1. Cancers in HIV: A Growing Problem
Ronald Mitsuyasu, MD
Professor of Medicine
Director, UCLA Center for Clinical AIDS Research and Education
Group Chairman,
AIDS Malignancy Consortium (AMC)

2. AIDS Defining Cancers Kaposi’s sarcoma B-cell non-Hodgkin’s lymphoma
Primary CNS lymphoma
Cervical cancer

3. Cancer Incidences in HIV in USA
Number of people living with AIDS, AIDS-defining cancers, non-AIDS-defining cancers, and all cancers in the USA during 1991–2005.
Cancer Incidences in HIV in USA
Number of people living with AIDS, AIDS-defining cancers, non-AIDS-defining cancers, and all cancers in the United States during 1991–2005. A) US AIDS population by calendar year and age group. B) The estimated counts and standardized rates of AIDS-defining cancers among people living with AIDS in the United States by calendar year and age group. C) The estimated counts and standardized rates of non-AIDS-defining cancers among people living with AIDS in the United States by calendar year and age group. Of note, the bars for 0–12 year olds in panels (B) and (C) are difficult to see because of small numbers of cancers in this age group during 1991–2005 (122 AIDS-defining cancers and 25 non-AIDS-defining cancers). D) The estimated counts and standardized incidence rates of total cancers among people living with AIDS in the United States, stratified by AIDS-defining cancers, non-AIDS-defining cancers, and poorly specified cancers. Bars depict the estimated number of cancers, and points connected by lines depict incidence rates standardized to the 2000 US AIDS population by age group, race, and sex.
Shiels M S et al. J Natl Cancer Inst 2011;103:

4. Categorizing Cancers in PWHA
AIDS Defining Cancer
(decreasing) KS
NHL (BL, CNS, DLCBL)
Cervical Cancer ( added in 1993)
Non AIDS defining Cancers (increasing)
Anal Cancer
Lung Cancer
Hodgkin Lymphoma
Liver Cancer
Elevated risk but rare
Merkel Carcinoma
Leiomyosarcoma
Salivary gland LEC
Unchanged risk
Breast
Colorectal
Prostate
Follicular lymphoma 4

5. Breakdown of causes of death: France 2005
AIDS
Cancer
Hepatitis C
CVD
Suicide
Non-AIDS infection
Accident
Hepatitis B
Liver disease
OD / drug abuse
neurologic
renal
pulmonary
digestive
iatrogenic
metabolic
psychiatric
other
unknown
N = 937 deaths
This shows the breakdown of cause of death from a study of deaths in 2005 in people with HIV in France.
The proportion of deaths due to AIDS is only 36%, leaving the majority due to other causes.
Looking at detail in the causes of death, the most common after AIDS are non-AIDS malignancy, hepatitis C, cardiovascular disease, suicide and non-AIDS infection.
ANRS EN19 Mortalité 2005
Percent
Lewden JAIDS 2008, 48:590-9

6. Cancers in HIV Disease 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 Carcinoma (oral) HPV
Merkel cell Carcinoma MCV
Hepatoma HBV, HCV

7. HIV-Cancers: Overview
Non-AIDS defining malignancies
Anogenital neoplasia
Lymphomas
Kaposi’s Sarcoma
Cancer Prevention

8. Non-AIDS Defining Cancers NADC

9. Non AIDS-defining Cancers Emerging Epidemiologic Features
Proportion of Cancers in HIV
NADC
31%
58%
Standardized Incidence Ratio
Lung
2.6
Hodgkin lymphoma
2.8
6.7
Larynx
1.8
2.7
Pancreas
0.8
2.5
Liver
3.7
Engels EA, Int J Cancer. 2008;123:

10. Factors Contributing to the Increase in Cancer cases in HIV
4-fold increase in HIV/AIDS Population
Patients living longer and not dyeing of OI
Rising proportion of HIV pts > 50 yo
Cancer incidence increases with age
Greater and earlier start to smoking in HIV
Increase in some CA incidence rate among HIV
Lung (3X), anal (29X), liver (3X), HL (11X)
Suggests may be additional risk from HIV

