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Ovid: Oxford Handbook of Genitourinary Medicine, HIV, and Aids

Editors: Pattman, Richard; Snow, Michael; Handy, Pauline; Sankar, K. Nathan; Elawad, Babiker Title: Oxford Handbook of Genitourinary Medicine, HIV, and Aids, 1st Edition Copyright ©2005 Oxford University Press > Table of Contents > HIV/AIDS > Chapter 52 – HIV: malignancies Chapter 52 HIV: malignancies P.498
Introduction Incidence of malignancy is ↑ with impaired cell mediated immunity, observed before HIV epidemic. Applies most commonly to a narrow spectrum of more unusual tumours, especially those induced by viral co-infections, rather than those most commonly seen in the general population. Some occur much more frequently in HIV infection, especially when immunosuppressed, with the following designated as AIDS defining illnesses:

  • Kaposi’s sarcoma
  • non-Hodgkin’s lymphoma
  • invasive cervical carcinoma.

Other associated malignant conditions include squamous cell carcinoma (anogenital, conjunctival, labial, and glossal), testicular tumours, melanomas, Hodgkin’s disease, multiple myeloma, leiomyosarcoma in children, and lung cancer. The following viral infections contribute to the induction of malignant disease in the immunosuppressed:

  • human herpes virus 8 (HHV-8)—KS and body cavity lymphomas. Found in ~100% in multicentric Castleman’s disease
  • human papilloma virus (HPV)—anogenital and possibly oral carcinomas
  • Epstein–Barr virus (EBV)—certain forms of lymphoma
  • hepatitis B and C viruses—hepatocellular carcinoma

Other factors such as specific sexual practices and cigarette smoking (which should therefore be discouraged) 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. Kaposi’s sarcoma (KS) Initially described in 1872 by Moritz Kaposi and rare before HIV epidemic. Four different types:

  • classic—usually elderly ♂ from eastern Mediterranean/Europe causing multiple skin lesions of lower limbs.
  • endemic—children and young ♂ in equatorial Africa. More virulent than classic.
  • acquired—people on immunosuppressant therapy. Resolves when drugs stopped.
  • epidemic—associated with HIV infection. Variable but generally more aggressive than other 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 homosexual ♂ new HHV-8 infection is associated with an HIV-positive partner. No evidence to support transmission by semen (HHV-8 rarely detected) and conflicting data on the role of rimming. P.499
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Epidemic KS Most common malignancy associated with HIV infection. Before HAART, was the AIDS defining disease in 15–20% of homosexual ♂ (found in up to 50% with AIDS early in the epidemic). Incidence decreasing prior to HAART but substantially ↓ since HAART. Predominantly found in homosexual ♂ and rare among IV drug users and haemophiliacs. Also rare in ♀ (possible hormonal factor) but if found often more aggressive and usually associated with HIV acquisition from a bisexual ♂. Mean time from HHV-8 seroconversion to KS development—33 months. KS found more commonly in those with advanced disease. 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. Clinical features Skin lesions May occur on any part of the body but facial (margin of nostrils, tip of the nose, and eyelids) involvement common. Typical pigmented macules, papules, plaques, 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. Oral lesions Found in ~33% of those with epidemic KS usually affecting hard palate (also gingiva, tongue, uvula, tonsils, pharynx, 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. Others

  • Gastrointestinal (GI) tract: prior to HAART found in 40% of at initial KS diagnosis. Unless symptomatic their presence does not influence prognosis. May occur without skin lesions and may cause GI bleeding or obstruction.
  • Respiratory: may involve lung parenchyma, bronchial tree, and pleura leading to large blood-stained pleural effusions. Usually symptomatic (dyspnoea, haemoptysis, cough, wheezing, and radiology often shows ill-defined nodules or areas of infiltration.
  • Lymph nodes: modest lymphadenopathy common. Rarely massive lymphadenopathy (possibly without KS elsewhere) necessitating diagnostic biopsy.
  • Lymphoedema: non-pitting, most commonly affecting feet and legs and may be complicated by ulceration and infection. May result from direct KS dermal lymphatic involvement.
  • Hepatic, splenic, cardiac, pericardial, bone marrow involvement all rarely reported, usually at autopsy.

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Social/emotional implications Lesions often obvious and disfiguring acting as a constant reminder leading to isolation, anxiety, and depression. Diagnosis and assessment

  • Clinical appearance and biopsy
  • Other specific investigations depending on site (e.g. radiology, scan, endoscopy).
  • HHV-8 antibody and viral load (VL) tests developed but not widely available. VL ↓ when KS treated with chemotherapy and HAART.

