                   AIDS INFORMATION NEWSLETTER
                   Michael Howe, MSLS, Editor
                     AIDS Information Center
                VA Medical Center, San Francisco
                     (415) 221-4810 ext 3305
                          May 17, 1996

                Opportunistic Infections (Part XXIV)
                            Lymphomas

[Opportunistic Infections and Related Disorders; From AmFAR's
AIDS/HIV Treatment Directory, Vol. 7, No. 3, January, 1995]

     DESCRIPTION: Lymphomas are abnormal, uncontrolled growth of
malignantly transformed lymphocytes, a type of white blood cell
vital to proper immune function.  As people with AIDS are surviving
longer, more and more cases of AIDS-related lymphoma are being
diagnosed.  Unlike other AIDS-associated neoplasms like Kaposi's
sarcoma which appears predominantly in homosexual men, lymphomas
develop in every population group at risk for AIDS.  Within this
group three types of lymphomas are generally observed.  These
include systemic NHL (intermediate or high-grade non-Hodgkin's
lymphoma), primary CNS lymphomas (high-grade NHL lymphomas confined
to the central nervous system) and less often, Hodgkin's disease. 
Usually, patients present with advanced stage disease with
aggressive clinical behavior.  Extra nodal involvement is
frequently seen.  These factors together with severe
immunodeficiency limit the management of lymphomas and indicate
poor prognosis.  Survival after treatment has been associated in
some studies with large cell histology, higher CD4 counts upon
diagnosis, lack of extranodal disease, good performance status and
a lack of history of opportunistic disease.

                  Non Hodgkin's Lymphoma (NHL)

     PATHOGENESIS: AIDS NHL is primarily of B-cell origin and has
been estimated to occur in 5% to 10% of individuals with HIV
infection, but may occur with higher frequency as survival with
severe immunosuppression is prolonged.  Several mechanisms are
likely to be involved in the etiology of AIDS NHL though the cause
still remains unknown.  NHL is frequently associated with Epstein-
Barr virus (EBV) which specifically infects B lymphocytes and leads
to ongoing proliferation of these cells.  EBV genomes can be
detected in about 50% of AIDS-related lymphomas.  Some cytokines
such as interleukin 1 (IL-1), IL-6 and tumor necrosis factor (TNF),
which enhance HIV-replication and are elevated during HIV-
infection, are known to induce B-cell activation and may also be
a factor in the development of NHL.  Shiramizu B et al. recently
identified 4 cases of non-B cell NHL lymphoma in which the HIV
virus inserted near a known oncogene indicated a pathway for HIV-
induced lymphoma, but this sort of lymphoma is thought to be quite
rare.

     SITES OF INVOLVEMENT: Common extranodal sites of AID NHL are
the central nervous system, bone marrow, gastrointestinal tract,
meninges, and liver. Some less common sites reported include the
mouth, heart and pericardium, and common bile duct.

     SYMPTOMS: Systemic NHL should be considered in patients
presenting with a mass legion at any site. Other symptoms may
include enlarged spleen, hepatic obstruction, rectal pain, cardiac
arrhythmia, unexplained gastrointestinal symptoms or GI bleeding.
Constitutional (so-call "B") symptoms are elevated fever,
unexplained weight loss, and night sweats.

     DIAGNOSIS: Lymphomas can only be reliably diagnosed by biopsy
of involved lymph nodes, organs or bone marrow. Staging may include
multiple x-rays, whole-body gallium scanning, computerized
tomography (CAT) scans, magnetic resonance imaging (MRI), bone
marrow biopsy and spinal tap. Lymph node biopsy should be performed
in patients with asymmetrical lymphadenopathy and rapidly enlarging
or bulky nodes. Elevated uric acid and lactate dehydrogenase may
indicate the need for evaluation to rule out lymphoma.

