HIV associated NEOPLASIA

1. HIV associated NEOPLASIA

2. AIDS-defining malignancies • Currently four : • Kaposi's sarcoma • non-Hodgkin's lymphoma (NHL) • primary CNS lymphoma (PCNSL) and • invasive cervical carcinoma

3. EPIDEMIOLOGY OF NHL IN AIDS • 25 to 40 % of HIV-1 seropositive patients eventually develop a malignancy which, in about 10 % of cases, is NHL • Compared to non-HIV-infected patients, seropositivity for HIV-1 increases the risk of development of a lymphoma 60 to 165 fold over that of the seronegatives • Primarily encountered in pts with more advanced HIV infection, with a CD4 count < 100/µL.

4. About 75 % of these lymphomas develop in those with poorly-controlled HIV infection One-quarter develop with undetectable viral load The association with lower CD4 counts and the RR of developing a lymphoma was strongest for IL (RR 1.64) and PCNSL (RR 2.29) HIV-related Burkitt's (and Burkitt's-like) lymphoma frequently develops when the CD-4 count is relatively high.

5. 70 to 90 % of the lymphomas are high-grade and are almost exclusively diffuse large B cell (immunoblastic variant) and Burkitt's-like lymphomas. These neoplasms may be more common in males than in females The RR for IL is more than 650-fold and for BLL 260-fold

6. Pathologically • Comprised almost exclusively of B-cell tumors of aggressive type. • Diffuse large B-cell lymphoma. • B-cell immunoblastic lymphoma. • Small non cleaved lymphoma, either Burkitt or Burkitt-like. • All three pathologic types are equally distributed and represent aggressive ds.

7. PATHOGENESIS • HIV infection → progressive impairment of dendritic cell function → increased production of cytokines (eg,IL-6 & IL-10) → development of lymphoid neoplasms. • The Tat protein of HIV may be taken up by B lymphocytes → dysregulation of the oncosuppressor protein products of the pRb2/p130 gene.

8. Immunosuppression and EBV infection favor the expansion of B cell clones, thereby allowing clones of cells that have undergone alterations in oncogenes or tumor suppressor genes to proliferate The enhanced adhesion of neoplastic lymphocytes to endothelial cells Genetic alterations play an important role in the pathogenesis, & also in determining the histology of the resulting clonal proliferation.

9. CLINICAL MANIFESTATIONS • Are typically protean • Majority have constitutional ("B") symptoms • Usually a paucity of clinically involved LNs. • At least 80% of pts have stage IV disease and, without therapy, over 95% eventually develop extra nodal spread • Most common sites are the GIT, liver, lung, bone marrow and the central nervous system • Fever

10. Clinical features • Correlate with histopathology. • The majority of pts with small noncleaved cell (Burkitt) lymphomas present with stage IV disease, mostly because of BM involvement, compared with an ≈ 40% stage IV presentation by those with immunoblastic and large cell lymphomas. • A particular prevalence for GI involvement has been noted in pts who have immunoblastic and large noncleaved cell lymphoma types.

11. GIT • The presenting site in ≈ 45 % of pts, and is the most frequent site of extra nodal ds. • Initial involvement • colon 46% , ileum 39%, and stomach 23%. • The major presenting features are pain and/or weight loss; • Complications → bleeding, perforation and obstruction occur in about 40%.

12. Liver, lung, and BM —involved in ≈ ⅓ of pts. Hepatic involvement clinically silent or associated with pain, a cholestatic picture, or elevated serum liver enzymes. Pulmonary disease may present as a mass lesion, multinodular densities or diffuse interstitial infiltrates. Pleural effusions develop in almost 70 % BM involvement is more likely with BLL, and is significantly associated with leptomeningeal spread.

13. Meninges and CNS —lymphomatous meningitis, occurs in 3 to 20 % of pts at the time of presentation One-quarter of these pts are asymptomatic and, even Sx, only a minority have meningeal signs. Other Sxs include headache and CN palsies. Frequently associated with recurrence, particularly in pts not treated with intrathecal prophylactic therapy during initial treatment of the lymphoma.

