Transcript Document

HIV associated NEOPLASIA
AIDS-defining malignancies
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Currently four :
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Kaposi's sarcoma
non-Hodgkin's lymphoma (NHL)
primary CNS lymphoma (PCNSL) and
invasive cervical carcinoma
EPIDEMIOLOGY OF NHL IN AIDS
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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.
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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.
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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
Pathologically
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Comprised almost exclusively of B-cell tumors
of aggressive type.
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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.
PATHOGENESIS
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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.
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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.
CLINICAL MANIFESTATIONS
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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
Clinical features
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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.
GIT
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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%.
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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.
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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.
Staging
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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 faradvanced 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 )
Treatment Option
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Essential components
 antitumor therapy
 highly active antiretroviral therapy
 prophylaxis for opportunistic infections, and
 recognition & treatment of intercurrent
infections
Challenges
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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
Chemotherapy
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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
Regimens for DLBCL/IL
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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
Regimens for BLL
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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
Influence of HAART
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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
Prognosis
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Associated with stage
Age
Severity of the underlying
immunodeficiency
Performance status, and
Prior AIDS diagnosis
Response to therapy
AIDS-RELATED KAPOSI'S SARCOMA
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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
EPIDEMIOLOGY
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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.
PATHOGENESIS
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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 latencyassociated nuclear antigens (LANA1 and
LANA2).
Latent infection predominates in KS cells
PATHOLOGY
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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.
Effect of HIV on HHV-8 related
tumorigenesis
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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
CLINICAL MANIFESTATIONS
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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.
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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
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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
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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
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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
Treatment decisions guided by the
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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
Effects of steroids and infection
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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
TREATMENT
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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)
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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
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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
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The current systemic treatments;
 newer liposomal anthracyclines,
paclitaxel, and vinorelbine
 Older agents, bleomycin, vinblastine,
vincristine, and etoposide.
PROGNOSIS
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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.
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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
THANK YOU
Emerging treatments
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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
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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.
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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.
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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.
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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
DIAGNOSIS OF ISOLATED PLEURAL
EFFUSION
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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
Management of PE
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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.
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
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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
The HIV-associated lymphomas can be
categorized into:
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Aggressive B-cell lymphoma.
Primary central nervous system
lymphoma (PCNSL), which
represents 20% of all NHL cases in
AIDS patients. Primary effusion
lymphoma.
Plasmablastic multicentric
Castleman disease.
Hodgkin's lymphoma.
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The rare, primary effusion
lymphoma consistently harbors
human herpes virus type-8 and
frequently contains EBV.[2] HIVrelated T-cell lymphomas have also
been identified and appear to be
associated with EBV infection.[3]
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Although HIV does not appear to have a direct etiologic
role, HIV infection does lead to an altered immunologic
milieu.
HIV generally infects T lymphocytes whose loss of
regulation function leads to hyper gammaglobulinemia
and polyclonal B-cell hyperplasia.
B cells are not the targets of HIV infection. Instead,
Epstein-Barr virus (EBV) is thought to be at least a
cofactor in the etiology of some of these lymphomas.
The EBV genome has been detected in varying
numbers of patients with AIDS-related lymphomas;
molecular analysis suggests that the cells were infected
before clonal proliferation began.[1]
EBV is detected in 30% of patients with small,
noncleaved lymphomas and in 80% of patients with
diffuse, large cell lymphomas.
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Radiation therapy alone has usually been used in this
group of patients. With doses in the 3,500 to 4,000
cGy range, median duration of survival has been only
72 to 119 days
Survival is longer in younger pts with better
performance status and the absence of OI
Most patients respond to treatment by showing partial
improvement in neurologic symptoms.
Autopsies have revealed that these patients die of OIs
as well as tumor progression.
Treatment of these pts is also complicated by other
AIDS-related CNS infections, including subacute AIDS
encephalitis, cytomegalovirus encephalitis, and
toxoplasmosis encephalitis.
Spontaneous remissions have been reported after
highly active antiretroviral therapy.
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CT scans show contrast-enhancing mass lesions that may not always
be distinguished from other CNS diseases, such as toxoplasmosis
MRI studies using gadolinium contrast may be a more useful initial
diagnostic tool in differentiating lymphoma from cerebral
toxoplasmosis or PML
Lymphoma tends to present with large lesions, which are enhanced by
gadolinium. In cerebral toxoplasmosis, ring enhancement is very
common, lesions tend to be smaller, and multiple
Use of positron emission scanning has demonstrated an improved
ability to distinguish PCNSL from toxoplasmosis. PSNCL has an
increased uptake while toxoplasmosis lesions are metabolically
inactive.
A lumbar puncture may be useful to detect as many as 23% of
patients with malignant cells in their cerebrospinal fluid (CSF).
Evaluating the CSF for EBV DNA may be a useful lymphoma-specific
tool since EBV is present in all patients with PCNSL
Despite all of these evaluations, however, the majority of pts with
PCNSL require a pathologic diagnosis. Diagnosis is made by biopsy.
AIDS-Related PCNSL
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was a rare disease.
PCNSL has increased dramatically in association with AIDS
accounts for approximately 0.6% of initial AIDS diagnoses
and is the second most frequent CNS mass lesion in adults
with AIDS.
usually aggressive B-cell neoplasms, either diffuse large cell
or diffuse immunoblastic NHL.
Unlike AIDS-related systemic lymphomas, in which 30% to
50% of tumors are associated with EBV, AIDS-related PCNSL
has been reported to have a 100% association with EBV.[2]
This percentage indicates a pathogenetic role for EBV in this
disease.
These patients usually have evidence of far-advanced AIDS,
are severely debilitated, and present with focal neurologic
symptoms such as seizures, changes in mental status, and
paralysis.
PATHOLOGIC CLASSIFICATION
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1. systemic non-Hodgkin's
lymphoma (NHL),
2. primary CNS lymphoma (PCNSL),
and
3. the primary effusion ("body
cavity") lymphomas
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The secretion of IL-6 is further significant
in AIDS-NHL because it may render the
tumor cells resistant to the cytotoxic
effects of chemotherapeutic drugs and/or
increase the side effects
The sensitivity of immunoblastic AIDS- or
SAIDS-DLBCL to TGF-beta1-mediated
growth inhibition may be overcome
through the stimulation of proliferative
and anti-apoptotic signals by IL-6,
particularly through the rapid activation of
STAT3.
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Analysis of the disease in humans or simians
implicates cytokine dysregulation as a fundamental
influence in pathogenesis.( IL-6, in particular)
IL-6 is a stimulator of B-cell proliferation and
differentiation that is expressed in EBV-positive AIDSBL and to high levels in AIDS-DLBCL of both
centroblastic and immunoblastic types.
Evidence indicates that the cytokine may be
expressed from the tumor cells themselves or from
tumor-infiltrating cells.
Tumor cells frequently express the receptor for IL-6,
thus rendering them responsive to autocrine and/or
paracrine IL-6-mediated stimulation.
70 to 90% of the lymphomas
encountered in HIV-infected patients
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Aggressive diffuse large B-cell
lymphomas (DLBCL), which
comprise about 30% of AIDSrelated lymphomas,
immunoblastic lymphoma (IL), or
the highly aggressive tumor small,
non-cleaved (Burkitt-like)
lymphoma (BLL).