Transcript Early report on KS

Kaposi’s sarcoma
Erwin Tschachler
Department of Dermatology
Medical University
of Vienna
Vienna
General Hospital
Kaposi’s sarcoma
Erwin Tschachler
Department of Dermatology
No conflict of interest to declare
The Austrian Society of
Dermatology and Venerology
125th Anniversary
Founded in 1890
At present:
> 800 members
> 500 practicing Dermatologists
Hosts 2 annual meetings
with 4-600 participants
The first president of the Austrian society:
Moriz Kaposi
Born: Moriz Kohn
(1837-1902)
Professor of Dermatology
Chief of the Clinics of Skin Diseases
at the University of Vienna in 1881
Co-authored with
Ferdinand von Hebra
„Pathology and Therapy of
the Skin Diseases“(1880)
Moriz Kaposi 1872: „idiopathic pigmented
sarcoma of the skin“
Until 1981We knew 3 different
„forms“ of Kaposi‘s sarcoma
 Classical Kaposi‘s sarcoma
(+ Mediterranian KS)
 Endemic African KS
 Transplantation associated KS
African KS
Classical KS
Early lesion of classic Kaposi‘s sarcoma
Slowly progressing classic Kaposi‘s sarcoma
Advanced classic
Kaposi‘s sarcoma
1981 - Reports on the occurrence of clusters of
patients suffering from Kaposi‘s sarcoma
Disseminated Kaposi's sarcoma syndrome in
young homosexual men.
Friedman-Kien AE
J Am Acad Dermatol - 1981 Oct;5(4):468-71.
AIDS Kaposi‘s sarcoma
DIFFERENCE TO PREVIOUS FORMS
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Primarily young men
Starts at multiple sites
Rapidly progressing
Systemic involvement frequent
AIDS Kaposi‘s sarcoma
 Found in 30% of AIDS patients
 Kaposi‘s sarcoma became a
frequent direct cause of death
Early discrete lesions of AIDS KS
Disseminated AIDS KS
Differential Diagnosis
Bacillary angiomatosis
• Angiomatous papules
and nodules
• Fever, weight loss,
lymphadenopathy
causative agents:
B. henselae, B. quintana
Advanced AIDS
Kaposi‘s sarcoma
with involvement
of internal organs
Regardless of the origin Kaposi‘s sarcoma,
lesions show an identical histopathology
Kaposi‘s sarcoma tumor cells
bear lineage markers of
lymphatic endothelial cells
Jusilla et al 1998,
Weninger et al 1999
The first solid evidence for the involvement of an
infectious agent in the pathogenesis of AIDS KS became
available in 1990 (Beral et al):
 High prevalence in homosexual AIDS patients
 No KS in hemophilic AIDS patients
 KS occurrence in female partners of bisexual men
Identification of herpesvirus-like DNA sequences
in AIDS-associated Kaposi’s sarcoma.
Chang Y., Cesarman W., Pessin M.S., Lee F., Culdepper J.,
Knowles D.M. and Moore, P.S.
Science, 266, 1865–1869 (1994).
KSHV
KSHV/HHV-8 is found in tumor cells of all stages
of KS regardless of its type
HHV-8/KSHV LANA1 (ORF73)
expression in a KS,
from Yang et al. 2001
HHV-8 latency associated T0.7 RNA expressionin KS, from Stürzl et al. 1997
Therefore:
Demonstration of HHV-8 DNA in
biospsies of Kaposi‘s sarcoma is
crucial to confirm the diagnosis in
when histopathology is inconclusive
KSHV/HHV-8 is an oncogenic virus
Occurrence:
non-ubiquitous
Major transmission route: sexual (Hs. men)
But: non-sexual transmission possible
The epidemiological patter of human Herpesvirus 8
infection (Dukes and Rezza 2004)
A,B,C,D,E,N HHV-8 subtypes
Diseases which are pathogenetically
linked to the infection with HV-8
• Kaposi‘s sarcoma
• Primary effusion lymphoma (PEL)
• Multicentric Castleman‘s disease (MCD)
Kaposi‘s sarcoma and HHV-8 Infection
Transplantation
-induced
immunosuppresion
HIV-induced
immunosuppresion
Exposure
Seroconversion
To HHV-8 Weeks (acute disease)
Months ?
Elderly
~2 years
~10 years
? years
How does HHV-8 contribute to KS
development ?
