Aids and malignancies

oncology

1. AIDS RELATED MALIGNANCIES

2. Kaposi sarcoma was the first malignancy, which was considered AIDS defining in young individuals. T he CDC definition evolved later on, and since 1993, three tumors have been considered AIDS-defining in the context of HIV: KS, certain NHL , and invasive cervical cancer . Combination antiretroviral therapy ( cART ) involving three or more drugs leads to preserved CD4 lymphocyte counts, preserved immune function, decreased immune activation, decreased infectious complications, and decreased mortality, transforming HIV infection into a manageable chronic disease.

3. Epidemiology Decrease in deaths from AIDS since the introduction of cART , the number of persons living with HIV in the United States has increased by more than 50 %. It is estimated that more than 1.1 million people in the United States are now infected with HIV. With HIV-infected individuals living longer, the population at risk for malignant complications has increased and aged, and this pattern may continue into the future.

4. In addition to AIDS-defining malignancies, HIV-infected patients are at increased risk of a number of other malignancies, including lung cancer, liver cancer, anal cancer, Hodgkin's lymphoma (HL), certain head and neck cancers, and Merkel cell carcinoma.

5. Various Malignant Conditions in Patients with AIDS AIDS-Defining Kaposi sarcoma Non-Hodgkin's lymphoma Burkitt lymphoma DLBCL Immunoblastic Primary diffuse large B-cell lymphoma of the CNS Cervix

6. Non–AIDS-Defining Hodgkin's lymphoma Oral cavity and pharynx Anus Lung Vagina and vulva Seminoma Penis Renal cell carcinoma

7. Non- AIDS defining Liver Myeloma Breast Colon Prostate

8. Human Immunodeficiency Virus (HIV)-Associated Lymphomas Lymphomas also occurring in immunocompetent patients    1.Burkitt lymphoma     2.  Diffuse large B-cell lymphoma         Germinal center subtype         Activated B-cell subtype     3.   Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue type (MALT lymphoma; rare, mainly in pediatric patients)     4.  Classic Hodgkin's lymphoma (commonly mixed cellularity or lymphocyte depleted forms)

9. Lymphomas occurring more specifically in HIV+ patients    1.   Primary effusion lymphoma    2.  Large B-cell lymphoma arising in HHV-8 associated multicentric Castleman disease    3. Plasmablastic lymphoma    4.   Primary diffuse large B-cell lymphoma of the central nervous system (in patients with AIDS, >95% EBV associated )

10. Lymphomas also occurring in other immunodeficiency states      Polymorphic B-cell lymphoma (PTLD-like)

11. With an estimated incidence in the United States of 97 per 100,000 person-years in the cART era, NHL is now the most common malignancy in HIV-infected individuals in the United States. With an estimated incidence in the United States of 62 cases per 100,000 person-years, and a broad variability in incidence that is related to CD4 count, KS is now the second most common tumor in people with HIV/AIDS in the United States.

12. AIDS-Defining Virus Kaposi’s Sarcoma HHV-8 Non-Hodgkin’s Lymphoma EBV, HHV-8 (systemic and CNS) Invasive Cervical Carcinoma HPV Non-AIDS Defining Anal Cancer HPV Hodgkin’s Disease EBV Leiomyosarcoma (pediatric) EBV Squamous Conjunctival Carcinoma HPV (?) Hepatoma HBV, HCV

13. Kaposi Sarcoma Pathophysiology – KS is characterized by inflammatory angiogenic lesions that arise in multiple sites. It occurs predominantly on the skin, but can involve virtually any organ, perhaps except the brain. Classic KS , predominantly involves lower extremities of elderly men, and is found mostly in Ashkenazi Jews or in individuals living near the Mediterranean Sea.

14. Endemic KS , was subsequently recognized in Africa. This form can occur earlier in life, often in the third or fourth decades, frequently involves the lymph nodes, and occurs in a higher percentage of females than classic KS. Also, it can develop in children, causing severe morbidity . Epidemic KS is used to describe KS arising in HIV-infected patients. It is generally more clinically aggressive than classic KS . KS can also occur in transplant recipients. KSHV is the etiologic agent for all forms of KS.

