HIV RELATED MALIGNANCIES

Dr KASESEGABORONE ONCOLOGY CENTRE

INTRODUCTION• Cancer and Aids are both

pandemics

• Shared characteristics:– Both have social and emotional

impact that goes beyond the physical disruption they cause

– Both attract billions of research funds

– Both receive priority over heart and mental health topics in news coverage and funding

PROBLEMS• Research is rapid but data

collection world wide takes years to compile. Results in problems with topicality and redundancy(title prepared in 2001 might loose relevance in 2005)

• Specific anticancer therapy for HIV related malignancies have not been addressed

• Major publications on HIV are concerned on research and epidemiology(where drug companies spend money)

• Radiotherapy and chemotherapy have a major role to play but there are only 200 articles and book chapters on the subject

CURRENT FACTS

• HIV patients have increased incidence of certain tumours– Kaposis sarcoma– Non-hodgkin lymphoma– Cervical cancer– Scc conjuctiva– Ano rectal carcinoma– Leiomyosarcoma in children

• Now evident over the past decade that HIV related malignancies are caused by oncogenic viruses

• HIV is not a direct oncogene virus, does not result in genetic modifications affecting cellular replication but facilitates the development of cancers by removing the immune system (causative)

• HIV patients have an increased risk of developing other malignancies

• Other common tumours are not frequent in aids patients therefore they are immune independent

• HAART has decreased aids related illnesses but has increased the number of people living with aids. Aids is not cured and this means a cumulative risk of developing malignancies

• Cancers developed do not necessarily contribute to the final cause of death of the patient because of competing risks of mortality from infection and other causes including treatment

Principles of management of HIV related malignancies

• Management of HIV related malignancies is set against a background of an underlying fatal disease

• The usual oncological rules of practise do not apply

• Very often the best decision is simply to treat with the simplest, most effective, palliative regimen available

• Individualised approach to decision making is more important

• Protocol driven treatment is usually inappropriate

• Patient should be fully involved in decisions concerning management of both HIV and of the malignant disease

Management

• Following options available – Active observation for asymptomatic

disease– Local treatment (palliative or radical)

for localised symptomatic disease– Systemic treatment(palliative or

radical) for disseminated symptomatic disease

• Multidisciplinary clinic with the following disciplines represented

• HIV/infectious diseases

• Virology

• Oncology (both radiation oncology and medical oncology and surgical oncologist)

• HIV counselling

• HIV nursing

• Cancer nursing

• Same ethical rights to be given as any other patient– The right to be treated as a human

being– The right to feel secure about the

health program– The right to privacy – The right to service

• The right to understand the cost of treatment

• The right to be advised of education or research activities

• The right to counselling on refusal to receive treatment

– Specific management problems related to the coexistence of HIV and malignant disease

• Impaired marrow function and impaired cellular immunity and therefore vulnerable to the myelosuppressive and immno-suppresive effects of anti-cancer therapy

• Impaired nutritional status and physical status may limit the ability to withstand treatment

• Many of the arvs are themselves myelosuppressive and this further limits the delivery of orthodox cancer treatment

• Important to identify concomitant treatments such as antibiotics, arvs, complementary therapies before starting cancer treatment

• Any HIV patient treated with drugs or radiation for malignant disease requires careful monitoring– Dose should be modified or

treatment abandoned if excessive toxicity noted

– Decisions to withdraw have to be rapid therefore good communication between oncologist, patient and primary care givers

• HIV itself may be more important than the tumour– Individualised approach to

therapeutic decision making– Multidisciplinary clinic– Full involvement of patient in

decision making

• Interactions with other treatments– Full drug history– Awareness of potential problems

• HIV related myelosuppression and immuno-suppression– Careful monitoring (clinical, FBC)– Prompt access to oncology services

and supportive care– Prophylactic antiobiotics

• Fear and anxiety– Careful and sensitive communication– Psychological support

Prognostic factors in HIV related malignancies

• Extent and bulk of tumour

• CD4 count (worse if less than 200)

• Weight loss of more than 10% over 6 months

• Night sweats

• History of opportunistic infection

• Evidence of encephalopathy: dementia, confusion

• Karnovsky status of less than 70%

• NB. Features are not absolute contraindications to radical treatment but indicate poor tolerance