HHV-8 genes with tumorigenic potential
Protein
ORF
Expression
LANA-1
ORF73
Latent
Binds p53 and pRB
V-Cyclin
Orf72
Latent
Cell cycle progression
vFLIP
ORF71
Latent
Inhibition of fas-induced apoptosis,
activation of NF-KB
K-12/T0.7
Latent
Unknown
vIRF1
K9
Latent
Inhibits IFN-induced gene expression,
interacts with p53
vGPCR
ORF74
Lytic
Tumor progression by paracrine
mechanisms
v-blc-2
ORF16
Lytic
Anti-apoptotic
K-2
Lytic
Cell cycle progression, anti-apoptotic
K-6, K-4, K4.1
Lytic
K-1
Latent &
Lytic
Kaposin
vIL-6
vMIP 1-3
K1
Major function
Angiogenesis induction
NF-KB and NFAT activation
Inhibits fas induced apoptosis
HHV-8 genes with tumorigenic potential
Protein
ORF
Expression
LANA-1
ORF73
Latent
Binds p53 and pRB
V-Cyclin
Orf72
Latent
Cell cycle progression
vFLIP
ORF71
Latent
Inhibition of fas-induced apoptosis,
activation of NF-KB
K-12/T0.7
Latent
Unknown
vIRF1
K9
Latent
Inhibits IFN-induced gene expression,
interacts with p53
vGPCR
ORF74
Lytic
Tumor progression by paracrine
mechanisms
v-blc-2
ORF16
Lytic
Anti-apoptotic
K-2
Lytic
Cell cycle progression, anti-apoptotic
K-6, K-4, K4.1
Lytic
K-1
Latent &
Lytic
Kaposin
vIL-6
vMIP 1-3
K1
Major function
Angiogenesis induction
NF-KB and NFAT activation
Inhibits fas induced apoptosis
vGPCR (ORF74)
• A seven-transmembrane receptor with sequence
similarity to the cellular IL-8 receptor
• does not require ligand binding for activation
• activates both the MAPK and PI3K pathways
• Expressed during lytic phase of viral life cycle
Infection of TIE2-Tva mice with a vGPCR/engineered
retrovirus leads to the development of vascular tumors
(Montaner et al Cancer Cell 2003)
The TSC2/mTOR pathway drives endothelial cell
transformation by vGPCR (Sodhi et al 2006)
S. Montaner 2007
The TSC2/mTOR pathway drives endothelial cell
transformation by vGPCR (Sodhi et al 2006)
S. Montaner 2007
How to treat Kaposi sarcoma?
Treatment options arethe same for all patients with Kaposi‘s
sarcoma and depend largely on the extent of the disease
Localized disease
 Surgery
 Cryotherapy
 Intralesional cytotoxic
therapy
 Irradiation
 Photodynamic therapy
 0·1% alitretinoin gel
 Interferon alpha
Advanced disease
 Interferon alpha
 Conventional cytotoxic
therapy
 liposomal anthracyklines
 Paclitaxel
In HIV-1 infected patients in combination with HAART
Which cytotoxic therapy to use in patients
with advanced disease ?
Monotherapies:
• Etoposide
• Vinblastine
• Vincristin
• Bleomycin
150–360 mg/m2 3 days/week/4 weeks
6 mg 1x weekly
2 mg /1-2 weeks
5-20 mg/m2 3 days/week/2-4 weeks
Remission rates 0-74 %
• ABV (Adriamycine 20-30mg/m2, Bleomycin 10 mg/m2,
Vincristin 1- 2 mg) every 2-4 weeks
Remission rates 28-88%
Therapy of Kaposi‘s sarcoma with liposomal
anthracyclines
• Pegylated Liposomal Doxorubicin
– 10-40 mg/m2 every 2-3 weeks
Remission rates 38-92 %
• Liposomal Daunorubicin
– 40–60 mg/m2 every 2 weeks
Remission rates 25-95%
Before therapy
Therapy of classical KS
with
pegylated liposomal
doxorubicin
After 5 cycles
Di Lorenzo et al, 2008
International, retrospective, multicenter study
55 patients, median follow-up 50 months
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Complet response
Major response (>50%)
Minor response (25-50%)
Stable disease
Progressive disease
29%
42%
11%
11%
7%
Therapy of Kaposi‘s sarcoma with taxanes
• Paclitaxel
– 135–175 mg/m2 every 3 weeks
– 100 mg/m2 every 2 weeks)
Remission rates 56-71% in patients in whom
a cytotoxic teatment has failed
• Initially reserved for patients with
anthracycline-resistant disease – compares
well also as first line therapy
Since the advent of combination antiretroviral
therapies the incidence of AIDS defining
malingnancies has steeply decreased
Shiels et al J Natl Cancer Inst 2011;
Kaposi‘s sarcoma and antiretroviral therapy 1
In mild cases of AIDS KS the administration of
antiretroviral therapy might suffice to induce
regression of the lesions
Kaposi‘s sarcoma and antiretroviral therapy 1
In mild cases of AIDS KS the administration of
antiretroviral therapy might suffice to induce
regression of the lesions
Kaposi‘s sarcoma and antiretroviral therapy 2
CAVE:
Although antiretroviral therapy is neccessary for
AIDS associated KS improvement and resolution,
it may in induce an immune reconstitution
inflammatory syndrome (IRIS) in up to 10% of
patients with disseminated disease.
N Engl J Med 2005, 352:1317
The TSC2/mTOR pathway drives endothelial cell
transformation by vGPCR (Sodhi et al 2006)
S. Montaner 2007
The TSC2/mTOR pathway drives endothelial cell
transformation by vGPCR (Sodhi et al 2006)
S. Montaner 2007
In Conclusion:
The approach to treating of Kaposi‘s sarcoma
differes depending on the patients‘s risk group“:
• Be „conservative“ in patients with classic KS
• Always add antiretroviral therapies when
treating patients with AIDS KS
• Reevaluate the immunusppressive regimen
in transplant patients with KS
Thank you for your attention!