52 HIV: malignancies

The overall incidence of many malignancies ↑ in patients with HIV. The incidence increases as the CD4 count falls below 500cells/μL. Certain malignancies occur more frequently in HIV infection, especially when immunosuppressed, and are often associated with other viral co-infection.

The following are designated as AIDS-defining illnesses:

Other associated malignant conditions include squamous cell carcinoma (anogenital, conjunctival, labial, and glossal), multicentric Castleman’s disease, testicular tumours (seminomas), melanomas, Hodgkin’s disease, multiple myeloma, leiomyosarcoma in children, colon cancer, breast cancer, and lung cancer.

The following viral infections contribute to the induction of malignant disease in the immunosuppressed.

Other factors such as specific sexual practices and cigarette smoking may play a part.

Overall risk of malignancy is doubled in an HIV-infected population. Natural history of malignancy may be altered in HIV infection with advanced rapidly progressive disease more likely. Treatment may be made difficult because of ↑ sensitivity to side-effects of chemotherapy if immunosuppressed and ↓ bone marrow reserve. HAART has had a dramatic effect on the incidence of some tumours, particularly 1° cerebral lymphoma.

Initially described in 1872 by Moritz Kaposi and rare before HIV epidemic. There are four different types.

Caused by HHV-8 (found in >90% of KS lesions) spread sexually, by mother-to-child contact and organ transplant. High viral levels in saliva suggest oral contact as a route of transmission. In ♂ who have sex with ♂ (MSM) new HHV-8 infection is associated with an HIV +ve partner. No evidence to support transmission by semen (HHV-8 rarely detected) and conflicting data on the role of rimming.

Most common malignancy associated with HIV infection. Before HAART, it was the AIDS-defining disease in 15–20% of MSM (found in up to 50% of patients with AIDS by mid-1980s). The incidence of KS started to decline prior to HAART introduction, but substantially so afterwards. Predominantly found in MSM and rare among IV drug users, haemo-philiacs and ♀ (where more aggressive and usually associated with HIV acquisition from bisexual ♂). KS found more commonly in those with advanced disease but may occur with preserved CD4 count. Rarely sole cause of death unless there is pulmonary involvement when respiratory failure may supervene. Prevalence of KS in different HIV populations reflects the background seroprevalence for HHV-8.

May occur on any part of the body but facial involvement common (margin of nostrils, tip of the nose, and eyelids) (Plate 22). Typical pigmented macules, papules, plaques, and nodules ranging in size from several millimetres to many centimetres. Colour varies from pink to deep purple with a yellow or green halo (extravasated erythrocyte pigments) characteristically surrounding them. Colourless subcutaneous nodules may also be found. In dark-skinned people the lesions are dark brown or black. Ulceration of nodules may lead to bleeding or infection. Large painful plaques may appear, especially on thighs and soles of feet. Pain suggests more progressive disease.

Found in ~33% of those with epidemic KS, usually affecting hard palate (also gingiva, tongue, uvula, tonsils, pharynx, and trachea). Often asymptomatic, although may cause local symptoms related to their site and extent. Usually appear as focal or diffuse red/purple plaques which may become nodular and ulcerate. May indicate more extensive mucosal involvement.

Lesions often obvious and disfiguring, acting as a constant reminder and leading to isolation, anxiety, and depression.

Staging based on distribution of KS, CD4 count, and other HIV-associated symptoms/opportunistic infections (OIs) to determine level of risk for disease progression. Patients with localized disease, CD4 >150cells/μL and no systemic symptoms have good prognosis. Poor prognosis if both extensive tumours and systemic illness.

HAART often significantly improves KS (in up to 80%) without further intervention. HAART should be offered to all patients. Additional treatment options depend on site, KS extent/activity, CD4 count, presence of systemic symptoms, and other OIs, past or present. These therapeutic interventions have been shown to improve survival and prolong time to KS treatment failure.