     TREATMENT: The optimal treatment for patients with AIDS-
associated NHL has not been defined. Treatment normally involves
combination cytotoxic chemotherapy. Combinations used have included
mBACOD, COMP, CHOP NHL-7 and PRO-MACE/MOPP and an oral combination
regimen. For individuals with poor immune function, evidence
indicates that less aggressive regimens in combination with
antiretroviral therapy may improve survival. The likelihood of
responding to chemotherapy depend on a number of factors including
CD4 count, prior AIDS-defining illnesses and the presence or
absence of extranodal NHL, response rates of 50% or more have been
documented in some studies, and some investigators suggest that
even higher response rates may be achieved with more intensive
therapy in selected patient groups with good prognostic features.
The addition of growth factors such as G-CSF and GM-CSF may
facilitate the administration of chemotherapy by preventing or
shortening the duration of neutropenia, permitting administration
of chemotherapy at scheduled intervals and decreasing the risk of
infection.
     Experimental treatment approaches include the administration
of monoclonal antibodies, produced by clones of a single immune
cell which can either destroy cancer cells themselves or carry
toxins directly to the target site. Trials involving OK-B7, a
monoclonal antibody attached to radioactive iodine, and anti-B4
attached to a potent immunotocin, ricin, are underway.
     Cytokines such as interleukin 2 (IL-2) and IL-4 which inhibit
tumor growth in vivo are currently under evaluation in several
clinical trials.
     Investigative trials underway for refractory AIDS-associated
NHL include suramin, a growth factor antagonist, and MGBG
(methylgloxal(bis)guanylhydraxone) whose activity is believed to
result from the inhibition of polyamine synthesis.
     Intrathecal prophylaxis against CNS lymphoma with ara-C
(cytosine arabinoside) or methotrexate is used in patients with
systemic NHL to prevent relapse of disease within the meninges. It
is also used when the lymphoma cells are present in the spinal
fluid (lymphomatous meningitis).

                      Primary CNS Lymphoma

     PATHOGENESIS: Primary CNS lymphoma often occurs as a late
complication of AIDS. Left untreated, the survival rate of patients
with AIDS-related primary CNS lymphoma is less than 2 months. With
high doses of radiation, response rates have been promising
(Baumgartner et al). Yet, survival rates remain short with reports
of median survival time limited to 2 to 5 months. Patients usually
expire due to opportunistic infections or progressive CNS lymphoma.
EBV sequences are consistently present in primary CNS lymphomas.
This suggest that EBV might have a role as a marker in its
diagnosis.

     SYMPTOMS: So et al. report focal neurologic signs such as
hemiparesis (partial paralysis affecting one side of the body) or
aphasia (loss of ability to speak or understand language) in 35%,
seizures in 15%, and cranial nerve palsies in 10% of people with
CNS lymphoma. Confusion, memory loss, and lethargy were reported
in 60%. Gill et al. report changes in personality, apathy and
confusion. Sometimes the only manifestation is a headache. Cranial
nerve palsies, other than facial nerve paralysis, should be
regarded as lymphomatous in origin until proven otherwise. Symptoms
are not unlike those to toxoplasmosis encephalitis adding further
complication toward a confirmed diagnosis.

     DIAGNOSIS: Definitive diagnosis is only possible by brain
biopsy. Biopsies are often not performed, however, for a variety
of reasons including the overall status of the patient and the
reluctance of some neurosurgeons to perform the procedure. However,
stereotactic guided needle biopsies are generally considered to be
associated with low risk. Magnetic resonance imaging (MRI) and
computed axial tomography (CAT) scans may help to make a
presumptive diagnosis. Lumbar punctures with cytologic examination
of the spinal fluid may permit a diagnosis. Lumbar punctures with
cytologic examination of the spinal fluid may permit a diagnosis
in some cases. CNS lymphoma may present as single or multiple
lesions which are sometimes indistinguishable from toxoplasmic
encephalitis. Patients with positive serologic tests for toxoplasma
may be treated empirically for toxoplasmosis. Those failing to
improve within 7 to 10 days should be rapidly evaluated for
lymphoma. If a biopsy cannot be performed and the patient has
negative serology tests for toxoplasmosis, radiation therapy should
be considered. Patients unresponsive to radiation should be further
evaluated.

