cancers

Article
Kaposi’s Sarcoma: Evaluation of Clinical Features, Treatment
Outcomes, and Prognosis in a Single-Center Retrospective
Case Series
Irene Russo 1,† , Dario Marino 2,† , Claudia Cozzolino 1,3 , Paolo Del Fiore 1, * , Fitnete Nerjaku 4 , Silvia Finotto 2 ,
Annamaria Cattelan 5 , Maria Luisa Calabrò 6 , Anna Belloni Fortina 7,8 , Francesco Russano 1 ,
Marcodomenico Mazza 1 , Sara Galuppo 9 , Elisabetta Bezzon 10 , Marta Sbaraglia 4,11 , Marco Krengli 9,12 ,
Antonella Brunello 2 , Simone Mocellin 1,12 , Stefano Piaserico 7,‡ and Mauro Alaibac 7,‡

1 Soft-Tissue, Peritoneum and Melanoma Surgical Oncology Unit, Veneto Institute of Oncology IOV – IRCCS,
35128 Padova, Italy; [email protected] (I.R.); [email protected] (C.C.);
[email protected] (F.R.); [email protected] (M.M.);
[email protected] (S.M.)
2 Oncology 1 Unit, Department of Oncology, Veneto Institute of Oncology IOV – IRCCS, 35128 Padova, Italy;
[email protected] (S.F.)
3 Department of Cardiac, Thoracic, Vascular Sciences, and Public Health, University of Padova,
35128 Padova, Italy
4 Department of Medicine (DIMED), School of Medicine, University of Padova, 35128 Padova, Italy;
[email protected] (F.N.); [email protected] (M.S.)
5 Infectious and Tropical Diseases Unit, Padova University Hospital, 35128 Padova, Italy;
[email protected]
6 Immunology and Molecular Oncology, Veneto Institute of Oncology IOV – IRCCS, 35128 Padova, Italy;
[email protected]
7 Dermatology Unit, Department of Medicine, University of Padova, 35128 Padova, Italy;
[email protected] (A.B.F.); [email protected] (S.P.); [email protected] (M.A.)
8 Pediatric Dermatology Regional Center, Department of Women’s and Children’s Health,
University of Padova, 35128 Padova, Italy
9 Radiotherapy Unit, Veneto Institute of Oncology IOV – IRCCS, 35128 Padova, Italy;
Citation: Russo, I.; Marino, D.;
[email protected] (S.G.); [email protected] (M.K.)
Cozzolino, C.; Del Fiore, P.; Nerjaku, 10 Radiology Unit, Veneto Institute of Oncology, IOV – IRCCS, 35128 Padova, Italy
F.; Finotto, S.; Cattelan, A.; Calabrò, 11 Department of Pathology, Azienda Ospedale—University of Padova, 35128 Padova, Italy
M.L.; Belloni Fortina, A.; Russano, F.; 12 Department of Surgery, Oncology and Gastroenterology (DISCOG), University of Padova, 35128 Padova, Italy
et al. Kaposi’s Sarcoma: Evaluation of * Correspondence: [email protected]; Tel.: +39-49-8215714
Clinical Features, Treatment Outcomes, † These authors contributed equally to the work.
and Prognosis in a Single-Center ‡ These authors share senior authorship.
Retrospective Case Series. Cancers
2024, 16, 691. https://doi.org/ Simple Summary: Kaposi’s sarcoma (KS) is a low-grade, vascular tumor associated with human
10.3390/cancers16040691 herpesvirus 8 (HHV8) infection. There are four widely recognized types of KS including classic,
Academic Editor: Athanasia Tourlaki endemic, iatrogenic, and epidemic forms. Although in most cases, KS is an indolent disease limited
to the skin, it may have a more aggressive behavior resulting in locally aggressive disease and/or
Received: 9 January 2024
involving the mucosae or visceral organs, especially in immunosuppressed patients. The main risk
Revised: 1 February 2024
factors are HHV-8 infection and immunosuppression status. The treatment is very heterogenous,
Accepted: 2 February 2024
because there is still no unified strategy for the treatment of KS. The aim of this study is to describe
Published: 6 February 2024
the demographic and clinical features, treatment outcomes, and prognosis of a cohort of patients
affected by KS treated at the University Hospital of Padua (AOPD) and at the Veneto Institute of
Oncology (IOV) between 1993 and 2022.
Copyright: © 2024 by the authors.
Licensee MDPI, Basel, Switzerland. Abstract: Kaposi’s sarcoma (KS) is a rare angioproliferative tumor classified in four different clinical–
This article is an open access article epidemiological forms. The diagnosis is based on histopathological and immunohistochemical
distributed under the terms and analyses. The treatment is heterogeneous and includes several local and systemic therapeutic
conditions of the Creative Commons
strategies. Methods: This is a retrospective cohort study including 86 KS patients treated between
Attribution (CC BY) license (https://
1993 and 2022 at the University Hospital of Padua (AOPD) and at the Veneto Institute of Oncology
creativecommons.org/licenses/by/
(IOV). The data were extracted from an electronic database. Survival curves were generated using
4.0/).