Consider if few skin lesions and no additional problems. Disfiguring lesions can be cosmetically camouflaged.

Patients with features suggesting poor prognosis should be given HAART in addition to liposomal daunorubicin (40mg/m² every 2 weeks) or pegylated liposomal doxorubicin (20mg/m² every 3 weeks). Those with good prognostic features can be given HAART alone. Liposomal doxorubicin and liposomal daunorubicin now standard of care for KS where treatment indicated. Preferentially absorbed by vascular KS lesions, producing targeted chemotherapy with ↓ side-effects. Main side-effects are bone marrow suppression (occurs in 50%, neutropenia can be treated with granulocyte colony-stimulating factor (G-CSF)), alopecia, and vomiting.

Second-line chemotherapy at a dose of 100mg/m² every 14 days plus HAART. Main side-effects are bone marrow suppression, myalgia, alopecia, and allergic reactions.

► Prophylaxis against Pneumocystis jiroveci (carinii) pneumonia (PCP) should be provided during chemotherapy because of 2° immunosuppression.

Rarely used in the era of HAART. May have a place in those with residual KS after immune reconstitution. Main side-effects are flu-like symptoms, depression, and neutropenia (ameliorated by G-CSF although this ↑ constitutional symptoms).

NHL is the second most common HIV-associated malignancy. First cases were reported in MSM in 1982. Prior to HAART it accounted for 2–3% of AIDS-defining illnesses, with haemophiliacs and those with other clotting disorders having the highest incidence. The incidence of AIDS-related NHL has decreased since the introduction of HAART, although the percentage as first AIDS-defining illness has increased.

Most NHLs are clinically aggressive monoclonal B-cell lymphomas, especially diffuse large B-cell lymphomas (DLBCL) and Burkitt’s or Burkitt-like lymphomas (BLs). Other much less frequent subtypes of HIV-related lymphomas include primary CNS lymphomas (PCL), primary effusion lymphomas, and plasmablastic lymphomas. More common in ♂ and Caucasians. EBV episome is found in 40–50% overall, ranging from ~100% of PCL to 20% of DLBCL.

Wide range of CD4 count at presentation including normal levels, but median is 100cells/μL. Typically presents with lymphadenopathy, fever, weight loss (>10%), and night sweats. Extra-nodal disease (any site) usual, with GI tract, CNS, bone marrow, and liver being frequently affected. GI presentation most common, and NHL should be considered if suspicious symptoms (e.g. dysphagia, GI bleeding/pain).

Difficult to distinguish from cerebral toxoplasmosis.

Prognosis still poor and partly dependent on control of OIs.

Accounts for 5% of HIV-associated lymphoma. Usually seen in MSM and associated with HHV 8 and co-infection with EBV in >50%. Characteristic features include involvement of the pleural, pericardial, and abdominal cavities as lymphomatous effusions in the absence of a solid tumour mass.

Treat with chemotherapy (similar to systemic lymphoma) but poor prognosis (2–5 months).

Induced by HHV-8 in HIV infection. Characterized by recurrent lymph-adenopathy, multiple organ involvement, hepatosplenomegaly, systemic symptoms, effusions and sometimes KS. Histological examination confirms the diagnosis and HHV-8 viral load is helpful.

Ideal treatment strategy unclear. Treat with chemotherapy (e.g. CHOP or single-agent chemotherapy), interferon α. Anti-CD20 monoclonal antibody (rituximab) may also be used as first-line therapy, for relapse, or following chemotherapy. Addition of HAART improves survival.

Although not an AIDS-defining illness, incidence is increased 10–20-fold compared with HIV-negative population. Tends to be more aggressive, with the mixed cellularity subtype predominating. Associated with EBV infection, usually developing with CD4 counts of 200–300cells/μL.

Presents with lymphadenopathy (glands often very large), Pel–Ebstein fever, anaemia, and systemic symptoms. Diagnosed by lymph node or bone marrow histology (Reed–Sternberg cells). Must have full staging assessment and bone marrow biopsy.