Anti-retroviral therapy• Introduction has transformed the

management of clinical consequences of HIV infection

• Use of protease inhibitors associated with a decline in incidence of KS

• Essential principles of arvs are similar to those of chemotherapy– Use multiple drugs synchronously

rather than sequentially– Use drugs with different modes of

action – Use drugs with non-overlaping

toxicities

Specific tumours• Kaposis Sarcoma

– First described by Moriz Kaposi in 1872 on five patients presenting with ‘sarcoma idiopaticum multiple hemorrhagicum’

– In 1912 Sternberg termed this disease Kaposi’s sarcoma-now refered as classsical KS

• An indolent tumour seen typically in men of mediterranean or east European Jewish origin

• In 1914 Hallenberg described the first case of African or endemic KS

• In 1960 the first report of KS following organ transplant and immuno-suppressive therapy

• In 1981 Hymes described the epidemic form associated with AIDS

Aetiology and pathogenesis• KS associated with gamma-2 herpes

virus known as HHV-8(KSHV)• Virus identified using PCR-based

techniques in all forms of KS– Classical– Endemic african– Paediatric– Epidemic(HIV related)

• HHV-8 transmitted in saliva

• In homosexual men rate of HHV-8 is related to the number of sexual partners

• Recent evidence from africa on HHV-8 prevelence in children suggests infection is acquired through normal social contacts within the family

• In developed countries seroprevalence of HHV-8 in general population is between 5 and 15%. For HIV positive homosexual men it is 30%

• In africa prevalence is higher and increases with age: <2% under the age of 5; 15% for ages between 15 and 40 and >27% for older than 40

• Action of HHV-8 in development of KS– Production of an analogue of cyclin

D which increase the propotion of cycling cells

– Production of a bcl-2 analogue(vbcl-2) and a protein (vFLIP) both which will prevent apoptosis

– Stimulation of angiogenesis mediated by a G protein coupled receptor (GPCR)

• Production of angiogenic proteines which are also inhibitory to macrophages (vMIPs)

Epidemiology• Most frequent neoplasm in AIDS

patients

• First malignancy to be described in AIDS

• Indirectly contributed to the identification of AIDS itself

• Two previous rare disease found together then something unexpected is happening– Unexpected event was an epidemic

• The conditions were KS and PCP

• The defined social group was homosexual male community

• By 1998 nearly 57000 people in the USA had developed KS as a result of HIV

• Swiss cohort study showed a significant decrease of KS in mid 90s due to HAART

Clinical features• Classic lesion of KS is a raised

macule purplish in calour

• Lesions may coalesce into plaques and may ulcerate and bleed

• KS may develop at sites of previous trauma

• Oedema is almost always a feature

• Visceral

Examples of KS lesions

Staging

• Stage I <10 lesions or one anatomic area

• Stage II >10 lesions or >anatomic site

• Sage III Visceral only

• Stage IV cutaneous and viscral

Treatment

• HAART

• Local treatment– Cryotherapy– Photodynamic therapy– Intralesional injection– Radiation therapy

• Systemic therapy– Immunotherapy-interferon alfa– Chemotherapy

• ABV• Liposomal doxorubicin• Taxol

• Experimental approaches– Antiangiogenasis approach

• Thalidomide• Interleukin 2

– Anti-kaposis associated herpes virus• ganciclovir

Non-hodgkin lymphomaRecognised as part of AIDS in 1982

Characteristically aggressive and often involve extra nodal sites

Aetiology and pathogenesis

• Some HIV individuals are more prone to develop lymphoma than others

• Related to particular variants of the chemokine receptor gene, CCR5

• Potentiation of the carcinogenic effect of Epstein-Barr virus (EBV) and Human herpes virus-8 (HHV-8)

• Lymphomas develop against a background of chronic antigenic stimulation and most are of B-cell origin

• Cytokenes stimulate expansion once malignant transformaton has occurred(IL-6, TNF-beta and IL-10)

• Chemokines produced by HIV infected macrophages and monocytes produce autocrine stimulation of the abnormal clone

Clinico-pathological categories of HIV related lymphomas

• Diffuse large cell lymphoma(DLCL)– Large non cleaved (LNCCL) ebv 40%– Immunoblastic plasmacytoid (IBPL)