15. KS lesions are characterized by vascular slits filled with blood that often extravasates and accounts for their purplish hue. Microscopically, tumors are heterogeneous but characterized by a predominance of KSHV-infected spindle-shaped cells with certain markers of lymphatic endothelial cells . Hyperproliferation of endothelial-derived spindle cells is important in the pathogenesis of this disease. Most of this hyperproliferation appears to be directly or indirectly induced by KSHV. a viral homologue to human IL-6 and three homologues of macrophage inhibitory protein that have been shown to have angiogenic activity

16. ORF74 of KSHV encodes for a constitutively active G-protein–coupled receptor (KSHV-GPCR) that induces production of vascular endothelial growth factor and other angiogenic factors . KSHV can be induced to undergo lytic replication by hypoxia, and it is possible that the tendency of KS to arise in the feet, which are relatively hypoxic, is partly the result of hypoxia-induced KSHV reactivation . KSHV transmission can occur by both sexual and nonsexual routes. Saliva of infected individuals has greater KSHV shedding than other body fluids.

17. Staging and Prognosis The most widely used staging system for KS, devised prior to available cART , is the AIDS Clinical Trials Group Oncology Committee TIS staging system . Patients are scored based on extent of tumor involvement (T), immune status (I), and systemic illness (S ). Risk is assigned as good or poor, depending on the presence or absence of localized tumor versus more extensive tumor with associated edema, ulceration, visceral disease, or extensive oral KS; CD4 more or less than 150 cells/mm 3 ; and the presence or absence of antecedent opportunistic infections, constitutional symptoms, other HIV-related illness, and Karnofsky performance status.

18. Good risk is designated with a subscript 0, and poor risk by subscript 1, the summary taking the form T or T 1 , I or I 1 , or S or S 1 a good risk (T S , T 1 S , or T S 1 ) and a poor risk (T 1 S 1 ). Criteria for a partial response include 50% decrease in the total number of lesions, 50% decrease in the area of measured cutaneous lesions, or flattening of 50% of nodular lesions in the absence of progressive disease .

19. Stage Good Risk (0) (All of the Following) Poor Risk (1) (Any of the Following) Tumor (T) Confined to skin and/or lymph nodes and/or non-nodular oral disease confined to the palate Tumor-associated edema or ulceration Extensive oral KS Gastrointestinal KS KS in other nonnodal viscera Immune system (I) (not included if HIV-sensitive to cART ) CD4 cells ≥150/ mcL CD4 cells <150/ mcL Systemic illness No history of opportunistic infection or thrush History of opportunistic infections and/or thrush; “B” symptoms present   No B symptoms (unexplained fever, night sweats, >10% involuntary weight loss, or diarrhea) persisting more than 2 weeks Performance status ≥70 (Karnofsky) Performance status <70 Other HIV-related illness (e.g., neurologic disease, lymphoma)

20. Systemic Therapies for Patients with Advanced Kaposi Sarcoma Therapy Type Response Rates (Ref.) Commonly used standard therapy    cART Variable; should be optimized in combination with other therapies   Liposomal doxorubicin 59%–76% (80,188)   Paclitaxel 59%–71% (84,189)

21. Alternative therapies   Interferon-α Variable, CD4 cell-dependent    Adriamycin / bleomycin / vinca alkaloids 24%–88% (higher response rates with higher doxorubicin doses, but greater toxicity)   Vincristine/vinblastine 45% Bleomycin/vinca alkaloids 23%

22. Kshv -Associated Multicentric Castleman Disease Several forms are: unicentric hyaline-vascular form, a multicentric plasma cell form, and a multicentric form associated with KSHV . Nearly all Castleman disease arising in the setting of HIV infection is KSHV-associated MCD (KSHV-MCD ). KSHV-MCD is characterized by intermittent flares of inflammatory symptoms, including fevers, fatigue, and cachexia , and edema, together with lymphadenopathy and/or splenomegaly . Gastrointestinal symptoms and cough are also common. Flares can be severe and often fatal; they are primarily caused by cytokine overproduction related to the highly lytic state of the KSHV in MCD. In particular, a KSHV-encoded analogue of interleukin-6 (vIL-6) and/or overproduction of cellular IL-6 are believed to cause many of the symptoms of KSHV-MCD.