HAART combined with chemotherapy improves prognosis: disease-free survival and complete remission rates approach those of HIV-negative patients.

Added to the AIDS case definition in 1993 following reports showing ↑ prevalence of cervical dysplasia with HPV infection and immuno-suppression (usually severe). Cervical intra-epithelial neoplasia (CIN) is more common and recurs more in HIV-positive ♀ especially if CD4 <200/μL. However, no substantial clinical evidence demonstrating ↑ incidence of ICC in ♀ with HIV not explained by other risk factors. May be due to the possibility of longer latency, improved screening and treatment to those at risk, and improved immunity with HAART.

Newly diagnosed HIV +ve ♀ should have a baseline colposcopy followed by annual cervical smear. The age range for cervical smear should be the same as for HIV −ve individuals. ICC should be managed as for ♀ without HIV infection. Abnormal cytology should be investigated by colposcopy with biopsy of suspicious areas. Mild dyskaryosis (CIN I) should be followed every 3–6 months as spontaneous regression is common. Standard treatment for moderate/severe dyskaryosis (CIN II and III) consists of lesional ablation, excision, or hysterectomy.

Anal cancer is more frequent in HIV +ve individuals and in MSM. However, the excess risk amongst HIV +ve MSM is difficult to quantify as anal receptive sexual intercourse is a strong independent risk factor for the two conditions. Similar to cervical cancer, high-grade HPV is an important aetiological factor. Prior to the HIV epidemic the relative risk of anal carcinoma in MSM was estimated to be 80× higher than in heterosexual controls. Recent data suggest that HIV-infected individuals with anal HPV infection are significantly more likely to develop high-grade dyskaryosis or anal carcinoma if they acquire other local infections (e.g. gonorrhoea, syphilis, HSV).

Similar to the female cervix, the anal canal has a transformation zone (TZ) at the junction of the anal squamous and rectal columnar epithelia. HPV infection of metaplastic cells ↑ tendency to oncogenic transformation in the anal TZ and thus the development of cancer.

Similar to cervical cancer, anal cancer is preceded by pre-cancerous changes referred to as anal intra-epithelial neoplasia (AIN). The role of anal cytology and anoscopy to detect pre-cancerous changes is not yet decided. Patients should be encouraged to report any anal symptoms and be clinically examined and referred to local specialists units as appropriate. Annual anal digital examination, especially for homosexual men, should be considered. HAART does not appear to alter AIN progression or the incidence of invasive cancer.

Anal carcinoma is treated as for those without HIV. Limited data are available on management of anal dyskaryosis but current practice suggests that treatment (by excision or laser ablation) should only be considered if severe dyskaryosis (AIN3).

↑ rate in children with HIV when, unlike in HIV uninfected children, tumours are induced by EBV.

The incidence of non-small-cell lung cancer, and to some extent adenocarcinoma, in HIV +ve individuals is higher than in age-matched HIV −ve controls. This difference is not explained by smoking alone. Compared with HIV −ve individuals, lung cancer usually occurs at a younger age and with advanced disease. Similar to HIV −ve individuals, it presents with cough, chest pain, haemoptysis, and dyspnoea. HAART does not improve survival; median time is 4 months. Patients with operable or locally advanced disease should be treated similar to HIV −ve individuals and HAART should be commenced if they are not already on it. Patients with metastatic disease may have palliative chemotherapy (poorly tolerated) and HAART interrupted.

Generally seen in context of HCV and/or HBV co-infection. Overall poor prognosis (28% 1 year survival) in HIV +ve patients. Presents at later stage and with more aggressive tumours than HIV −ve patients. If offered active treatment, survival approaches HIV −ve population. Screening for HCC should be used in specific groups ( Chapter 41). Solitary small lesions can be resected even if multiple. Liver transplant may be considered if cirrhotic. Ethanol injections and chemo-embolization may be used palliatively and lead to significant improvement in life expectancy.