14. Staging • In general, the Ann Arbor system. • Important in selecting the treatment of pts with NHL who do not have AIDS, the majority of pts with AIDS-related lymphomas have far-advanced ds. • A number of factors that are important for determining prognosis are not included in the staging system. • At dx, 66% of the pts have stage IV disease. • Extra nodal disease at presentation → 87% • Another → 33% ( 43% N +EN )

15. Treatment Option • Essential components • antitumor therapy • highly active antiretroviral therapy • prophylaxis for opportunistic infections, and • recognition & treatment of intercurrent infections

16. Challenges • Poor bone marrow reserve, which compromises the potential for drug dose intensity • Intercurrent OI is a risk that may also lead to a decrease in drug delivery • Chemotherapy itself compromises the immune system and increases the likelihood of OI • HIV-1 infection may render lymphocytes relatively resistant to the cytotoxic activity of some of the drugs used in these regimens

17. Chemotherapy • Majority of pts are not eligible for potentially curative local therapies • Optimal therapy has yet to be defined • First-line CT regimens → lower rates & durability of complete response in pts with AIDS → increased expression of the MDR-1 in the lymphocytes of AIDS-related lymphomas

18. Regimens for DLBCL/IL • CHOP • m-BACOD and • infusional CDE (cyclophosphamide, doxorubicin, and etoposide) • Intrathecal CT is usually considered for those pts at higher risk for CNS involvement; • BM involvement or • EBV identified in the primary tumor or in the CSF • Methotrexate & C-arb

19. Regimens for BLL • Dysregulation of the c-myc oncogene • Unresponsive to moderate dose CT • Require more intensive CT • CODOX-M/IVAC (Magrath) • CALGB-9251 • CNS prophylaxis strongly considered

20. Influence of HAART • Reduction in OIs, and a median OS • Allowed the use of standard dose and even intensive CT regimens • In a retrospective review of 363 pts with HIV-associated lymphoma, survival of pts with • HIV-DLBCL improved • HIV-BL remained poor • Virologic response independently ass. • Attainment of CR • Event free survival

21. Prognosis • Associated with stage • Age • Severity of the underlying immunodeficiency • Performance status, and • Prior AIDS diagnosis • Response to therapy

22. AIDS-RELATED KAPOSI'S SARCOMA • KS is a low-grade vascular tumor associated with human herpes virus 8 (HHV-8), • Four epidemiologic forms of KS • 1. Classic • 2. Endemic or African • 3. Organ transplant-associated • 4. AIDS-associated or epidemic KS

23. EPIDEMIOLOGY • KS is principally a disease of men. incidence 15 times greater in men than in women. • Four factors associated with a higher risk of KS • presence of HIV infection, • increasing anti-HHV-8 antibody titers, the • presence of HHV-8 viremia, and • lack of neutralizing antibodies.

24. PATHOGENESIS • KS is caused by a sexually transmitted agent, probably HHV-8. • HHV-8 has two phases of infection: lytic and latent. • During the lytic phase, KSHV replicates in infected cells, which results in cell lysis. • In the latent phase, virus does not replicate, although cells harbor viral episomes and express several proteins, such as latency-associated nuclear antigens (LANA1 and LANA2). • Latent infection predominates in KS cells

25. PATHOLOGY • Three histological features characteristic of KS: • angiogenesis, • inflammation, and • proliferation • Two major abnormalities: • whorls of spindle-shaped cells with leukocytic infiltration; and • neovascularization with aberrant proliferation of small vessels • HIV infection may promote HHV-8 replication indirectly by impairing immunity of the host.

26. Effect of HIV on HHV-8 related tumorigenesis • HIV may play a direct role in inducing tumorigenesis through the production of cytokines. • A number of these cytokines are able to stimulate KS spindle cell growth in vitro, and induce normal endothelial cells to acquire the characteristics of spindle cells. • These include IL-6, oncostatin M, TNF-α, and PDGF

27. CLINICAL MANIFESTATIONS • Variable clinical course • Skin involvement is characteristic but extra cutaneous spread of KS is common, particularly to the oral cavity, gastrointestinal tract, and the respiratory tract.