Cancers 2024, 16, 691. https://doi.org/10.3390/cancers16040691 https://www.mdpi.com/journal/cancers

Cancers 2024, 16, 691 2 of 14

the Kaplan–Meier method, and Cox regression models were employed to explore associations with
overall and disease-free survival. The male sex (89.53%), classical variant (43.02%), and cutaneous
involvement (77.9%) were predominant. More than 61.6% of patients received a single treatment.
Surgery, antiretroviral therapy, and chemotherapy were the mostly adopted approaches. A persistent
response was observed in approximately 65% of patients, with a 22% relapse rate (at least 2 years).
The overall survival ranges from 90 to 70% at 2 to 10 years after the diagnosis. Iatrogenic KS
demonstrated a higher mortality (52.9%). This study reflects our experience in the management of KS.
Comorbidities are very frequent, and treatments are heterogeneous. A multidisciplinary approach
involving multiple referral specialists is essential for the appropriate management of this disease
during diagnosis, treatment, and follow-up.

Keywords: Kaposi’s sarcoma; vascular sarcoma; iatrogenic disease; HIV-related disease; immunosup-
pression status

1. Introduction
Kaposi’s sarcoma (KS) is a rare angioproliferative tumor usually arising in the skin.
Although in most cases, KS is an indolent disease limited to the skin, it may have a more
aggressive behavior resulting in locally aggressive disease and/or involving the mucosae
or visceral organs, especially in immunosuppressed patients.
Over the years, four different clinicoepidemiological forms of KS have been identified:
a sporadic form with an indolent course, affecting elderly men from the Mediterranean
area (classical KS) [1,2]; a more aggressive form of KS, which affects young adults and
children in sub-Saharan Africa (endemic KS) [3]; a form observed in transplant recipients
and patients receiving aggressive immunosuppressive therapies (iatrogenic KS) [4]; and
finally, a form reported in HIV-positive patients (epidemic KS) [5,6].
The data from the RARECARENet project report an incidence rate in Europe of 0.28 per
100,000 people/year [7]. The incidence in men is four times higher than in women. The
main risk factors are human herpesvirus 8 (HHV-8) infection and immunosuppression
status [8,9].
The diagnosis of KS is based on histopathological and immunohistochemical anal-
yses. The treatment is heterogeneous and includes local and/or systemic therapeutic
strategies [9].
Our study aimed to describe the characteristics of patients with KS, who were diagnosed
and treated at the University Hospital of Padova (AOPD) and at the Veneto Institute of
Oncology (IOV) between 1993 and 2022. The goal was to describe the demographic and
clinicopathological characteristics of patients, disease features, and the diagnostic–therapeutic
pathway through the creation of a unique database with the aim of better characterizing the
disease, expanding knowledge, and providing better patient care.

2. Materials and Methods

2.1. Study Design
This is a retrospective cohort study of patients diagnosed and/or treated for KS
between 1993 and 2022 at University Hospital of Padova (AOPD) and at the Veneto Institute
of Oncology (IOV), which represent level III referral centers in the northeast of Italy.

2.2. Patients
The study included 86 patients. Most patients came for diagnosis and/or first-line
treatment, while some patients came to our centers for disease progression assessments
after being treated in local level II centers (Figures 1 and 2).
 2.2.Patients
2.2. Patients
Thestudy
The studyincluded
included86 86patients.
patients.Most
Mostpatients
patientscame
camefor
fordiagnosis
diagnosisand/or
and/orfirst-line
first-line
Cancers 2024, 16, 691 treatment, while some patients came to our centers for disease progression assessments
3 of 14
treatment, while some patients came to our centers for disease progression assessments
after being treated in local level II centers (Figures 1 and
after being treated in local level II centers (Figures 1 and 2).2).

Figure1.1.
Figure
Figure 1.Temporal
Temporalevolution
Temporal evolutionof
evolution ofKaposi’s
of Kaposi’ssarcoma
Kaposi’s sarcomaincidence:
sarcoma incidence:analysis
incidence: analysisof
analysis ofthe
of thetime
the timetrend
time trendof
trend ofnew
of newcases
new cases
cases
from
from 1993
from1993
1993to to 2022.
to2022. The
2022.The dashed
Thedashed regression
dashedregression line
regressionline was
linewas estimated
wasestimated using
estimatedusing the
usingthe ordinary
theordinary least
ordinaryleast squares
leastsquares (OLS)
squares(OLS)
(OLS)
method.
method.
method.