11. Anogenital Cancers

12. Anogenital Cancers Invasive cervical carcinoma Anal cancer1
Considered an AIDS-defining condition
Leading cause of cancer death in women worldwide
Anal cancer1
Not AIDS defining but very common and growing incidence
Oral and Head/Neck cancer also HPV related
HPV involvement1-2
Both derive from precancerous lesions due to HPV
Most cancer causing strains: 16, 18, 31, 33, 35, 45
Repeated infections and infection with multiple HPV strains increase the risk of developing neoplasia
Cancer can be prevented with early diagnosis and vaccines
Slide #26: Cervical and Anal Cancers
Invasive cervical cancer has been recognized as an AIDS-defining malignancy for nearly 10 years.1
Prevalence of abnormal cervical cytology as high as 60% in some centers.
Nationwide, invasive cervical cancer was found in 1.3% of all women with AIDS and appears to be increasing.
Martin and colleagues reported that the HIV-positive population was at increased risk of anal cancer.1,2
25 to 87 cases per 100,000 reported among homosexual men versus 0.7 cases per 100,000 across the overall male population.
Cervical and anal cancers have similar etiologies:3
Progression of squamous intraepithelial lesions to invasive tumors.
Other correlative features include comparable risk factors including receptive intercourse, smoking, and infection with high-risk and multiple genotypes of human papilloma virus (HPV).
HPV involvement in both invasive cervical cancer and anal cancer within the HIV-positive population is correlated with certain oncogenic strains, including 16, 18, 31, 33, and
These genotypes are associated with a high rate of proliferation of certain genes expressed during latent infection and may produce cellular immortalization within affected epithelial cells.
References
Mitsuyasu RT, Cooper JS. AIDS-related malignancies. In: Reckling S, ed. Cancer Management: A Multidisciplinary Approach. 5th ed. Melville, NY: PRR; 2001:
Phelps RM, Smith DK, Heilig CM, et al. Cancer incidence in women with or at risk for HIV. Int J Cancer. 2001;94:
Martin F, Bower M. Anal intraepithelial neoplasia in HIV-positive people. Sex Transm Infect. 2001;77:
1Phelps RM, et al. Int J Cancer. 2001;94:
2Martin F, et al. Sex Transm Infect. 2001;77:

13. Spectrum of HPV disease
Morphologic Continuum
Low-grade disease
High-grade disease

14. Dentate (pectinate) line External sphincter ani muscles
Anal anatomy
Rectal mucosa
Columns of Morgagni
Dentate (pectinate) line
Squamous mucosa
Skin
Levator ani muscle
Subcutaneous
Deep
External sphincter ani muscles
Superficial
Ryan DP et al. New Engl J Med. 2000;342: 14

15. Anal and Cervical Cancer Incidence
Cervical cancer prior to cervical cytology screening in general pop: 40-50/100,000
Cervical cancer currently: 8-10/100,000
Anal cancer among HIV+ MSM in USA: up to 137/100,000
American Cancer Society. Cervical cancer facts Daling JR et al. N Engl J Med. 1987;317:
Chin-Hong PU, Palefsky JM. Dermatol Ther. 2005;18:67-76.

16. Prevalence of anal HPV detection among MSM Population-based data
All participants
HIV-negative participants
HIV-seropositive participants
Chin-Hong et al. Ann Int Med. 2008;149;300-6. 16 16

17. Lymphomas

18. 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
Slide #15: Pathology of AIDS-Related Non-Hodgkin’s Lymphoma
Non-Hodgkin’s lymphoma is among the most commonly diagnosed cancers in the patients with HIV disease.1
Two main histologic categories:1
Small noncleaved-cell lymphoma (SNCCL).
Include Burkitt’s lymphoma and Burkitt-like lymphoma
Make up 40% of all cases of non-Hodgkin’s lymphoma.
Diffuse large-cell lymphoma (DLCL).
Large noncleaved-cell lymphoma and immunoblastic lymphoma plasmocytoid are the most prevalent types of DLCLs, and they represent 25% each of all non-Hodgkin’s lymphomas.
CD30+ anaplastic large B-cell lymphoma is another AIDS-related non-Hodgkin’s lymphoma.
It is important that these lymphomas are accurately diagnosed and categorized as either SNCCL or DLCL, as the lymphoma type reveals pertinent information regarding the prognosis.1
Reference
1. Tirelli U, Spina M, Gaidano G, Vaccher E, Franceschi S, Carbone A. Epidemiological, biological, and clinical features of HIV-related lymphomas in the era of highly active antiretroviral therapy. AIDS. 2000;14:
Tirelli U, et al. AIDS. 2000;14:

19. EBV-positive tumors
Burkitt’s lymphoma
Nasopharyngeal carcinoma 19

20. AIDS-related Lymphoma Experience Suggests Cancer Treatment Outcome Can be Equivalent to General Population
Besson et al. Blood. 2001; 98:
Little et al Blood. 2003; 101:

21. Hodgkin’s Disease Association with HIV-infection
Hodgkin’s disease: RR: 5 to 30
Non-Hodgkin’s disease: RR: 24 to 165
Incidence increasing rapidly in post HAART era
>95% are EBV+
Patients with HIV present with:
B symptoms (70% to 96%), worse histology, higher-stage tumor (74% to 92% are III or IV), bone marrow involvement (40% to 50%), pancytopenia
Good response to MOPP/ABV
Complete response: 74.5%
2-year disease-free survival: 62% but more relapses in HIV
Early good results with Stanford V, BEACOPP and brentuximab vendotin
Slide #32: Hodgkin’s Disease
Hodgkin’s disease is associated with HIV disease, however this association is lower than that seen with non-Hodgkin’s lymphoma (relative risk: 5-30 vs , respectively).1,2
HIV-infected patients diagnosed with Hodgkin’s disease frequently present with:1,2
B symptoms that are typically associated with poorer prognoses. These symptoms include fever, night sweats, and loss of more than 10% of body weight.
Higher grade of disease than is found in newly diagnosed patients who are not HIV-positive.
<1% of all patients with Hodgkin’s disease exhibit lymphocyte depletion. However, most of these cases are found in patients with HIV.
Indicative if advanced disease, there is a greater chance of bone marrow involvement and pancytopenia being present at diagnosis.
The MOPP/ABV regimen has produced good results, with a complete response rate of 74.5% and a 2-year disease-free survival rate of 62%.3
References
Spina M, Vaccher E, Nasti G, Tirelli U. Human immunodeficiency virus-associated Hodgkin’s disease. Semin Oncol. 2000;27:
Re A, Casari S, Cattaneo C, et al. Hodgkin disease developing in patients infected by human immunodeficiency virus results in clinical features and a prognosis similar to those in patients with human immunodeficiency virus-associated non-Hodgkin lymphoma. Cancer. 2001;92:
Gerard L, Galicier L, Boulanger E, et al. Improved survival in HIV-related Hodgkin’s lymphoma since the introduction of highly active antiretroviral therapy. AIDS. 2003;17:81-87.
Gerard L, et al. AIDS. 2003;17:81-87.

22. Kaposi’s Sarcoma

23. Kaposi’s Sarcoma One of the first recognized AIDS-defining illnesses
Vascular tumor that may involve mucocutaneous, lymphatic, gastrointestinal, and pulmonary sites
Human herpesvirus-8 (HHV8) or KSHV
HHV8
DNA virus found in both HIV+ and HIV- KS.
Tropism for B cells and endothelial cells, high titers in saliva
Also associated with primary effusion lymphoma, Castleman’s disease, and angioimmunoblastic lymphadenopathy in HIV
Genome codes for viral homologs of human proteins involved in cell cycle regulation and signaling
HIV- and Kaposi’s sarcoma-induced angiogenic and inflammatory cytokines also stimulate Kaposi’s sarcoma cell growth
Slide #8: Characteristics of Malignancies in AIDS
Kaposi’s sarcoma was one of the first AIDS-defining conditions.1
Once a rare cancer of elderly men of Mediterranean origin, it became epidemic in the early years of AIDS.
Virus associated with Kaposi’s sarcoma.1
Kaposi’s sarcoma-associated herpesvirus (KSHV), also known as human herpes virus-8 (HHV8).
HHV8 is sexually transmitted although it is not found in high concentrations in semen.2
Recent research has detected viral replication in the oropharynx, suggesting an oral route of transmission. If true, then high-risk behaviors would be expanded to include “deep kissing” and oral/genital contact; and it would be expected that high rates of infection would be seen within the heterosexual community. Instead, the prevalence of HHV8 in heterosexuals is low, and MSMs are more likely to develop Kaposi’s sarcoma than their heterosexual counterparts, except in Africa where the incidence of Kaposi’s sarcoma is approximately equal in the two genders. The possibility of oral transmission of KSHV raises many unanswered questions.
Levine and Tulpule observed that while HAART has been directed at reducing HIV-induced immunosuppression, it has also been associated with a drop in the incidence of Kaposi’s sarcoma. The study of Kaposi’s sarcoma thus could yield insight into pathogenesis-based therapeutic interventions.3
References
Osmond DH, Buchbinder S, Cheng A, et al. Prevalence of Kaposi’s sarcoma-associated herpesvirus in homosexual men at the beginning of and during the HIV epidemic. JAMA. 2002;287:
Webster-Cyriaque J, Kendrick K. Detection of Kaposi’s associated herpesvirus in the oral cavity of immunocompetent and immunosuppressed individuals. International Association for Dental Research 80th General Session Abstract 1747.
Levine AM, Tulpule A. Clinical aspects and management of AIDS-related Kaposi’s sarcoma. Eur J Cancer. 2001;37:

24. AIDS-associated Kaposi’s Sarcoma
Transmission
Mostly MSM in US
IVDU and Heterosexual as well
Resource limited setting – Africa and S. America
KS still most common cancer in HIV
Prevalence
1300 cases/100,000 persons/yr 1992
170 cases/100,000 persons/yr 2006
Decline of 10% / year
Cause of considerable morbidity and mortality in Africa and Latin America

25. Clinical Manifestations
Mucocutaneous, macular or nodular, dark color
Lymphadenopathy
Visceral
Often asymptomatic
Mouth, esophagus, stomach, bowel, liver, spleen
Pulmonary KS
Rapidly fatal
Dyspnea without fever, hemoptysis
Diffuse reticulo-nodular infiltrates, mediastinal enlargement, pleural effusions
Edema, can be extensive and symptomatic

26. Kaposi’s Sarcoma

29. Oral Kaposi’s Sarcoma

30. KS in Africa – A “Different” Disease?

31. Pulmonary KS on CXR & CT Scan

32. Treatments for Kaposi’s Sarcoma
Local1
Systemic1,2
Radiation therapy
Photodynamic (laser) therapy
Cryotherapy
Alitretinoin gel – 9-cis retinoic acid (topical)
Antiretroviral therapy
Liposomal anthracyclines
Paclitaxel
Bleomycin
Vinca alkaloids
Gemcitabine
Alpha Interferon
Slide #9: Treatment for Kaposi’s Sarcoma
Kaposi’s sarcoma lesions may be treated locally with various therapies.1
Efficacy of local radiation is variable, but this treatment may result in complete remission for some patients.
Photodynamic (laser) therapy, intralesional chemotherapy (vinblastine or vincristine),cryotherapy, alitretinoin topical gel.
Recurrence following remission induced by local therapy is quite common.
Systemic therapy is useful for the treatment of visceral lesions that do not respond to other therapies, but efficacy varies greatly among patients.1,2
Interferon-alfa has a 30% response rate. Flu-like symptoms, neutropenia, peripheral neuropathy, and central nervous system effects are dose-limiting toxicities for this treatment.
Liposomal anthracyclines are recommended as first-line therapy for advanced Kaposi’s sarcoma.
Paclitaxel is recommended as second-line therapy for those who have failed the anthracyclines.
Other systemic therapies include bleomycin, vinca alkaloids (such as vinblastine, vincristine, and vinorelbine), cytokines, retinoids, and antivirals, such as cidofovir.
Toxicity is common with systemic therapy and may range from hair loss to myelosuppression and neurotoxicity, depending on the specific therapy.1
References
Levine AM, Tulpule A. Clinical aspects and management of AIDS-related Kaposi’s sarcoma. Eur J Cancer. 2001;37:
Mitsuyasu RT, Cooper JS. AIDS-related malignancies. In: Reckling S, ed. Cancer Management: A Multidisciplinary Approach. 5th ed. Melville, NY: PRR; 2001:
1Levine AM, et al. Eur J Cancer. 2001;37:
2Mitsuyasu RT, et al. Cancer Management. 2008:

33. Cancer Prevention Smoking Cessation – Highest priority
Hepatitis and HPV vaccination
Yearly cervical and anal Pap tests – Gyn and HRA
Maintain high index of suspicion for cancer
Yearly breast, prostate (incl. PSA) exam
Advise sun screen and avoid overexposure
Complete family history for malignancies
If Hepatitis B or C positive, follow LFTs and
perhaps AFP periodically (?)

34. Summary
As patients live longer with HIV, morbidity and mortality from cancers are increasing
The types of cancers in HIV may vary in different populations around the world
Treatment of malignancies in HIV should be vigorous and appropriate to the situation
Side effects of therapy should be treated/prevented
Prevention strategies for virally-associated malignancies in HIV need to be investigated
Through prospective clinical trials research can treatment and prevention strategies be effectively evaluated
Slide #44: Summary
As patients live longer with HIV disease, we need to be alert to the development of cancers.
Simultaneous treatment of HIV infection and cancer can make meaningful differences in patients’ lives.
Treatment of side effects, including anemia, can make meaningful differences in patients’ quality of life.
Groups like the AIDS Malignancy Consortium are working to sponsor and coordinate trials that can explore the best methods for treating these diseases and enabling patients to tolerate these treatments.
Research contributes not only to improved treatment regimens but to our general understanding of the mechanisms of oncogenesis, viral proliferation, immune-system functions, and cell-cycle biochemistry.