     TREATMENT: Large dose whole-brain radiation is the preferred
method of treatment in patients with AIDS-related primary CNS
lymphoma. Corticosteroids such as dexamethasone produce further
shrinkage of edema and tumor. Although radiation often results in
complete remission (20-50%), relapse is likely and the overall
prognosis is grim. Although radiotherapy may not greatly prolong
median survival, improvement in the quality of life has been
reported in a significant proportion of patients. The role of
chemotherapy (both systemic and intrathecal) prior to and following
whole-brain radiation therapy is under investigation; this approach
has produced improved results in patients with primary CNS lymphoma
unrelated to HIV infection.

                        Hodgkin's Disease

     PATHOGENESIS: Hodgkin's disease arises in the lymph nodes and
spreads stepwise from one group of nodes to contiguous groups.
Hessol et al. have observed an excess number of cases of Hodgkin's
disease in a cohort of HIV-infected homosexual men, and suggest
that it may be an HIV-related malignancy. Others, however, have not
confirmed an excess number of cases. The clinical behavior of
Hodgkin's disease in AIDS patients is rather unpredictable though
presentation usually involves late clinical stages (III and IV)
with mixed cellularity as the predominant histological type. The
etiology of Hodgkin's disease remains unknown. Case clustering,
multiple cases in a single household, may suggest a viral origin.
EBV has also been implicated.

     SYMPTOMS: Most patients present with cervical or mediastinal
adenopathy. Systemic symptoms including pruritus, high fever, night
sweats and weight loss may or may not be present. Bone involvement
may produce pain in the diseased area.

     DIAGNOSIS: The diagnosis of Hodgkin's disease rests on the
identification of Reed-Sternberg cells or morphological variants
through lymph node biopsy. Frequent bone marrow involvement
indicates the value of bone marrow biopsies in staging.

     TREATMENT: For the non-HIV infected patient with Hodgkin's
disease, disease stage is the principle factor in selecting an
appropriate treatment. Within this group, advanced stage disease
(III and IV) is treated with combination chemotherapy. MOPP and
ABVD are both effective 4-drug regimens. MOPP alternating with ABVD
has shown similar benefit. Oral combination programs are also being
evaluated. Early stage (I and II) Hodgkin's disease is most
frequently treated with radiation therapy. The optimal treatment
for Hodgkin's disease in HIV-infected patients is not known. As in
NHL, the complete response rate to chemotherapy is much lower in
HIV-related cases. The addition of colony-stimulating factors along
with the reduction of chemotherapy dosage may reduce the rate of
primary failure and risk of long term complications.

     REFERENCES: Baumgartner J et al. Primary central nervous
system lymphomas: Natural history and response to radiation therapy
in 55 patients with acquired immunodeficiency syndrome. J Neurosurg
73:206-211, 1990.

     Gill PS et al. HIV-related malignant lymphoma: clinical
aspects, treatment, and pathogenesis. Canc Invest 6:413-6, 1988.

     Hessol NA et al. Increased incidence of Hodgkin disease in
homosexual men with HIV infection. Ann Int Med 117:309-11, 1992.

     Hernier BG et al. Pathogenesis of AIDS lymphomas. AIDS 8:1025-
1049, 1994.

     MacMahon EM et al. Epstein-Barr virus in AIDS-related primary
central nervous system lymphoma. Lancet 338:969-73, 1991.

     Schiramizu B et al. Identification of a common clonal human
immunodeficiency virus integration site in human immunodeficiency
virus-associated lymphomas. Cancer Res 54:2069-72, 1994.

     So Y et al. Primary central nervous system lymphoma in AIDS:
A clinical and pathological study. Ann Neurol 20:566-72, 1986.

     OTHER REPORTS: Canellos GP et al. Chemotherapy of advanced
Hodgkin's disease with MOPP, ABVD, or MOPP alternating with ABVD.
NEJM 327:1478-84, 1992.