Staging based on distribution of KS, CD4 count, and other HIV associated symptoms/opportunistic infections (OIs) to determine level of risk for disease progression. Poor prognosis if both advanced tumours and systemic disease. P.502
Management HAART often significantly improves KS (in up to 80%) without further intervention. Treatment options depend on site, KS extent/activity, CD4 count, presence of systemic symptoms, and other OIs, past or present. No interventional treatment Consider if few skin lesions and no problems. Disfiguring lesions can be cosmetically camouflaged. Local therapy

  • Cryotherapy—small flat lesions on thin skin (e.g. face, genitals). Repeat treatment usually required. May leave hypopigmented scar.
  • Radiotherapy—for lesions that are painful, causing lymphatic obstruction, oropharyngeal, or ophthalmic. Side-effects include local erythema, hair loss, mucositis, and pigmented scarring. Although lesions regress with irradiation, regrowth within 6 months common.
  • Intralesional vinblastine, vincristine, or alpha interferon—limited mucocutaneous disease. Painful injections causing inflammatory response before lesions shrink or disappear leaving a scar. Repeat injections required and relapse within 6 months common.

Liposomal chemotherapy Liposomal doxorubicin and liposomal daunorubicin now standard of care for KS. Preferentially absorbed by vascular KS lesions producing targeted chemotherapy with ↓ side-effects. Liposomal doxorubicin (20mg/m2 every 2–3 weeks) appears to be more effective (response rate 90%) and is licensed for extensive skin or visceral KS and CD4 counts <200cells/µL. Bone marrow suppression occurs in 50% but the associated neutropenia can be treated with granulocyte-colony-stimulating factor (G-CSF). Cytotoxic chemotherapy Now largely superseded by liposomal chemotherapy. Usually a combination of 3 or more of—bleomycin, doxorubicin, etoposide, tenoposide, vinblastin, vincristine. Paclitaxel has a 50% response rate. ▶ Prophylaxis against Pneumocystis jiroveci (carinii) pneumonia (PCP) should be provided during chemotherapy because of 2° immunosuppression. Alpha interferon Best results in early KS if limited to the skin, CD4 count >200cells/µL, no systemic symptoms or history of OIs. Improvement in ~40%. Flu-like symptoms are usual, depression can occur, and neutropenia may develop (ameliorated by G-CSF though this ↑ constitutional symptoms). Retinoic acid (oral and topical) Variable data with ~33% showing some response. P.503
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Non-Hodgkin’s lymphoma (NHL) First cases of NHL in homosexual ♂ reported in 1982. Prior to HAART accounted for 2–3% of AIDS defining illnesses with haemophiliacs/those with other clotting disorders having the highest incidence. Occurs in up to 10% of those with AIDS although not necessarily as the presenting disease. Conflicting data on incidence since HAART introduced but survival improved. NHL immunoblastic lymphoma in 60% (↑ with age), Burkitt’s lymphoma 21% (most common 10–19 years), and 1° lymphoma of the brain in 19% (any age). Each type found twice as commonly in whites as in blacks and in ♂ as in ♀. ~95% are of B-cell origin with aggressive histological appearances. EBV episome is found in 40–50% overall, ranging from ~100% of 1° brain lymphoma to 20% of immunoblastic tumours. Systemic lymphoma 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. Extranodal 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). Diagnosis and staging

  • Biopsy of 1° lesion
  • Staging by CT/MRI scanning and bone marrow biopsy

Management

  • Chemotherapy (improved tolerance if CD4 count >200cells/µL) usually cyclical. PCP prophylaxis should be taken as treatment causes immunosuppression. Regimen examples include:
    • CHOP (cyclophosphamide, hydroxydaunomycin [doxorubicin], oncovin [vincristine], prednisolone). Addition of G-CSF reduces neutropenia. Reported response rate—67%
    • m-BACOD (methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, dexamethasone). Reported response rate—46%.
  • Rituximab (monoclonal antibody causing B-cell lysis)—if resistance to chemotherapy. Has also been used in combination with CHOP.

Survival better than with 1° brain lymphoma and has ↑ since the introduction of HAART, although its optimal use during chemotherapy has not been established. Alternatives and their consequences are to:

  • discontinue HAART—↑HIV replication and exaggerated CD4 ↓
  • continue HAART (with close monitoring)—risk of ↓ drug levels (with indinavir, didanosine, efavirenz, nevirapine) and ↓ side-effects
  • modify HAART to ↓ interaction/side-effects.