28. Skin —appear most often on the lower extremities, face, oral mucosa, and genitalia May also be symmetrically distributed Not painful or pruritic and usually do not produce necrosis of overlying skin or underlying structures. Lymphedema may be related to both vascular obstruction by LAP and the cytokines involved in the pathogenesis

29. Oral cavity —one-third of pts ; it is the initial site of the disease in about 15 percent. The intra oral site most commonly affected is the palate followed by the gingiva Gastrointestinal tract —is involved in approximately 40 % of pts at initial diagnosis and in up to 80 % at autopsy; involvement can occur in the absence of cutaneous disease

30. Testing the stool for occult blood to screen for GI involvement Further studies pts who test positive for occult blood or have GI Sx Biopsies may not demonstrate KS, lesions tend to be submucosal High grade lesions are more likely to be associated with invasion and dissemination

31. Respiratory system pts can present with shortness of breath, fever, cough, hemoptysis, or chest pain, or as an asymptomatic finding on chest x-ray. Radiographic findings are nodular, interstitial and/or alveolar infiltrates, pleural effusion, hilar and/or mediastinal adenopathy, or an isolated pulmonary nodule

32. Treatment decisions guided by the presence of respiratory symptoms, extent of radiographic and bronchoscopic disease, and exclusion of a concomitant pulmonary infection as the cause of the clinical findings Other systemic involvement — LN involvement is not uncommon and may occur with no evidence of mucocutaneous ds

33. Effects of steroids and infection • Corticosteroid therapy & OIs has been associated with the induction and exacerbation of preexisting KS • High levels of proinflammatory cytokines, which have been demonstrated in the setting of OIs, may account for these effects

35. TREATMENT • No known curative therapy • Major goals of treatment are palliation of symptoms, shrinkage of tumor to alleviate edema, organ compromise, psychological stress, and prevention of disease progression. • One form of therapy used is HAART • Other therapies are directed at the tumor • The choice depends upon the tumor, the HIV-1 viral load, and the host (CD4 cell count and overall medical condition)

36. Efficacy of HAART —a decreased proportion of new AIDS cases, regression in the size of existing KS lesions, and possibly improved survival in pts with or without chemotherapy Local therapy —topical alitretinoin gel, intralesional chemotherapy, radiation therapy, laser therapy, cryotherapy are often effective at controlling local tumor growth Vinblastine is widely used intralesional agent

37. Radiation therapy can effectively palliate symptomatic ds that is too extensive to be treated with intralesional chemotherapy Chemotherapy — Generally accepted indications for systemic therapy include: Widespread skin involvement (usually more than 25 lesions) Extensive cutaneous KS that is unresponsive to local treatment Extensive edema Symptomatic visceral involvement

38. The current systemic treatments; newer liposomal anthracyclines, paclitaxel, and vinorelbine Older agents, bleomycin, vinblastine, vincristine, and etoposide.

39. PROGNOSIS • The median survival with extensive pulmonary KS → 2 to 10 months • Poor prognostic factors included: • Presence of a PE • Severe SOB • CD4 count below 100 • Median survival in another study of 30 pts with symptomatic pulmonary disease treated with chemotherapy was 6.5 mos.

40. Poor prognostic factors in this study were: Absence of cutaneous KS Presence of previous OI CD4 count below 100 Hemoglobin below 10 g/dL Lack of radiographic response to chemotherapy

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42. Emerging treatments • Recent advances in the understanding of the pathogenesis of KS are uncovering potential targets for KS therapies. Such targets include angiogenesis, sex hormones, vitamin D and its analogs, & cellular differentiation

43. PULMONARY KS — Approximately one-third of KS patients will have clinically evident pulmonary disease and one-half have pulmonary involvement at autopsy. Parenchyma — KS involves the lung typically in either an interstitial or nodular pattern. Usually manifested clinically by dyspnea, hypoxemia, and dry cough. Hemoptysis, fever, and occasionally respiratory failure can also occur. Endobronchial lesions — Violaceous or bright red lesions are found in some patients on the mucosa of the lower airways, esp. at branching points, or, much less commonly, in the upper airways. Lesions usually cause no symptoms, although intractable cough, hemoptysis, wheezing, upper airway obstruction, and atelectasis are occasionally seen.