Figure2.2.
Figure
Figure 2.Temporal
Temporalevolution
Temporal evolutionof
evolution ofthe
of thedistribution
the distributionof
distribution ofKaposi’s
of Kaposi’ssarcoma
Kaposi’s sarcomatypes
sarcoma typesover
types overthe
over theyears.
the years.
years.

2.3.Diagnosis
2.3. Diagnosisand
andTreatment
Treatment
Treatment
KS was diagnosed
KS was diagnosed using usinghistopathological
histopathologicalandandimmunohistochemical
immunohistochemicalanalysesanalysesfrom
from
the biopsy
the biopsy ofof the
of the lesion.
the lesion.
lesion. Diagnostic
Diagnostic and therapeuticclinical
and therapeutic decisionsresulted
clinical decisions resultedfromfrom aa
multidisciplinary
multidisciplinary collaboration
collaboration between
between different
different specialists
specialists including
including dermatologists,
dermatologists,
multidisciplinary collaboration between different specialists including dermatologists,
infectious disease
infectiousdisease specialists,
diseasespecialists, oncologists, radiation
specialists,oncologists,
oncologists, radiation oncologists,
oncologists, radiologists,
radiologists, pathologists,
pathologists,
infectious radiation oncologists, radiologists, pathologists,
and surgeons.
and surgeons. A follow-up
surgeons.AA follow-up
follow-up was was carried
was carried out
carried out using
out using contrast-enhanced
using contrast-enhanced
contrast-enhanced CT CT scanning
CT scanning
scanning and and
and
and
lymph
lymph node
node and
and soft
soft tissue
tissue ultrasounds.
ultrasounds. The
The RECIST
RECIST (response
(response evaluation
evaluation criteria
criteria in
in solid
solid
lymph node and soft tissue ultrasounds. The RECIST (response evaluation criteria in solid
tumors) criteria
tumors)criteria were
criteriawere used
wereused
usedtoto assess
toassess the
assessthe disease
thedisease progression
diseaseprogression
progressionor or response
orresponse
responseto to treatment
totreatment [10].
treatment[10].
[10].
tumors)
2.4. Data Collection
2.4.Data
2.4. DataCollection
Collection
All data were extracted from an electronic database purposely built for this study.
Alldata
All data wereextracted
extractedfrom
fromananelectronic
electronicdatabase
databasepurposely
purposelybuilt
builtfor
forthis
thisstudy.
study.
Patients werewere
divided into four groups according to the clinical–epidemiological type of
Patients
Patients were divided into four groups according to the clinical–epidemiological type of
disease: were divided
classic, intoepidemic,
endemic, four groups
and according
iatrogenic. to thedemographic
The clinical–epidemiological type of
information included
the age at diagnosis, sex, and race, while information regarding the tumor included the
anatomic site, involvement, and histopathologic features. Patients’ comorbidities were
assessed, and neoplastic and autoimmune comorbidities were evaluated separately. Thera-
Cancers 2024, 16, 691 4 of 14

pies included medical, surgical, and radiotherapy treatments and were classified as single
or multiple treatments. The follow-up data were extracted during scheduled visits.

2.5. Statistical Analysis

Continuous data were summarized as the median and interquartile range (IQR).
Disease-free survival (DFS) was calculated from the date of diagnosis to the date of the
event or last follow-up visit, where the event was a relapse after initial treatment or other
recurrences of disease. Survival curves were estimated with the Kaplan–Meier method,
and (overall survival and disease-free survival) hazard ratios (HR) were calculated with the
Cox regression model. All models are intended to be univariate, with the exception of the
tumor site and treatments, for which a multivariable regression was fitted. Reciprocal HR,
1/HR, and <1 indicate a worse survival rate than the reference class, >1 indicates better.
Values of p < 0.10 were formatted in bold, and results with p-value < 0.05 were considered
statistically significant. The statistical analyses were performed using R 4.1 (R Foundation
for Statistical Computing, Vienna, Austria) [11].

2.6. Ethics Considerations

The study was conducted in accordance with the principles of the 1975 Declaration
of Helsinki, and patients gave their informed consent to the collection of their data for
scientific purposes. The study was approved by the local ethics committee.

3. Results
The study included 86 patients, whose demographic, tumor, clinical, and treatment
characteristics are reported in Table 1.

Table 1. Demographic, tumor, and treatment characteristics of patients with a histologically confirmed
Kaposi’s sarcoma who were treated at our institutions between 1993 and 2022.

Variable Value
Min/max 13.9/85.6
Age Med [IQR] 57.2 [45.1; 69.2]
Mean (std) 56.9 (14.7)
Woman 9 (10.47%)
Gender
Man 77 (89.53%)
Single site 53 (61.63%)
Lower limbs 44 (51.16%)
Head and neck 4 (4.65%)
Upper limbs 3 (3.49%)
Trunk 2 (2.33%)
Multiple sites 33 (38.37%)
Tumor Site Lower and upper limbs 8 (9.30%)
Lower limbs and trunk 7 (8.14%)
Lower and upper limbs, trunk, head, and neck 4 (4.65%)
Lower and upper limbs, head, and neck 4 (4.65%)
Lower limbs, trunk, head, and neck 3 (3.49%)
Lower and upper limbs and trunk 3 (3.49%)
Other combinations 4 (4.65%)
Classic 37 (43.02%)
Endemic 3 (3.49%)
Type of KS
Epidemic 29 (33.72%)
Iatrogenic 17 (19.77%)
Cancers 2024, 16, 691 5 of 14

Table 1. Cont.