     Galleto G and Levine A. AIDS-associated primary central
nervous system lymphoma (commentary). JAMA 269:922-3, 1993.

     Levine A. Lymphoma in acquired immunodeficiency syndrome. Sem
in Oncol 17(1):104-112, 1990.

     Levine A et al. Low-dose chemotherapy with central nervous
system prophylaxis and zidovudine maintenance in AIDS-related
lymphoma. JAMA 266:84-8, 1991.

     Remick SC et al. Novel oral combination chemotherapy in the
treatment of intermediate-grade and high-grade AIDS-related non-
Hodgkin's lymphoma. J Clin Onc 11:1691-1701, 1993.

     Urba WJ and Longo DL. Hodgkin's disease (review article). NEJM
326:678-87, 1992.

.................................................................
           CENTERS FOR DISEASE CONTROL AND PREVENTION
                       HIV/AIDS PREVENTION
           CDC NATIONAL AIDS HOTLINE TRAINING BULLETIN
.................................................................

June 13, 1994

These are answers from the National Cancer Institute to questions
concerning HIV-1 associated cancers.

1.   How is the way HIV causes cancer different from the way it
     causes other opportunistic illnesses?

     In a recent report from the University of San Francisco,
     California, (Shiramizu, B. et al., Identification of a Common
     Clonal Human Immunodeficiency Virus Integration Site in Human
     Immunodeficiency Virus-associated Lymphomas, Cancer Research
     1994, 54:2069-2072) researchers found that the HIV -1 virus
     was able to be inserted or integrated into cells of the tumor
     in a monoclonal or single site fashion.  In the 4 non B-cell
     tumors studied in detail in this report, all were found to
     have evidence that the HIV-1 virus was inserted adjacent to
     a gene called an oncogene, which has been associated with
     cancer.  The authors speculated that this juxtaposition of the
     virus to the oncogene may have contributed to the occurrence
     of lymphoma.  Since the virus contains a promotor or switch-on
     function in the portion integrated adjacent to the oncogene,
     it is possible that the virus could turn on the oncogene and
     thus cause the lymphoma.  This mechanism of cancer causation
     is called insertional mutagenesis.

     While lymphomas have been recognized as common in AIDS
     patients, the non B-cell tumor type reported in this report
     is uncommon.  Almost all AIDS-associated lymphomas occur in
     B-cells and appear to involve an indirect mechanism related
     to immunodeficiency.  According to the authors, the rare non
     B-cell tumor type could result from a direct effect of the 
     HIV-1 virus on a cancer-causing oncogene.

2.   News reports said that some lymphomas appear to be caused by
     cancer-causing genes (oncogenes).  How is Kaposi's sarcoma
     caused?  Could KS be a direct result of oncogenes?

     The etiology of Kaposi Sarcoma is not known.  Significant
     insights have come from basic research suggesting that the
     AIDS virus, through its effects on various growth factors, can
     indirectly stimulate the target cell of the tumor to grow.
     Epidemiologic studies have raised the possibility that a
     transmissible factor could be involved, but none has been
     identified.  There is no evidence that the HIV virus
     integrates in the Kaposi sarcoma tissue in juxtaposition to
     an oncogene, as been suggested for some cases of non B-cell
     lymphoma.

3.   What percentage of people with HIV-infection/AIDS get
     lymphomas and other cancers?  Is it know what percentage of
     them got lymphoma from immune suppression vs. oncogenes?