90%

• Burkitt’s lymphoma (BL) ebv 30%• Primary lymphomas of the central

nervous system(PCNSL) ebv 100%• Primary effusion lymphomas (PEL)

ebv 90%, HHV-8 100%

• Degree and duration of HIV affects type of lymphoma that developes

• Primary CNS lymphomas are associated with profound immunosuppression and occur late in the course of HIV

• The other types may occur early

Epidemiology

Less than 5% aids defining diagnosis in developed countries but cause 15% of aids related deaths(occures late in the course)

HAART has changed the pattern

Extranodal lymphomas more common in AIDS patients

• Relative risk of AIDS compared to general population– Burkitts 261– High grade difuse 652– Intermediate grade 113– Low grade 14

Clinical features

• Primary CNS– 75% develop in known AIDS patients

– 50% have CD4 of less than 50/dl

– Symptoms similar to SOL (headache, change in consciousness, focal neurological symptoms, visual disturbances)

– Rapid onset and therefore difficult to differentiate from infection

• Nodal NHL including Burkitt’s– Wide spread nodal disease– Unusual nodal sites

• Occipital

• Epitrochlear

• parotid

– Involvement of bone marrow present in 25%

– Direct involvement of overlying skin

• Gastrointestinal NHL– Tumours can be anywhere from

posterior pharyngeal wall to rectum– Upper GIT present with dysphagia,

nausea, vomiting, and anorexia– Small bowel lymphoma causes

symptoms of malabsorption, weight loss and subacute obstruction

• Rectal tumours will cause bleeding, discharge, change in bowel habit, pain and tenesmus

• Meningeal NHL– Craneal nerve palsies, backache,

spinal root pain, confusion

• Primary effussion lymphomas (body cavity lymphomas)– Pleural effusion or ascitis without evidence

of bulk disease– Thickening of pleural or peritoneal

membranes with no evidence of tumour masses

• Symptoms are from accumulation of fluid– Dyspnoea, chest or abdominal discomfort

• Castleman’s disease– Multifocal lymphadenopathy with

splenomegally– Fever and splenomegaly are the

cardinal features– Hepatomegally oedema,

cough,dyspnoea– Hypersplenism and anaemia,

leucopenia and thrombocytopenia

Diagnosis

• Biopsy

• CT or MRI for CNS +- biopsy

Treatment

• CNSRadiotherapy

Other lymphomasCHOP

R-CHOP if CD20 positive

HAART

Cancer of the cervix

• Most common cancer in women in sub-sahara

• Association with HIV noted in 1983 but criteria for defining AIDS were modified to include cervical cancer in 1993

Aetiology and pathogenesis• Human papilloma virus (HPV) 16 qnd

18• Risk factors

– Low socio-economic status– First intercourse at early age– Sexual promiscuity– Large number of pregnancies– HIV

Clinical features

• Post coital bleeding

• Intermenstrual bleeding

• Excessive menstrual bleeding

• Fowl smelling discharge and backache are late symptoms

• Vesico-vaginal or recto-vaginal fistulae

• Metastasis

Diagnosis

• PAP smear

• Colposcopy

• Biopsy

Management• CIN –

diathermy,conisation,cryocautery – Recurrence depends on degree of

immunosuppression– HAART

• Stage IA– If fertility an issue treat as above– If not hysterectomy,EBT,

Brachytherapy

• Stage IB and IIB– Wertheim hysterectomy– Radical radiotherapy

• Stage IIB and IIIB– Radical radiotherapy

• Stage IV– Palliative treatment

• Future – vaccine

Other tumours• SSC of conjuctiva

• Not common even in countries with high exposure to the sun but incidence now manifests in epidemic

• High incidence in sub-sahara especially Uganda and Rwanda

– 2 tumours per million population from 1970 to 1988

– Ten fold increase between 1988 to 1992

• Common in age group of 40 and above before the advent of HIV but now shifted to 20s

Treatment• Surgical excision for early stage with

minimum 2mm excision margins. Followed by beta plaque radiotherapy. 60 Gy

• For moderately advanced tumours caesium needles implant may be considered

• Advanced disease– Enucleation +- exantaration + RT

Anal cancer

• Incidence of premalignant lesions common in HIV patients

• Not an aid defining illness but occurance in HIV warrants consideration in the context of HIV infection

• Aetiology– HPV 16 18 31 33 35 45 51 52 56

• Treatment – Chemo-radiation using mytomycin-c