Variable Value
Only cutaneous 67 (77.91%)
Involvement Cutaneous and extracutaneous (node or mucosal) 14 (12.28%)
Only extracutaneous (node or mucosal) 5 (5.81%)
No 56 (65.12%)
HIV
Yes 30 (34.88%)
Yes 13 (15.12%)
Transplant
No 73 (84.88%)
No 12 (13.95%)
Comorbidity
Yes 74 (86.05%)
ND 35 (39.53%)
HHV-8 Status No 3 (3.37%)
Yes 48 (55.81%)
Single 53 (61.63%)
Treatment
Multiple 33 (38.37%)
No 30 (34.88%)
Persistent Response
Yes 56 (65.12%)
No 67 (77.91%)
Relapse
Yes 19 (22.09%)
No 69 (80.23%)
Deceased
Yes 17 (19.77%)
COPD or respiratory failure 5 (%)
Cardiac 1 (5.88%)
Infection, pneumonia, or sepsis 3 (%)
Cause of Death Liver failure 4 (23.53%)
Chronic renal failure 1 (5.88%)
Neoplasm 2 (11.76%)
Of old age 1 (5.88%)
Min/max 0.02/30.1
Follow-up Time (Years) Med [IQR] 5.8 [2.4; 9.7]
Mean (std) 6.6 (5.1)
Min/max 0.3/15.0
Time to Relapse (Years) Med [IQR] 2.7 [1.2; 5.6]
Mean (std) 4.0 (3.8)
Min/max 0.02/11.1
Time to Death (Years) Med [IQR] 2.4 [1.2; 5.9]
Mean (std) 3.8 (3.7)

The age of our patients ranged from 13.9 to 85.6 years, with a median age at diagnosis
of 57.2 years and a mean age at diagnosis of 56.9 years. Of the 86 cases, 77 were men
and only 9 women, with a male/female ratio of 8.5:1. The majority of patients (61.6%)
had a single anatomical site involved, while 38.3% had multiple sites involved. The most
frequently affected anatomical site was the lower limbs, followed by the head and neck,
upper limbs, and trunk.
Based on the clinical–epidemiological type, the subjects were distributed into four
groups. The classical variant was the most frequent (43%), followed by epidemic (33.7%),
iatrogenic (19.7%), and endemic (3.4%) KS.
The majority of patients presented only with cutaneous involvement (77.9%) while
5.8% had an exclusively extracutaneous presentation of the disease. Patients presenting
with both cutaneous and extracutaneous involvement were 12.2%.
 with both cutaneous and extracutaneous involvement were 12.2%.
Epidemic KS, thus related to HIV-1 and 2, constituted a considerable percentage in
our study (34.8%).
Cancers 2024, 16, 691 Of the iatrogenic type, 76.4% were organ transplant patients (with the liver being the
6 of 14
most frequently transplanted organ).
In terms of comorbidities, 86% of the patients were affected by other diseases
includingEpidemic KS, thus(19.7%)
autoimmune related to HIV-1
and and 2, constituted
neoplastic a considerable
(25.5%) disorders. Thepercentage
HHV-8 statusin was
our study (34.8%).
established in 55.8% of cases and was positive in 94.1% (48/51) of patients tested.
Of the iatrogenic type, 76.4% were organ transplant patients (with the liver being the
most frequently transplanted organ).
3.1. Treatment
In terms of comorbidities, 86% of the patients were affected by other diseases, including
autoimmune
About 61.6% (19.7%) and
of the neoplastic
patients (25.5%)only
received disorders. The HHV-8 while
one treatment, status was established
in 38.3% of the cases
in 55.8%
it was of cases and
necessary was positive
to use severalin treatments
94.1% (48/51)combined
of patients tested.
in various ways. Treatment
approaches
3.1. Treatmentwere both local and systemic and included antiretrovirals
immunosuppression
About 61.6% of the dose reduction,
patients received onlytopical application
one treatment, of 38.3%
while in imiquimod,
of the cases,interferon
it
therapy, cryotherapy,
was necessary chemotherapy,
to use several surgery, inelectrochemotherapy,
treatments combined various ways. Treatment and radiotherapy
approaches
(Figure
were3). Twenty
both patients
local and were
systemic andtreated
included with chemotherapy:
antiretrovirals, among these, dose
immunosuppression 5 patients
re- also
duction, topical application of imiquimod, interferon therapy, cryotherapy,
underwent second- or third-line therapies. Thirteen patients received liposomal chemotherapy,
surgery, electrochemotherapy,
doxorubicin and radiotherapy
as a first-line treatment, (Figure 3).
and six patients Twentygemcitabine
received patients were (three
treated as first-
with chemotherapy: among these, 5 patients also underwent second- or third-line therapies.
line and three as second-line therapies). Paclitaxel was administered to four patients (first-
Thirteen patients received liposomal doxorubicin as a first-line treatment, and six patients
line received
therapygemcitabine
only in one (threecase). The and
as first-line two three
other patients received
as second-line therapies).a Paclitaxel
combination of
vinorelbine and bleomycin
was administered or doxorubicin,
to four patients bleomycin
(first-line therapy andcase).
only in one vinorelbine
The two respectively
other
Another patient
patients received
received etoposide
a combination as a third-line
of vinorelbine therapy.or doxorubicin, bleomycin
and bleomycin
and vinorelbine respectively. Another patient received etoposide as a third-line therapy.

