The document discusses several AIDS-defining and non-AIDS defining cancers that are more common in HIV-positive individuals. Kaposi sarcoma, caused by HHV-8, and two types of non-Hodgkin lymphoma were originally considered AIDS-defining cancers. While antiretroviral therapy has decreased AIDS deaths and increased the population of HIV-infected individuals, it has also led to an increase in both AIDS-defining and non-AIDS defining cancers due to people living longer with HIV. The document provides details on the pathogenesis, diagnosis and treatment of several AIDS-defining cancers including Kaposi sarcoma, multicentric Castleman's disease, and plasmablastic lymphoma.

3.  Kaposi sarcoma was the first malignancy, which
was considered AIDS defining in young
individuals.
 The 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.

4.  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.

5.  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.

6. AIDS-Defining Kaposi sarcoma
Non-Hodgkin's
lymphoma
Burkitt lymphoma
DLBCL
Immunoblastic
Primary diffuse
large B-cell
lymphoma of the
CNS
Cervix

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

8. Non- AIDS defining
Liver
Myeloma
Breast
Colon
Prostate

9.  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)

10.  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)

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

12.  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.

13. 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

14. 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.

18.  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.

19.  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

20.  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.

21.  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/mm3; and the presence or absence
of antecedent opportunistic infections, constitutional
symptoms, other HIV-related illness, and Karnofsky
performance status.

22.  Good risk is designated with a subscript 0, and
poor risk by subscript 1, the summary taking the
form T0 or T1, I0 or I1, or S0 or S1a good risk (T0S0,
T1S0, or T0S1) and a poor risk (T1S1).
 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.

23. 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
Performance status <70
Other HIV-related illness
(e.g., neurologic disease,
lymphoma)

24. 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)

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

26.  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.

27.  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.

28.  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.

29.  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.

30.  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.

31.  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.

32.  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.

33.  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

34. CHOP +
Rituximab
CHOP
Alone
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/mm3
• 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

35.  Dose-adjusted EPOCH chemotherapy
 Etoposide 200 mg/m2 (96-hour infusion)
 Vincristine 1.6 mg/m2 (96-hour infusion)
 Doxorubicin 40 mg/m2 (96-hour infusion)
 Prednisone 60 mg po on days 1–5
 Cyclophosphamide IV on day 5
 CD4 <100 cells/mm3: 187 mg/m2
 CD4 >100 cells/mm3: 375 mg/m2
 Dose adjusted in cycles 2 through 6 to a maximum of 750
mg/m2
Little RF, et al. Blood. 2003;101:4653-4659.

36. CD4
(cells/mm3)
<100 >100 Total
Number of patients 16 23 39
Complete
response (%)
56 87 79
Relapse 2 0 2
Progression-free
survival (%)
73 93 87
Overall survival (%) 36 87 60
• Median follow-up
– 53 months
• Median CD4
– 190 cells/mm3
• Not prognostic
– Tumor proliferation
– p53 overexpression
Little RF, et al. Blood. 2003;101:4653-4659.

37.  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)

38.  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.

39.  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.

40.  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.

41.  HIV-infected patients have an increased
incidence of several cancers caused by HPV,
including cancer of the cervix, anus, penis,
vulva, oral pharynx, and tonsil.

42.  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.

43.  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

44.  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 Disease1,2
1Mitsuyasu RT, et al. Cancer Management. 2006:609-632.
2Martin F, et al. Sex Transm Infect. 2001;77:327-331.

45.  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.

46.  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.

48. THANKYOU