23. Diagnosis of KSHV-MCD generally requires excisional lymph node biopsy and demonstration of KSHV-infected plasmablasts . Laboratory abnormalities include anemia, thrombocytopenia, hypoalbuminemia , hyponatremia , and elevated C-reactive protein . Patients with MCD should undergo computed tomography (CT) of neck, chest, abdomen, and pelvis . There is no standard therapy for KSHV-MCD. HIV-infected patients should receive cART , although intolerance to a number of drugs, including antiretrovirals , may occur until MCD is controlled.

24. CD20 monoclonal antibody rituximab , Rituximab combined with liposomal doxorubicin, Ganciclovir , IFN-α, and high-dose zidovudine combined with ganciclovir , Splenectomy has sometimes been used to manage severe cytopenias in KSHV-MCD.

25. Rarer Peripheral ARLs: Plasmablastic Lymphoma and PEL Plasmablastic lymphoma (PBL) is an EBV-associated B-cell NHL proposed as a new entity in 1997. Although most common in the setting of HIV, PBL also occurs in organ transplantation patients and elderly individuals . It often presents with disease within the oral cavity, but may occur at other extranodal or nodal sites . HIV-associated PBL usually presents as either stage I or stage IV disease and has a 7:1 male predominance.

26. PBL is characterized by a high proliferative index and aggressive clinical course. Historically, the prognosis has been poor, with median survival less than 2 years . PEL is a rare KSHV-associated aggressive mature B-cell lymphoma that usually presents as a lymphomatous effusion in serous body cavities; patients are at risk for other concomitant KSHV-associated malignancies. Many cases are pleural, but peritoneal, pericardial, and leptomeningeal presentations are seen.

27. Diagnosis of PEL depends on the demonstration of KSHV infection of tumor cells. In more than 70% of cases, tumor cells are coinfected with EBV. Common B-cell surface markers (CD19, CD20, CD79a) are absent, while activation markers (CD30, CD38, CD71, CD138) are often present. Doxorubicin-based regimens report initial complete response rates as high as 40%, but the clinical course is characterized by rapid relapse, with a median survival of less than 6 months.

28. Pathology of AIDS-Related Non-Hodgkin’s Lymphoma Small noncleaved-cell lymphoma Burkitt’s lymphoma and Burkitt-like lymphoma Immunoblastic lymphoma (primary CNS) Diffuse large-cell lymphoma (90% CD20+) Large noncleaved-cell lymphoma CD30+ anaplastic large B-cell lymphoma Plasmablastic lymphoma Advanced stage (>75% III or IV) Extranodal involvement Central nervous system, liver, bone marrow, gastrointestinal Tirelli U, et al. AIDS . 2000;14:1675-1688.

29. Therapeutic Approaches for AIDS-Related Non-Hodgkin’s Lymphoma Outgrowth of lymphoma treatment in general Multiple agent, non-cross resistant chemotherapy Increase dose intensity (infusional therapy, high dose or multiple drugs) Central nervous system treatment or prophylaxis Supportive antibiotics and hematopoietic growth factors Importance of HAART Use of monoclonal antibodies (rituximab) AMC 010 and 034 High dose chemotherapy with ASCT

30. AIDS Malignancies Consortium Study 010: CHOP With or Without Rituximab CHOP + Rituximab CHOPAlone Number of patients 99 51 Complete response (%) 58 48 Median time to response (weeks) 11.0 10.5 Median event-free survival (weeks) 52 51 Death due to infection 13* 1 Median overall survival (weeks) 139 110 Phase II trial 149 patients Median CD4 count: 133 cells/mm 3 Regimens Rituximab (day 1) + CHOP (day 3) CHOP Patients restaged every 2 cycles Median F/U 137 wk * P =0.035 vs CHOP alone. Kaplan LD, et al. Blood 2005;106:1538-1543

31. Dose-Adjusted EPOCH (NCI) in HIV-Infected Patients Dose-adjusted EPOCH chemotherapy Etoposide 200 mg/m 2 (96-hour infusion) Vincristine 1.6 mg/m 2 (96-hour infusion) Doxorubicin 40 mg/m 2 (96-hour infusion) Prednisone 60 mg po on days 1–5 Cyclophosphamide IV on day 5 CD4 <100 cells/mm 3 : 187 mg/m 2 CD4 >100 cells/mm 3 : 375 mg/m 2 Dose adjusted in cycles 2 through 6 to a maximum of 750 mg/m 2 Little RF, et al. Blood. 2003;101:4653-4659.