Figure 3. Kaposi’s
Figure sarcoma
3. Kaposi’s sarcomatreatment distributions
treatment distributions in our
in our cohort.
cohort.

FiveFive patients
patients weretreated
were treated with
withelectrochemotherapy
electrochemotherapyalone and were
alone and all categorized
were all categorized
as KS classic type.
as KS classic type.
3.2. Response and Relapse
3.2. Response and Relapse
A persistent response (for at least 2 years) was achieved in about 65% of patients.
Seventeen patients
A persistent died from
response (fortheatfollowing causes:was
least 2 years) respiratory,
achievedliver,
in or kidney
about 65%failure,
of patients
infection, neoplasm, cardiac complications, and old age.
Seventeen patients died from the following causes: respiratory, liver, or kidney failure
The median follow-up was of 5.8 years, while the median interval to disease recurrence
infection,
was 2.7neoplasm, cardiactime
years. The median complications,
interval between and
theold age. of KS and death occurrence
diagnosis
The2.4median
was years. follow-up was of 5.8 years, while the median interval to disease
recurrence was occurred
Relapse 2.7 years.inThe median
about 22% oftime
cases.interval between
A total of 35.1% ofthe diagnosis
patients of KSKS,
with classic and death
33.3% of was
occurrence those2.4
with the endemic type and 17.2%. of those with the epidemic type had a
years.
relapse.
Relapse Nooccurred
patients with iatrogenic
in about 22%KS ofhad a relapse
cases. (Figure
A total 4A). of patients with classic KS
of 35.1%
The mortality was higher in patients affected by iatrogenic KS (52.9%), followed by
33.3% of those with the endemic type and 17.2%. of those with the epidemic type had a
the endemic type (33.3%), classic (10.8%), and epidemic type (10.3%) (Figure 4B).
relapse. No patients with iatrogenic KS had a relapse (Figure 4A).
Cancers 2024, 16, x FOR PEER REVIEW 7 of 14

Cancers 2024, 16, 691 The mortality was higher in patients affected by iatrogenic KS (52.9%), followed
7 of 14 by
the endemic type (33.3%), classic (10.8%), and epidemic type (10.3%) (Figure 4B).

Figure 4. Relapse
Figure 4. Relapseevents
events ininthe
the 4 clinical–epidemiological
4 clinical–epidemiological types (A)types (A) and
and mortality mortality
in the in the four
four clinical–
clinical–epidemiological types (B).
epidemiological types (B).

3.3. Survival Analysis

3.3. Survival Analysis
The overall survival (OS) at 2.5 years after diagnosis of KS was about 90%, while it
Theabout
was overall
80%survival
at 5 years.(OS) at 2.5 years
The tendency of theafter
curvediagnosis of very
is to decrease KS was aboutafter
gradually 90%, thewhile it
was first
about 80% at 5 years.
2.5 years (Figure 5A). The tendency of the curve is to decrease very gradually after the
first 2.5 years
The OS(Figure 5A).was almost 100% in patients with a persistent response (of at least
at 2.5 years
two
The OS at 2.5 yearsthe
years) and 70% in wasgroup without
almost 100%a persistent response
in patients with a(Figure 5B). The
persistent disease-free
response (of at least
survival (DFS) at the 2.5-year follow-up was 77% in patients without
two years) and 70% in the group without a persistent response (Figure 5B). a persistent response
The disease-
and 90% in patients with a persistent response. At the 5-year follow-up, the DFS was 60%
free in
survival (DFS) at the 2.5-year follow-up was 77% in patients without a persistent
patients without a persistent response, while it was 90% in patients with a persistent
response and(Figure
response 90% in patients with a persistent response. At the 5-year follow-up, the DFS
5C).
was 60%The in OS
patients without
at 2.5 years a persistent
was almost 100% in response,
endemic KS,while
95% initpatients
was 90% withinclassic
patients
and with a
persistent
epidemicresponse
types, and(Figure
65% in5C).
iatrogenic KS (Figure 6A). The DFS at the 2.5-year follow-up
was 100% in patients with the iatrogenic type, 90% in patients with the epidemic type, 75%
in the classic type, and 60% in the endemic type. At the 5-year follow-up, the DFS was
nearly 70% in the patients with classic and endemic types, while it was 85% in the epidemic
type and 100% in the patients with the iatrogenic type (Figure 6B).
The analysis of survival with a Cox regression model clearly shows that mortality is
significantly higher in the iatrogenic type (0.011) and consequently, in transplanted subjects
(0.008) (Table 2). The other significant finding (0.001) is that subjects with a persistent
response have a significantly better disease-free survival.
Cancers
Cancers 2024, 16, 691
2024, 16, x FOR PEER REVIEW 8 of 14
8 of 14

