5% CR
and 36.4% partial response (PR) were obtained by
RT. High response rates are reported in the control of
symptoms, especially pain and pruritus.
In addition to the high RT response rates, palliation
shows a long-term persistence. Data on whether
the effect of RT is permanent in the long term have
been reported in classical KS studies because of its long
survival values. For example, Akmansu et al.[] evaluated
31 CKS lesions and 93% CR was observed in the 1st
year control and this rate was not changed in the 5-year
control. In the Kasper et al.[] study, high-dose-rate
(HDR) brachytherapy was applied to 16 lesions in a patient
with non-HIV-associated and non-IKS, and 100%
CR was obtained, and no recurrence was observed during
the 41-month median follow-up. In the literature
sources with long-term data, the RT effect was found
to be high persistent (Table 1).[,,,]
Kaposi's Sarcoma-RT Techniques
Due to the lack of prospective randomized studies, there
is no standard approach to optimal RT techniques.[] Electron and low energy photon are frequently preferred
in Kaposi's sarcoma RT.[] On the other hand, 3D, intensity-
modulated RT (IMRT), volumetric arc therapy
(VMAT) techniques can be used for planning. In the
Park et al.[] study, photons, electron, HDR, IMRT, and
VMAT techniques were compared dosimetric, and it
was observed that better dose values were achieved with
VMAT in multiple lesions. In the study of Nicolini, electron
versus photons (with VMAT) were compared and
acceptable dose values and better treatment times were
reported with VMAT.[18] In dosimetric studies that
comparing modern RT techniques versus conventional
techniques, similar dose values are observed. However,
there are deficiencies in clinical trials where treatment
response and side effects are evaluated together.
According to the width of the lesion, the applicator
could be used in conventional electron treatments
between 1.5 and 20 cm.[] Plexiglas tissue-equivalent
material of 0.5 or 1 cm thickness can be supported to
provide a dose peak on the skin surface. In photon
treatments, opposite lateral fields are generally used.
[] Using low-energy photons, dose accumulation on
the surface of the lesion is targeted.
Orthovoltage devices that can be used in low energy
(Kv) and used in superficial treatments have been
applied in many clinics in the treatment of KS.[,]
Kv energy orthovoltage devices with 45 etkin100 Kv
energy with 3-5 mm margin to 1 cm depth of effective
treatments can be applied; however, in many clinics today,
this treatment is not available.
Brachytherapy is an RT option in the treatment
of KS. Clinical response and cosmetic results of
brachytherapy have also been reported as excellent. In
2019, Ruiz et al.[] applied 5 Gy×5 fractions (frc) HDR
to a total of 5 lesions of 3 patients and achieved 100%
CR, and it was recommended to apply brachytherapy,
especially in elderly patients and in cases where surgery
and cosmetic results would be poor. On the other hand,
Kasper et al.[] applied 24-35 Gy/4-6 frc HDR to 16
patients and obtained 100% CR in the lesions. In summary,
HDR brachytherapy is a successful alternative in
elderly patients in cases where the cosmetic result of
the operation is not good and lesions smaller than 2
cm. In general, 24 Gy/3 frc doses were applied.[,]
Extremities are irregular surfaces, so bolus materials
are used to control dose distribution.[,] The
bolus material contributes to homogeneous dose distribution
in irregular areas and also contributes to the
superstructure of the applied energy build-up point.[]
Mainly used boluses; are tissue equivalent substancepelxiglass
and water bolus.
The choice of energy/technique should be determined
with the help of a medical physicist considering
the width and depth of the lesion.[]
Treatment Doses in Kaposi's Sarcoma RT
In the literature review, different schemes ranging from
6 Gy/1 frc to 45 Gy were observed (Table 1).[] The
most commonly used doses were 8 Gy/1 frc; 30 Gy/10
frc, and 20 Gy/4-5 frc. Less frequently, 40 Gy/20 frc
and 16 Gy/4 frc are also applied.[ Fractional treatments
are preferred if large area irradiation is to be
performed. Furthermore, fractional therapies are more
appropriate in mucosal lesions.[]
Overall RT response rates are high. It has long been
studied which of the different dosing schemes provides
higher CR. In the Harrison et al.[] study, 16 Gy/4 frc
versus 8 Gy/1 frc doses were prospectively compared and
there was no significant difference in response between
the two doses. However, in the study of Stelzer et al.,[]
8 Gy/1 frc versus 20 Gy/10 frc versus 40 Gy/20 frc were
compared and significantly higher CR was observed in
fractionated therapies. Kandaz et al.[] reported that
the fractionated therapies that total dose is over 20 Gy
have a better response rate than 8 Gy/1 frc treatment. In
summary, studies have shown that fractionated therapies
are more effective in the literature data.
In a valuable study by Yıldız et al., the single dose of
RT was prospectively examined for dose reduction. In
the study of Yıldız et al.,[] 8 Gy/1 frc versus 6 Gy/1
frc were compared and significantly lower CR was observed
in the 6 Gy arm. According to these data, less
than 8 Gy in cutaneous single-fraction RT is not recommended.
The studies that fractionated schemas evaluated
and their entirety are available in the literature. In
a study conducted by Singh et al.[] in 2008, 24 Gy/12
frc versus 20 Gy/5 frc were prospectively randomized
and there was no significant difference in terms of
treatment response, side effect, and progression-free
survey/OS. Geara et al.[] (1991) reported a significantly
lower objective response in the total dose 20 Gy
arm compared to the 30 Gy arm (97% vs. 83% p=0.04).
Oysul et al.[] (2008) presented the results of RT in
18 patients with CKS. Higher CR has been reported
in cases where an equivalent dose of more than 20 Gy
is administered. In summary, high control rates have
been reported in all RT schemes for cutaneous lesions.
In single fraction treatments below 8 Gy, efficacy of RT
is lower. More effective results are obtained in fractionated
schemes that total doses of 20 Gy or more.[]
RT can also be applied successfully in extracutaneous
lesions. Eyelid and conjunctival KS are known to
be more radiosensitive and have a higher response rate
than cutaneous forms (Table 1).[] In Le Bourgeois's
study, they recommended 15 Gy for oral lesions; 20 Gy
for eyelid conjunctival and scrotal lesions.[] Similarly,
in the series of 643 patients of Kirova et al.,[]
15 Gy for oral lesions; 20 Gy for eyelid conjunctiva and
genital lesions; and 30 Gy for cutaneous lesions are recommended.
In the study of Piedbois et al.[] (early
1990), 453 patients were evaluated. This study suggests
that 15 Gy for oral lesions, eyelid conjunctive scrotal,
penile-anal hand, and foot 20 Gy and 30 Gy for cutaneous
lesions of the other region was sufficient. Kirova
et al.[] the first 10 Gy was applied, then a 10-day
break, then the remaining 10 Gy was applied. Moreover,
weekly follow-up was recommended to patients
with eyelid, conjunctiva, lips, and genitals KS. In addition,
it is recommended that the daily dose be administered
as 1.5-1.6 Gy due to the risk of mucositis.[]
Planning target volume (PTV) is created with 2-5
mm in orthovoltage devices and 0.5-2 cm margin in
other treatments.[,] The first control is the 4th week
after the end of RT. For other areas, the patient should
be called for control after 1-2 weeks.[]
Side Effects
Most of the RT side effects are mild and moderate, and
the patients have a high treatment tolerance. Grade 1
radiodermatitis (RD) is most commonly observed.
Oral lesions are common, especially in HIV-associated
KS patients and RT and mucositis can be observed. In
general, it is aimed to reduce side effects by reducing
the total and fraction dose of mucosal RT.[]
