1. HIV/AIDS Kaposi’s Sarcoma A Practical Approach
Anisa Mosam
MB ChB( Natal), FC Derm(SA), MMed( Derm)
NRMSOM, UKZN
AWACC
1-2 October 2009
ICC

2. Epidemiologic Types Classic Endemic Iatrogenic Epidemic
KS, an unusual neoplasm described in 1872 is characterised clinically by discrete reddish brown nodules and histologoically bu spindle cells and neoangiogenesis.There are 4 distinct types based on clinical and epidemiologic characteristics

3. Introduction
Multicentric tumour originating from vascular and lymphatic endothelial cells
Sites:
Skin
Lymphatics
Mucosal
Visceral: GIT & Pulmonary
Most frequently presents with skin lesions which can occur at any site but most frequently on the

4. Cutaneous Features Asymptomatic pink to purple or brown
Patches, papules, plaques, nodules or tumours
Round, oval, elongated, fusiform
Undiagnosed or overlooked
Most frequently presents with skin lesions which can occur at any site but most frequently on the

5. Head and neck, earlobes, occiput
Cutaneous Sites
Head and neck, earlobes, occiput

6. Cutaneous Sites upper torso, extremities
Widespread, symmetric, Langers lines

7. Mucosal Involvement Oral cavity in 20% at diagnosis
Tongue, hard & soft palate
Associated with GIT KS

8. Visceral Involvement: GIT
>50% clinically
80% at autopsy
May be asymptomatic
Symptoms: Abd pain, bloody stools, LOW

9. Visceral Involvement: Pulmonary
30% clinically
50% at autopsy
Symptoms: dyspnoea, cough, effusions
Survival poor

10. Lymphatic Involvement
Lymphadenopathy
Lymphoedema
Woody hard induration
Non-pitting oedema

11. KS mimickers Patch Papules Nodules Bruises Secondary Syphilis PPE
Pyogenic Granuloma
Purpura
Lichen Planus
Bacillary Angiomatosis
Haemangiomas
Basal Cell Carcinoma
Dermatofibroma
Naevi
Squamous Cell Carcinoma

18. Investigations biopsy CD4 and HIV-1 viral load CXR Stool occult blood
Sputa MCS and AFB
If GIT symptoms, endoscopy
If abnormal CXR or symptoms, bronchoscopy

19. Biopsy: Skin, endoscopic or transbronchial
Diagnosis
Biopsy: Skin, endoscopic or transbronchial
Proliferation of abnormal vascular spaces, lymphaplasmacytic infiltrates
Endothelial cells contain HHV 8
Spindle cells predominant cell

20. Aetiopathogenesis HIV Tat protein, angiogenic
Inhalant nitrites and exposure of lymphatic and vascular endothelium to nitrites in semen
Saliva
HHV 8
HIV transactivating protein stimulates angiogenesis
Nitrite have strong oxidative potential, they cause mutations and can induce or promote carcinogenesis
HHv 8 does this thru various mechanisms
Hormonal influence by BHCG on KS cells in pregnancy..similar to B chain of LH present cyclically in high concentrations in non pregnant mature women…may help to explain lower incidence in females
Role of saliva important in sexual and non sexual transmission it contains high concentration of viral particles of HHV 8..viral shedding early after infection may explain HHV 8 transmission

21. HHV 8 and KS Genes homologous to cellular oncogenes Alter cell cycle
Inhibit apoptosis
Evade immune mechanisms
Promote angiogenesis

22. Direct role of HIV-1 in KS
Production of the HIV-1 Tat protein
Indirectly increases B-FGF  Angiogenesis
Activates HHV 8
Increases viral loads
Expression of viral oncogenes
v-GPCR
V-Bcl-2
Promoting cytokine production
Tumour initiation
Progression
This direct role may come in the form of least 2 crucial paracrine mechanisms. The first is the production of the HIV-1 Tat protein. This competes competitively for binding sites for beta-fibroblast growth factor. This in turn increases the concentration of beta-FGF which is a well-described angiogenetic factor.
It also activates KSHV, increasing the viral loads and expression of KSHV oncogenes. The second, by promoting cytokine production, resulting in tumour initiation and progression.

24. Staging 1988 ACTG: Good risk and Poor risk T tumour extent
I immune status CD4
S systemic symptoms
Validated by Krown et al
TIS system effectively predicted survival Prior to HAART
Data from 281 patients from 34 ACTG sites
Staging of KS difficult because cannot be classified as other cancers TNM because KS primarily multifocal and mortality usually related to underlying immunosuppression rather than KS itself…
the importance of any staging system is to predict overall prognosis and direct therapy..
however in HIV KS mortality is more commonly due to complications of HIV and immune def rather than KS itself..
hence staging systems were developed to include immunologic parameters and systemic symptoms of HIV

25. Staging Classification- “TIS”
Good Risk (All)
Poor Risk (Any) T
(Tumor)
T0: 27 mo survival
Skin, minimal oral mucosa, lymph node only
T1: 15 mo
Edema or ulceration
Extensive oral mucosa
Visceral KS I
(Immune System)
I0: 40 mo
CD4>150
I1: 13 mo
CD4<150 S
(Systemic Illness)
S0: 22 mo
No OI’s or thrush
No B symptoms
Karnofosky >70%
S1: 16 mo
Hx of OI’s or thrush
B symptoms present
Karnofosky<70%
Other HIV related disease
Krown, SE J Clin Oncol 1989; 7:120

26. Staging in HAART era Nasti et al, 2003
211 patients from 2 prospective Italian cohort studies
3yr survival:
85% T % T1 (p=0007)
83% S % S1 (p=.003)
83% I % I1 (p=.06)
In multivariate anlyses only poor tumour stage (T1) and poor systemic disease ( S1) identified patients with unfavourable prognosis