Figure5.5.The
Figure The10-year
10-yearsurvival
survival curve
curve (A),
(A), comparison
comparison of survival
of survival in persistent
in persistent and nonpersistent
and nonpersistent
responsegroups
response groups (B),
(B), and
and disease-free
disease-free survival
survival in the
in the persistent
persistent response
response and and nonpersistent
nonpersistent response
response
groups(C).
groups (C).

The OS at 2.5 years was almost 100% in endemic KS, 95% in patients with classic and
epidemic types, and 65% in iatrogenic KS (Figure 6A). The DFS at the 2.5-year follow-up
was 100% in patients with the iatrogenic type, 90% in patients with the epidemic type,
75% in the classic type, and 60% in the endemic type. At the 5-year follow-up, the DFS was
Cancers 2024, 16, x FOR PEER REVIEW 9 of 14

Cancers 2024, 16, 691 nearly 70% in the patients with classic and endemic types, while it was 85% in the
9 of 14 epi-
demic type and 100% in the patients with the iatrogenic type (Figure 6B).

Figure6.6.Overall
Figure Overallsurvival forfor
survival different types
different of KS
types of(A)
KSand
(A) disease-free survival
and disease-free for different
survival types oftypes
for different
of KS (B).
KS (B).

2. Cox
Table The regression
analysis of analysis.
survival with a Cox regression model clearly shows that mortality is
significantly higher in the iatrogenic type (0.011) and consequently, in transplanted sub-
Overall Survival DFS
jects (0.008)
Variable(Table 2). The other significant finding (0.001) is that subjects with a persistent
response have a significantly better disease-free survival.
1/HR p-Value 1/HR p-Value

Age 0.993 0.689 0.973 0.137

Gender Man (ref woman) 0 0.998 0 0.998
Lower limbs (present, ref absent) 1.136 0.916 0.428 0.421
Head and neck (present, ref absent) 2.103 0.533 2.780 0.213
Tumor Site
Upper limbs (present, ref absent) 1.773 0.461 0.731 0.568
Trunk (present, ref absent) 4.563 0.152 0.482 0.179
Endemic (ref classic) 0.298 0.282 0.958 0.967
Type of KS Epidemic (ref classic) 1.015 0.985 2.758 0.077
Iatrogenic (ref classic) 0.211 0.011 >>10 0.998
Cutaneous and extracutaneous (ref only cutaneous) 1.466 0.613 0.298 0.017
Involvement
Only extracutaneous (ref only cutaneous) >>10 0.998 >>10 0.998
Cancers 2024, 16, 691 10 of 14

Table 2. Cont.

Overall Survival DFS

Variable
1/HR p-Value 1/HR p-Value

HIV Yes (ref no) 2.308 0.192 1.977 0.23

Transplant Yes (ref no) 0.254 0.008 >>10 0.997
Comorbidity Yes (ref no) 0 0.997 0.351 0.309
ND (ref no) 3.401 0.244 0 0.998
Autoimmune/Immunologic
Yes (ref no) 3.220 0.314 0 0.998
ND (ref no) 2.653 0.358 2.636 0.362
Neoplastic
Yes (ref no) 1.478 0.719 5.022 0.172
Surgery (undergone, ref not) 3.630 0.052 0.759 0.649
Antiretroviral drugs (undergone, ref not) 2.747 0.171 1.942 0.429
Chemotherapy (undergone, ref not) 1.092 0.897 0.480 0.226
Treatment Dose reduction of immunosuppressive therapy
0.930 0.918 >>10 0.998
(undergone, ref not)
Radiotherapy (undergone, ref not) 3.296 0.252 0.526 0.263
Electrochemotherapy (undergone, ref not) 2.593 0.372 0.577 0.336
Persistent Response Yes (ref no) 2.958 0.032 5.616 0.001
HR: Hazard ratio (1/HR >1 indicates better survival than the reference class, <1 indicates worse); Bold formatting
is used for p-value < 0.10 to better visualize statistically significant variables.