     Malignancies are a significant complication of AIDS.  About
     20% of AIDS cases have thus far developed Kaposi sarcoma,
     mainly among homosexual men.  As a consequence of the rising
     incidence of AIDS among heterosexuals and drug users the
     proportion of AIDS associated with Kaposi sarcoma is
     declining.  There is a lifetime risk of approximately 6% for
     non Hodgkins lymphomas among HIV positive individuals, and the
     overwhelming majority are of the B-cell type, and, as such,
     are not of the type recently reported with insertion of the
     virus directly causing the lymphoma.  Further study is needed
     to quantify the frequency of these rarer tumors.  It should
     be noted, however, that oncogenes may play a role in many
     B-cell tumors by a translocation of a normal cellular promotor
     gene adjacent to an oncogene called c-myc. Translocations of
     this type have been implicated in non-Hodgkins lymphoma,
     especially in association with Epstein Barr virus. 

4.   Does everyone have oncogenes?  If not, can a person with HIV
     be tested for them to see if they are at greater risk of
     developing cancers?

     Oncogenes are present in the cells of all normal persons and
     presumably play a function in normal cell activities.  Most
     are genes which are involved in the signaling or intracellular
     communication pathway for regulating cell growth and
     proliferation.  Abnormalities of these genes, as well as genes
     called suppressor genes, are frequent in many types of cancer.

     An important ongoing research focus is on defining whether
     abnormalities in these genes can be detected before a cancer
     occurs and whether these abnormalities can be reversed or
     controlled as a means of preventing the development of cancer.

     Such studies will take time to complete and will have
     implications for understanding not only AIDS-associated
     cancers but cancer in general.  However, at this time, there
     are no tests for detecting abnormalities.

5.   Will KS and lymphomas continue to be classified as
     opportunistic illnesses?

     The use of the term "opportunistic" to describe AIDS-defining
     cancers is something of a misnomer since, unlike opportunistic
     infections," these cancers occur because of fundamental
     changes in the genetics of a cell, causing an uncontrolled
     growth of the tumor.  Infections represent non-cellular
     organisms, either bacteria, protozoa, or fungi, which overgrow
     the host in the setting of immunodeficiency.  The cancers also

     overgrown.

6.   Can someone who is HIV+ do anything to lessen their chances
     of contracting cancer?

     While no specific trigger has been identified, avoiding any
     unsafe sexual activity is prudent, even though little is know
     concerning whether such behavioral modification will prevent
     cancer or any other AIDS-associated condition.  Current
     research is focusing on trying to characterize predictors of
     cancer risk, but this research is still in an early stage. 
     General guidelines for cancer prevention include good dietary
     practices and avoiding adverse exposures such as cigarette
     smoking, excessive alcohol consumption, and chemical exposures
     such as to herbicides and, perhaps, hair dyes which have been
     linked to lymphomas. 
     
7.   Could KS and lymphomas occur before immunosuppression?

     All persons with HIV-1 infection have some level of
     immunosuppression.  In general, the greater the level of
     immune compromise, the higher the risk for malignancy.
     However, some lymphomas and Kaposi sarcomas occur in persons
     who appear to have a relatively intact immune system. Further
     information is needed concerning the relationship of level of
     immune function to cases such as those recently reported
     involving insertional metagenesis.

8.   What implications does this study have for treatments?  Will
     all possible vaccines potentially cause cancer, or only those
     made with live virus?  Will this study affect any treatment/
     vaccine currently being tested or developed?

     The concept of insertional mutagenesis, whereby a retroviral
     gene inserts into the genetic material of a cell adjacent to
     an oncogene, was first proven in an animal model of chicken
     leukemia.  As such, there has been concern that live
     attenuated retroviral vaccines or retroviral vectors being
     used for gene therapy could lead to cancer by inserting
     adjacent to an oncogene and turning on that gene to cause
     cancer.  The recent report of 4 lymphomas which may have been
     caused by such a mechanism heightens this concern. However,
     it is unclear how frequently such events occur among HIV-1
     infected persons.  If such instances are extremely rare, the
     potential benefit of gene therapy or an effective live
     attenuated vaccine would far outweigh potential risk. 
     Furthermore, understanding why HIV-1 appears to target a
     particular site in the host genome provides an opportunity to
     understand insertional mutagenesis and modify any retroviral
     vaccine or vector to remove or modify the offending structure
     and thus ameliorate the potential risk.
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