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Primary CNS lymphoma An EBV induced tumour 1000× more frequent in those with HIV infection. Associated with very low CD4 count (<50cells/µL in 75%) and a history of OIs. Usually presents with confusion, amnesia, and lethargy. In addition focal symptoms may appear (e.g. seizures, hemiparesis, cranial nerve palsies, aphasia). Diagnosis Difficult to distinguish from cerebral toxoplasmosis.

  • Computerized tomography (CT)/magnetic resonance imaging (MRI) Single (~50%) or multiple lesions. (Former suggests NHL as ~20% of those with toxoplasmosis have a single lesion).
  • Fundal and slit lamp examination (20% have ocular involvement).
  • Lumbar puncture for:
    • lymphoma cells
    • EBV DNA using PCR.
  • Toxoplasma serology (toxoplasma unlikely if negative serology).
  • Brain biopsy—usually delayed until failure of response to anti-toxoplasma therapy is demonstrated.

Management

  • HAART ↑ survival.
  • Whole brain radiotherapy (usually with short-term dexamethasone to reduce oedema)—response reported in up to 75% but median survival only up to 4.8 months.
  • Combined radiotherapy and chemotherapy (no evidence of ↑ benefit).

Prognosis poor and partly dependant on control of other OIs. Has improved with HAART. Primary effusion lymphoma (body cavity lymphoma) Account for 5% of HIV associated lymphoma. Usually seen in homosexual ♂ and associated with HHV 8. Presents with effusions (pleural, pericardial, ascites). Treat with chemotherapy (similar to systemic lymphoma) but poor prognosis (2–5 months). P.506
Multicentric Castleman’s disease Induced by HHV-8 in HIV infection. Characterized by recurrent lymphadenopathy, fevers, hepatosplenomegaly, and sometimes KS. May be fatal even without frank malignant transformation. Treat with combination chemotherapy, e.g. CHOP, steroids, anti-CD20 monoclonal antibodies. Prognosis is poor with a median survival of less than 30 months. Hodgkin’s disease Although not an AIDS defining diagnosis found 8 times more commonly in those with AIDS. Tends to be more aggressive with the mixed cellularity subtype predominating. Associated with EBV infection, usually developing with CD4 counts 200–300cells/µL. Presents with lymphadenopathy (glands often very large), Pel-Ebstein fever, anaemia, and weakness. Bone marrow and systemic involvement common. Diagnosed by lymph node or bone marrow histology (Reed– Sternberg cells). Stages I/II most frequently treated with radiotherapy and stages III/IV with combination treatment, e.g. MOPP (mechlorethamine, oncovin [vincristine], procarbazine, prednisolone). Invasive cervical carcinoma (ICC) Added to the AIDS case definition in 1993 following reports showing ↑ prevalence of cervical dysplasia with HPV infection and immunosuppression (usually severe). However, no substantial clinical evidence demonstrating a ↑ 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. Annual cervical cytology is advised. ICC should be managed as for ♀ without HIV infection. Abnormal cytology should be investigated by colposcopy with biopsy of suspicious areas. Mild dyskaryosis (CIN1) 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 or excision. Recurrence rate is higher in HIV infected ♀. Anal carcinoma Relation with HIV infection difficult to assess as both are associated with unprotected anal intercourse and multiple partners. Strongly linked with high grade HPV infection. Prior to the HIV epidemic the relative risk of anal carcinoma in homosexual ♂ was estimated to be 80-fold higher than heterosexual controls. Recent data suggests that HIV infected individuals P.507
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). HAART does not appear to be protective. Although not routine clinical practice, anal cytology may be used to detect dyskaryosis. High/moderate grade lesions can be further investigated by anoscopy using a colposcope having pre-treated the anal canal with 3% acetic acid to allow identification of tissue for biopsy. Anal carcinoma is treated as for those without HIV infection. Limited data 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). Leiomyosarcoma ↑ rate in children with HIV when, unlike in HIV uninfected children, tumours are EBV induced. Lung cancer Eight-fold increase in HIV infection compared with age and gender matched controls and is not explained by smoking alone. Current rising incidence results from improved survival with HAART (its development is not immunodeficiency dependent). Compared to those HIV negative lung cancer usually occurs at a younger age and with advanced disease. Presentation similar with cough, chest pain, haemoptysis, and dyspnoea common symptoms and typical changes on x-ray. Both small cell and non-small cell tumours occur. Progression and response to treatment worse than with HIV negative patients and not improved by HAART. Chemotherapy poorly tolerated. Radiotherapy has a high rate of radiation oesophagitis. Prognosis can only be significantly improved with early diagnosis followed by curative surgical resection.

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