4. Discussion
This study presents an analysis of the demographic and clinicopathological characteris-
tics of a cohort consisting of 86 cases of KS, with the aim of expanding the knowledge about
this rare form of cancer. Our findings show data of a KS cohort enrolled over almost two
decades in a single center in northern Italy, a Mediterranean area with middle/low HHV-8
seroprevalence and inclusive of all four subtypes. An interesting and novel feature of our
study resides in the analysis of the different factors related to the complex management of
this sarcoma, which highlights the need for a multidisciplinary approach.
The demographics of our study confirmed the findings from previous studies [7].
In our case series, the average age at diagnosis was 56.9 years, confirming that KS is a
disease that predominantly affects adults in their sixth decade. While KS typically exhibits
a higher prevalence in men, our study observed a male-to-female ratio of 8.5:1, exceeding
the ratio documented in the existing literature and probably explained by the high number
of cases of classical and epidemic KS in our series [7]. Interestingly, the gender difference
was attenuated in iatrogenic KS (male-to-female ratio of 3.25:1), thus confirming the data
from a recent study about sex differences in cancer incidence among OTRs [12]. This study
hypothesizes that immunosuppression in the setting of transplantation may balance cancer
risk and decrease the male-to-female ratio reported in other subtypes [12].
The main risk factors for KS are HHV-8 infection and immunosuppression status [9].
Recently, chronic inflammation has also been recognized as a factor that plays an important
role in the pathogenesis and prognosis of sarcomas [13].
Furthermore, C-reactive protein levels seem to have a significant positive correlation
with poor prognosis [14].
A limitation of our study concerns the lack of data regarding HHV-8 status. The HHV-8
status was established in 55.81% of cases, but when tested, was positive in 48/51 (94.1%) of
patients; we reported few cases with a negative immunohistochemistry for HHV-8 (3/51) but
histologic confirmation of KS. Previous case reports suggested that in cases with a negative
immunohistochemistry for HHV-8 but a clinical and histology compatibility with KS, it is
useful to perform PCR to confirm the presence of HHV-8 [15]. The literature also suggests
that negativity for HHV-8 may be associated with the dedifferentiation of the disease [16].
Cancers 2024, 16, 691 11 of 14

Patients with classical KS constituted the largest group in our study, supporting the
evidence that Italy is one of the countries with the highest HHV-8 seroprevalence and
incidence of sporadic/Mediterranean disease in Europe [17].
Patients with epidemic KS represented about one third of our sample. In HIV-positive
patients, the mean age at diagnosis was generally lower, and disseminated disease with
the involvement of skin, mucous membranes, lymph nodes, and viscera were more fre-
quently observed.
An HHV-8 infection and low CD4 count are the main risk factors for developing the
disease in HIV-positive patients, but given the retrospective nature of our study, it was
difficult to retrieve complete data.
The introduction of combination antiretroviral therapy (cART) led to a remarkable
decline in epidemic KS incidence and a significant improvement in KS prognosis due to the
rise in CD4 T-cell count and immune reconstitution [18–20]. However, the risk of developing
KS in HIV-positive patients with a normal CD4 T-cell count remains substantially higher
than in the general population [21].
In our case series, the most widely used therapeutic strategy in HIV-positive patients
was cART alone or combined with surgery, radiotherapy, and/or chemotherapy.
The literature data report that epidemic KS can regress following starting cART alone,
although the response rates were variable [22,23].
In our case series, the iatrogenic KS group was mainly constituted by organ trans-
plant recipients (OTRs), who had several comorbidities and a higher mortality (p-value
0.008), mainly unrelated to KS but to the inherent complexity and fragility of these patients.
The high incidence of KS and high mortality in OTRs have been reported also by the
literature [17,22,23]. Italian OTRS have an increased risk (about 100 times greater) for KS
compared to the general population, especially during the first two years after transplanta-
tion [24]. Both an age over 30 at transplantation and a more aggressive immunosuppressive
regimen were identified as independent risk factors for disease [25].
Interestingly, in our cohort, a decrease in cases of iatrogenic KS has been observed
in the last decade. The decrease in the incidence of iatrogenic KS may be related to the
introduction in clinical practice of new generation immunomodulatory drugs, which have
led to an overall reduction in the immunosuppressive status of these patients [26]. In
particular, the increasing use of mTOR inhibitors, which exhibit antitumoral and antian-
giogenetic activities, may have played a role in the decline of KS occurrence in transplant
recipients [27].
The comparison of the two most representative populations included in our study (HIV-
positive patients vs. OTRs) suggests that the immunosuppression status has a significant
impact on the KS patient’s response to therapy and prognosis. The population represented by
OTRs is burdened with a high mortality likely related to comorbidities, but it is also strongly
influenced by immunosuppression due to the chronic required immunosuppressive regimen.
In HIV-positive patients, c-ART, by reducing immunosuppression, results in a benefit to these
patients. Unfortunately, we have no comprehensive data on CD4 counts to support the link
between the immunosuppressive status and prognosis of KS.
About 40% of our patients received multiple treatments. The high recurrence rate,
which is an inherent feature of the disease, results in the need for a long treatment course
consisting of several different approaches. In addition, the lack of treatment guidelines
frequently poses difficulties in initiating a timely and effective therapeutic intervention.
Iatrogenic KS usually responds to immune reconstitution, though lowering the im-
munosuppressive dose risks graft rejection. Switching the chemical immune-suppressive
regimen from cyclosporine A/FK506 to mammalian target of rapamycin (mTOR) inhibitors
such as rapamycin/sirolimus/everolimus often leads to KS regression [27,28].
Epidemic KS responds to immune reconstitution and HIV suppression. The responses
to cART alone are variable, and the complete remission of KS occurs in 20 to 80% of patients
and is more common in cART-naïve patients with limited-stage disease compliant with HIV
therapy [29,30]. The mechanism of KS regression is thought to be immunological and specif-
Cancers 2024, 16, 691 12 of 14

