HIV/AIDS Kaposis Sarcoma A Practical Approach

Anisa Mosam
AWACC

MB ChB( Natal), FC Derm(SA), MMed( Derm) NRMSOM, UKZN

1-2 October 2009 ICC

Epidemiologic Types
Classic Endemic Iatrogenic Epidemic

Introduction
Multicentric tumour originating from vascular and lymphatic endothelial cells Sites:
Skin Lymphatics Mucosal Visceral: GIT & Pulmonary

Cutaneous Features
Asymptomatic pink to purple or brown Patches, papules, plaques, nodules or tumours Round, oval, elongated, fusiform Undiagnosed or overlooked

Cutaneous Sites
Head and neck, earlobes, occiput

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

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

Visceral Involvement: GIT

>50% clinically 80% at autopsy May be asymptomatic Symptoms: Abd pain, bloody stools, LOW

Visceral Involvement: Pulmonary

30% clinically 50% at autopsy Symptoms: dyspnoea, cough, effusions Survival poor

Lymphatic Involvement

Lymphadenopathy Lymphoedema Woody hard induration Non-pitting oedema

KS mimickers
Patch
Bruises

Papules
Secondary Syphilis PPE Lichen Planus

Nodules
Pyogenic Granuloma

Purpura

Bacillary Angiomatosis

Haemangiomas Naevi

Basal Cell Carcinoma Squamous Cell Carcinoma

Dermatofibroma

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

Diagnosis
Biopsy: Skin, endoscopic or transbronchial

Proliferation of abnormal vascular spaces, lymphaplasmacytic infiltrates Endothelial cells contain HHV 8 Spindle cells predominant cell

Aetiopathogenesis
HIV Tat protein, angiogenic Inhalant nitrites and exposure of lymphatic and vascular endothelium to nitrites in semen Saliva HHV 8

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

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

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 Classification- TIS

Good Risk (All) T (Tumor) I (Immune System) S (Systemic Illness)
T0: 27 mo survival Skin, minimal oral mucosa, lymph node only I0: 40 mo CD4>150 S0: 22 mo No OIs or thrush No B symptoms Karnofosky >70%

Poor Risk (Any)

T1: 15 mo Edema or ulceration Extensive oral mucosa Visceral KS I1: 13 mo CD4<150 S1: 16 mo Hx of OIs or thrush B symptoms present Karnofosky<70% Other HIV related disease

Krown, SE J Clin Oncol 1989; 7:120

Staging in HAART era

Nasti et al, 2003 211 patients from 2 prospective Italian cohort studies 3yr survival: 85% T0 69% T1 (p=0007) 83% S0 63% S1 (p=.003) 83% I0 71% I1 (p=.06)

3 year survival
T1S1

53%

poor risk

T0S0 88% T1S0 80% T0S1 81% (p= .0001)

good risk

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 3 2004:399-402

HAART and KS
16
Adjusted incidence ratio

14 12 10 8 6 4 2 0

1992

1997
Int Collaboration of HIV and Cancer,

J Nat Cancer Inst, 92(22) :1823-30 : 2000

HAART and KS
Decreased HIV Tat and cytokines Indirectly by CD4 restoration Restored immunity to HHV 8 PIs antiangiogenic

PIs vs NNRTIs
PIs have anti-angiogenic activity both PI and NNRTIs similarly improved HHV 8 immunity to and clearance of viraemia No evidence that PIs regimen of choice HAART durable HIV VL suppression and CD4 restoration is key
Bourboulia AIDS 18,485-493 2004

Baseline

8 weeks

12 weeks

16 weeks HAART

20 weeks HAART

48 weeks HAART

IRIS related oedema

Baseline 2 weeks HAART

KS IRIS
Before 4 Weeks HAART

8 weeks post HAART

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
Lipman Curr Opinion Inf Dis 2006;19:20-25 Bower J Clin Oncol 2005 Aug 1;23(22):5224-8

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

Treatment
HAART Local therapy Systemic therapy

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

Systemic cytotoxic therapy

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

Systemic cytotoxic therapy

Indications :
palliation of tumour-related symptoms (pedal or scrotal oedema) treatment of pulmonary KS, progressive mucocutaneous lesions (> 25 lesions) extensive Kaposis sarcoma of the oral cavity Symptomatic visceral involvement IRIS

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

Local Policy
HIV CD4 FBC Histology On HAART

Public Sector Policy

If CD4 >150 Oral Etoposide 50-100 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

Public Sector Policy

If CD4 count <150 Continue HAART Review in 6 months If local control required/palliation 8Gy RXT single dose Max 20-30 Gy esp for oral disease

ALGORITHMIC APPROACH TO HIV KS

Kaposis sarcoma Biopsy HIV CD4

HAART

Localized disease

Systemic disease

Limited to skin

Lymphoedema Fungating tumour Bleeding

Disseminated Cutaneous Lymphedoema

Visceral disease IRIS Large oral lesions

Intralesional drugs Cryotherapy

Radiotherapy

Etoposide

ABV/BV/V

Thank You

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

Response
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