32. Response to Dose-Adjusted EPOCH in HIV-Infected Patients CD4 (cells/mm 3 ) <100 > 100 Total Number of patients 16 23 39 Complete response (%) 56 87 79 Relapse 2 2 Progression-free survival (%) 73 93 87 Overall survival (%) 36 87 60 Median follow-up 53 months Median CD4 190 cells/mm 3 Not prognostic Tumor proliferation p53 overexpression Little RF, et al. Blood. 2003;101:4653-4659.

33. Primary CNS Lymphomas in HIV-Infected Patients Incidence: <5% of AIDS patients. Now very rare Diagnostic approaches Cranial CT or MRI scan Most important differential diagnosis: toxoplasmosis Stereotatic brain biopsy essential for diagnosis When biopsy not possible, EBV-PCR of CSF is useful, 100% sensitive, 80% specific Therapeutic approaches Traditional: radiation (4000-5000 cGy)- 10% 1yr survival High-dose methotrexate based chemotherapy Non-AIDS patients: shows promise High-dose ZDV + GCV +/- IL-2 may have benefit (JAIDS 1999;15:713-19)

34. Primary Effusion Lymphomas in HIV-Infected Patients B-cell non-Hodgkin’s lymphoma Most cases are dually infected with HHV8 and EBV Median survival: 6 months Traditional treatment: CHOP High-dose methotrexate plus CHOP Retrospective series of 7 patients treated: 3 in complete remission 18, 26, and 78 months after diagnosis 3 died with progressive PEL 1 achieved complete remission, but died with plasmablastic non-Hodgkin’s lymphoma at 9 months Boulanger E, et al. Am J Hematol. 2003;73:143-148.

35. Hodgkin's Lymphoma Patients with HIV-associated HL generally present at a younger age, with higher-stage disease, less frequent mediastinal involvement, more frequent involvement of extranodal sites of disease, and more frequent “B” symptoms as compared with the general population . Mixed cellularity or lymphocyte-depleted histology is most commonly seen.

36. In general, complete response rates in HIV-associated HL are relatively high with systemic chemotherapy (50% to >80%), but relapse is common . For patients successfully treated for HL, long-term control of HIV appears to improve overall survival.

37. Hpv -Associated Cancer in HIV Infection HIV-infected patients have an increased incidence of several cancers caused by HPV , including c ancer of the cervix, anus, penis, vulva, oral pharynx, and tonsil.

38. Immunization Against HPV HPV infection induces type-specific immune responses Promising vaccine candidate: Virus-like particles (VLP) are recombinant viral capsids that induce type-specific neutralizing antibodies VLPs are nontoxic and highly immunogenic Both bivalent (HPV 16,18) and quadravalent (HPV 6,11,16,18) vaccines available.

39. Guidelines for assessment of CIN in HIV+ women Pap smear at initial evaluation Repeat Pap smear 6 months later If both negative, can do annual Pap Low threshold for colposcopy Role of HPV testing Screening for women over 18

40. Treatments for Cervical SIL and Invasive Cervical Cancer Cryoablation Laser therapy Cone biopsy Loop electrosurgical excision procedure (LEEP) Topical 5-FU Trans-retinoic acid Podophyllin cream Imiquimod cream Antiretroviral Therapy (?) Surgery (stage I) Radiation therapy Cisplatin or carboplatin Local Disease HSIL Invasive Disease 1,2 1 Mitsuyasu RT, et al. Cancer Management. 2006:609-632. 2 Martin F, et al. Sex Transm Infect . 2001;77:327-331.

41. Anal cancer Routine periodic cytologic examination of the anal mucosa should also be considered in high-risk individuals, and programs to screen HIV-infected women and men for anal intraepithelial neoplasia and to treat high-grade lesions are being considered . Current options for high-grade anal intraepithelial neoplasia include local treatment with topical immune modulators (e.g., imiquimod ) or antiviral agents (e.g., cidofovir ), electrocautery , laser or infrared coagulation, and surgery.

42. The standard of care for stages I–III anal cancer is concurrent chemoradiation , and patients with HIV should receive standard regimens. Given concern of hematologic toxicity associated with mitomycin -C–based chemoradiation in patients with HIV, cisplatin -based regimens have been advocated by some . The alternative to chemoradiation is surgical abdominoperineal resection, leaving patients with a permanent colostomy.

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