ically associated with the reconstitution of an effective cytotoxic cell–mediated response

targeting HHV-8. However, as KS can rapidly progress and affect vital organs, patients with
advanced-stage KS need additional systemic anticancer treatments alongside cART [31,32].
There are no controlled trials to evaluate the best care of these patients, although systemic
chemotherapy for KS and avoiding steroid treatment which was associated with disease
progression seems appropriate, as reported in small series and case reports [33–37]. KS
generally has a good prognosis. In our study, the 5-year OS was 83%, while the DFS was
80%, and no patient in our sample died from KS. The 5-year survival in our case series is
slightly higher than that which is described in a recent epidemiological study on the U.S.
population, which reports a 5-year relative survival in older adults (>40 years) of 77.5%
and in adolescents and young adults (AYAs, 15–39 years) of 68.7%. The worse prognosis
in AYAs may be explained by the higher incidence of HIV-associated KS among young
patients [38].
Overall, comorbidities were very frequent in all patients with KS. Therefore, a multi-
disciplinary approach and the presence of multiple referral specialists is essential for the
appropriate management of this disease.
Our study has some limitations, primarily related to its retrospective nature that makes
it difficult to collect some important data including the HHV-8 status, HIV viral load, and
CD4 lymphocyte counts. Because of the retrospective design of our study, missing data,
and the small number of patients enrolled, our results should be interpreted with caution,
and larger multicenter studies are needed.
The most interesting finding that has emerged concerns the complexity of these
patients, suggesting the need to create an integrated multidisciplinary team capable of
providing dedicated care to KS patients. The dermatologist could then assume the role of
mediator among the various specialists in order to provide better patient care.

5. Conclusions
This study reflects our experience in the management of KS and provides valuable
insights into KS characteristics, treatments, and outcomes. Comorbidities are very frequent
in patients affected by KS, and despite the wide range of systematic and local treatment op-
tions, there is still no unified strategy for the treatment of KS. Therefore, a multidisciplinary
approach for treating the patient with KS and the presence of multiple referral specialists are
essential for the appropriate management of this disease during the diagnosis, treatment,
and follow-up.

Author Contributions: Conceptualization, I.R., P.D.F., D.M. and S.F.; methodology, I.R. and P.D.F.;
formal analysis, C.C. and P.D.F.; investigation, F.N.; resources, S.M. and A.B.; data curation, F.N., C.C.
and P.D.F.; writing—original draft preparation, I.R.; writing—review and editing, I.R., P.D.F., M.L.C.
and S.P.; visualization, C.C.; supervision, M.L.C., F.R., M.M., S.G., M.K., A.C., E.B., M.S., A.B., S.M.,
A.B.F., S.P. and M.A. All authors have read and agreed to the published version of the manuscript.
Funding: This research has received “Current Research” funds from the Italian Ministry of Health to
cover publication costs.
Institutional Review Board Statement: The study was approved by the ethics committee of the
Veneto Institute of Oncology (CESC-IOV) (protocol code: 2014/91; date of approval: 10 May 2014).
The study was conducted according to the Helsinki Declaration principles, and all patients gave their
consent to have their anonymized data used for scientific purposes.
Informed Consent Statement: Informed consent was obtained from all subjects involved in the study.
Data Availability Statement: The datasets presented in this study can be found in online repositories.
The name of the repository/repositories and accession number(s) can be found here: https://zenodo.
org/records/10473499 (accessed on 26 January 2024).
Acknowledgments: This article is dedicated to the memory of Luigi Chieco-Bianchi and Savina
Maria Lucia Aversa.
Conflicts of Interest: The authors declare no conflicts of interest.
Cancers 2024, 16, 691 13 of 14

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