27. 3 year survival T1S1 53% poor risk T0S0 88% T1S0 80%
T0S % good risk
(p= .0001)
Based on the above suggested that there should be only two groups good and poor risk

28. HAART and KS Profoundly influenced natural history of KS
Incidence declined
Lengthened time to rx failure
Improved survival in pulmonary KS with CXT
KS regression
Krown JCO vol 22 no :
Durable suppression of HIV replication and CD4 restoration is associated with decreased morbidity and mortality rates due to OI and Cancers

29. HAART and KS 1992 1997 Adjusted incidence ratio
Int Collaboration of HIV and Cancer,
J Nat Cancer Inst, 92(22) : : 2000

30. HAART and KS Decreased HIV Tat and cytokines
Indirectly by CD4 restoration
Restored immunity to HHV 8
PI’s antiangiogenic
Although HAART is an important component of rx for all patients with HIV KS, and can induce regression of limited KS..there is insufficient data about its activity in patients with advanced symptomatic disease..

31. PI’s vs NNRTI’s PI’s have anti-angiogenic activity
both PI and NNRTI’s similarly improved
HHV 8 immunity to and clearance of viraemia
No evidence that PI’s regimen of choice
HAART durable HIV VL suppression and CD4 restoration is key
Bourboulia AIDS 18,

32. Baseline
8 weeks
12 weeks
16 weeks HAART
20 weeks HAART
48 weeks HAART

33. IRIS related oedema
Baseline
2 weeks HAART

34. KS IRIS
Before
4 Weeks HAART

35. 8 weeks post HAART

36. KS IRIS
Worsening of existing KS or development of new lesions on HAART
Associated with rapid decline in HIV VL and increase in CD4
Close monitoring required
pulmonary involvement fatal
HAART continued but CXT required
British cohort of 150 KS 6.6% developed IRIS KS
Higher CD4, KS oedema, PI + NNRTI regimen
For the KS pt who is initiating , changing or resuming HAART ..particularly for those with pulmonary involvement
Lipman Curr Opinion Inf Dis 2006;19:20-25
Bower J Clin Oncol 2005 Aug 1;23(22):5224-8

37. Corticosteroids and KS
Corticosteroids have been associated with the induction or exacerbation of KS in HIV patients
Generally, should be avoided
Use only in:
acute respiratory distress syndrome accompanying HIV-related opportunistic pulmonary infection
tuberculosis meningitis or pericarditis
immune thrombocytopenic purpura, if necessary
Important b/c of frequent use of steroids in HIV+ pts with a variety of d/o including ITP, PCP

38. Treatment
HAART
Local therapy
Systemic therapy

39. Local treatment of KS Radiation therapy
Cryotherapy : 80% RR regardless of CD4
Laser surgery
Excisional surgery
Electrocauterization
Intralesional chemotherapy
Topical retinoids

40. Kaposi's sarcoma before and after radiotherapy

41. Systemic cytotoxic therapy
Important factors :
Extent of KS
performance status
organ function (especially liver and bone marrow)
Degree of immunosuppression (CD4 count),
Concomitant medications

42. Systemic cytotoxic therapy
Indications :
palliation of tumour-related symptoms (pedal or scrotal oedema)
treatment of pulmonary KS,
progressive mucocutaneous lesions (> 25 lesions)
extensive Kaposi’s sarcoma of the oral cavity
Symptomatic visceral involvement
IRIS

43. Combination chemotherapy
ABV / ABVb
Oral Etoposide
most widely used in poor resource settings
Standard of care in the past
Been replaced by newer drugs
More toxic and less effective than
Liposomal anthracyclines
Paclitaxel
Should only be reserved where Liposomal anthracyclines and paclitaxel aren't available

44. Local Policy
HIV
CD4
FBC
Histology
On HAART

45. Public Sector Policy If CD4 >150
Oral Etoposide mg for 3 weeks
Repeated for at least 3-6 months
If tumour progression
IVI CXT with AVB
If T progression and good HIV control and performance….3rd line CXT

46. Public Sector Policy If CD4 count <150 Continue HAART
Review in 6 months
If local control required/palliation
8Gy RXT single dose
Max Gy esp for oral disease

47. ALGORITHMIC APPROACH TO HIV KS
Kaposi’s sarcoma
Biopsy
HIV
CD4
HAART
Localized disease
Systemic disease
Etoposide
ABV/BV/V
Radiotherapy
Intralesional drugs
Cryotherapy
Limited to skin
Lymphoedema
Fungating tumour
Bleeding
Disseminated
Cutaneous
Lymphedoema
Visceral disease
IRIS
Large oral lesions

49. Thank You

50. Assessing response numerous cutaneous lesions
reproducible lesion counts difficult
Estimates of <10;10-50 and >50 used
Photographs of all body areas
3-5 marker lesions selected
photos and body diagrams
Tumour-assd oedema documented
Checklist of anatomical area
Accurate documentation difficult esp in pats with numerous cutaneous lesions..

51. Complete response (CR) resolution of any detectable disease for 4 weeks.
Partial response (PR) is a 50% or > decrease in number and/or size of all existing lesions for at least 4 weeks, without the appearance of new lesions. A response may be assigned to a diminution in the diameter of all lesions, or to flattening of at least 50% of the lesions. The size of each lesion will be the product of the longest dimension and the maximum dimension perpendicular to it.
Stable disease (SD) response not meeting the criteria for progression or PR
Progression is defined as at least a 25% increase in the size of any lesion or the appearance of any new lesions Krown J Clin Oncol 1989
Response
Stable disease will be classifies as any response not meeting the criteria for progression or PR