44. Pleura — Pleural effusions are radiographically visualized in up to two thirds of patients with parenchymal KS and occasionally as an isolated phenomenon. The effusion may be unilateral or bilateral and range from small to large. They are typically clear or serosanguineous and are almost always exudates. Transudates and chylous effusions are rare. Many effusions are asymptomatic. However, chest pain can occur and, when the effusions are large, respiratory distress can be a serious problem. Intrathoracic adenopathy — Enlarged mediastinal nodes have been reported in up to 46 percent of cases, although the origin of the nodes is seldom documented in these reports. The clinical significance of adenopathy in KS is related to the need to distinguish KS from other diseases which can cause adenopathy, such as infection.

45. Chest radiograph — Parenchymal involvement generally shows one of two patterns on chest radiographs: Tumor infiltrating the septa presents radiographically as patchy interstitial infiltrates that frequently occur in a perihilar distribution. This pattern is seen in approximately 60 percent of cases. Ill-defined nodular densities are also common, occurring in approximately 25 percent of chest radiographs. Overlap radiographic patterns, areas of focal consolidation, a solitary nodule, coalescence of nodules, and normal radiographs can also be seen in selected patients. CT scan and MR imaging — There are two CT findings that are highly suggestive of parenchymal KS: hilar densities extending into the parenchyma along perivascular or peribronchial pathways; and a characteristic septal or nodular pattern with concomitant pleural effusions.

46. Bronchoscopy — The diagnosis of parenchymal KS is considered clinically confirmed if characteristic endobronchial lesions of KS are seen at bronchoscopy, since these lesions are often associated with concomitant parenchymal involvement. Unfortunately, endobronchial and transbronchial biopsies have an extremely low diagnostic yield, and significant hemorrhage has occurred following biopsy in up to 30 percent of patients in some series. Cytologic examination is not helpful, as a large biopsy specimen is needed to see the characteristic architecture of spindle cells surrounding thin vascular channels. Accurate diagnosis of pulmonary KS by detection of the putative causative agent, human herpes virus 8 (HHV 8, also called Kaposi's sarcoma-associated herpes virus), in bronchoalveolar lavage fluid has been reported

47. DIAGNOSIS OF ISOLATED PLEURAL EFFUSION • Establishing the dx of isolated PE due to KS is difficult. Pleural bx and cytology are not helpful in documenting KS, but they may be useful for excluding infection or lymphoma. • There are, however, some features that can be used to predict whether the effusion is due to KS. • The presence of cutaneous KS has a positive predictive value of 80 % that KS is the cause of the effusion. • The absence of fever and progressive symptoms are also helpful, having predictive values of 80 % and 83 %, respectively, that KS is the cause of the effusion. • On the other hand, the combination of the absence of cutaneous KS and the presence of fever and progressive symptoms carries a negative predictive value of 92 % that the effusion is not due to KS

48. Management of PE • Difficult • Sclerosis is usually tried if the effusions recur after thoracentesis, but it is often ineffective. • Repeated thoracentesis is the modality most often used to relieve symptoms, frequently in combination with chemotherapy in an attempt to control the disease.

49. There are conflicting data on the influence of HAART on the incidence of NHL in persons with AIDS. The most likely effect of is a reduction in the proportion of pts with the lowest CD4 levels, the group most likely to develop high grade NHL

50. The intermediate grade lymphomas, predominately diffuse large B cell lymphoma, comprise about 20 percent of AIDS-related lymphomas, while the low-grade lymphomas are less common . The relative risk of these tumors compared to the HIV-negative population is increased more than 110 and 14-fold, respectively. Other genetic mutations may adversely affect the risk of developing an AIDS-related lymphoma [41]. One group has shown that a polymorphism in the gene that encoses for the CXCR-4 chemokine receptor was associated with a two to four fold increase in the risk of developing an AIDS-related non-Hodgkin's lymphoma