Hodgkin's Disease in the Setting of Human
Immunodeficiency Virus Infection
Alexandra M. Levine*
*
Correspondence to: Alexandra M. Levine, M.D., Division of Hematology, University of Southern California
(USC), USC/Norris Cancer Hospital, 1441 Eastlake Ave., MS 34, Los Angeles, CA 90033.
Although Hodgkin's disease (HD) is not usually associated with congenital or acquired
immunodeficiency disorders, recent evidence would suggest a statistically significant increase in
HD among individuals infected with human immunodeficiency virus (HIV). In the setting of
underlying HIV infection, clinical and pathologic characteristics of HD may differ from usual
expectations. Thus, 70%-100% of HIV-infected patients with HD present with systemic "B"
symptoms. Likewise, disseminated, stage III or IV disease is reported in approximately 75%90%. Bone marrow is a common site of extranodal HD, occurring in 40%-50%. Complete
response rates after multiagent chemotherapy range from approximately 45% to 70%, although
median survival has been only in the range of approximately 18 months. Hematologic toxicity
from multiagent chemotherapy may be substantial, even with the use of hematopoietic growth
factor support. It is apparent that new strategies of therapeutic intervention must be explored.
Relationship Between Hodgkin's Disease and Underlying Immunodeficiency
Non-Hodgkin's lymphoma is known to occur with increased frequency in various settings of
congenital, acquired, or iatrogenic immunosuppression (1-4). It was thus not surprising to
observe significantly increased rates of lymphoma in patients infected with human
immunodeficiency virus (HIV). Similarly, the other current acquired immunodeficiency
syndrome (AIDS)-defining cancers, Kaposi's sarcoma and cervical cancer, are also associated
with diverse types of abnormal immunity, including immunosuppression related to organ
transplantation or to therapy for autoimmune or malignant disorders (2,3,5,6). Within the context
of this background, Hodgkin's disease (HD) represents a somewhat different situation. Thus,
while the risk of HD is increased in children with ataxia telangiectasia (7), the magnitude of this
increase is quite modest, and HD is not seen with increased frequency in other types of
congenital immune deficiency disease. Furthermore, the incidence of HD is not increased in the
setting of organ transplantation or in the setting of prior cancer chemotherapy or
immunosuppressive therapy for autoimmune disease (2,3). The expectation that HIV-infected
patients would be at risk for HD was thus not initially considered a prominent concern.
Epidemiology of De Novo HD
In patients who are not infected by HIV, the epidemiology of HD has been well described.
Correa, MacMahon, and others (8-10) have demonstrated a clear relationship between
geographic and socioeconomic factors and the ensuing clinicopathologic characteristics of HD.
Thus, the "type 1 pattern" of HD is seen in underdeveloped areas of the world, associated with
lower socioeconomic conditions. In this setting, two age peaks of disease are observed, with the
first in childhood (primarily affecting boys) and the second in the fifth or sixth decade. The
pathologic spectrum of HD in the type 1 setting includes a predominance of mixed-cellularity or
lymphocyte-depletion disease, with proclivity toward advanced stage and presence of systemic
"B" symptoms. The overall prognosis of such patients is relatively poor, when compared with
that of patients in other settings and with other patterns of disease.
The "type 3 pattern" of HD is seen in industrialized nations and is also characterized by two
modal peaks of disease (8-10). However, in these areas of higher socioeconomic background, the
first modal peak occurs in adolescent or young-adult females, who tend to present with nodular
sclerosis HD, often presenting with rather limited stage disease localized to the mediastinal
lymph nodes. The second peak occurs in the fifth and sixth decades, is seen primarily in males,
and may be associated with a broader spectrum of pathologic subtypes. Various characteristics
associated with higher socioeconomic status have been described with increased frequency in
young patients who develop HD within type 3 areas.
In the "type 2 pattern," all three age peaks of disease are encountered, with a broad spectrum of
pathologic subtypes and clinical outcome. This pattern has been described in developing areas of
the world, such as Mexico.
Of interest, areas of lower socioeconomic status within the United States have been described in
which the clinicopathologic spectrum of HD resembles that seen in type 2 or developing nations
(11). Because of these divergent epidemiologic, clinical, and pathologic characteristics, any
differences between HIV-associated and de novo HD must be considered within the context of
the usual expectations for HD in that particular region under study.
Immune Function in De Novo HD
Defects in cell-mediated immunity have been well described in patients with de novo HD,
occurring even in patients with early stage disease and in those who have been free of HD for
many years (12). Thus, patients with HD are often anergic to delayed cutaneous hypersensitivity
testing, as described by Dorothy Reed as early as 1902 [see (13)]. While more common in
patients with advanced, symptomatic HD, dinitrochlorobenzene skin testing may also be
abnormal in patients with good prognosis, early stage HD (12). In vitro testing of immune
function is also abnormal in patients with de novo HD. Thus, decreased mitogenic responses to
phytohemagglutinin and to concanavalin A have been described, even prior to the initiation of
chemotherapy (14). While significant reductions in T cells have been described in peripheral
blood and spleen of approximately 30% of patients with untreated, advanced HD (15), no
alteration in the ratio of helper or cytotoxic/suppressor T cells has been found; moreover, there is
no evidence of cellular activation (15). Furthermore, most patients with HD do not have
lymphocytopenia, indicating that the major cell-mediated defect is a functional impairment, as
opposed to an absolute depletion of T cells in blood or tissues.
These defects of cell-mediated immunity may also be surmised by the fact that patients with HD
may be at increased risk for certain infections known to be associated with depressed T-cell
function. Of interest, increased susceptibility to tuberculosis among patients with HD was well
described as early as 1928, while the earliest description of HD was complicated by the fact that
some of Thomas Hodgkin's initial HD patients actually had tuberculosis (16). Furthermore, in a
large series of 300 adult patients with HD, Notter et al. (17) noted the development of
opportunistic infections in 4%, consisting of Pneumocystis carinii pneumonia, disseminated
vaccinia, herpes zoster, and progressive multifocal leukoencephalopathy, among others.
When considering the immune function of patients with HIV-related HD, it is important to
realize that any immune defect etiologically related to HIV will, by definition, be augmented by
the known defects in cell-mediated immunity that are inherent to HD itself.
Incidence of HD Among HIV-Infected Persons
Of interest, at the outset of the AIDS epidemic, the incidence of de novo HD appeared to have
decreased among HIV-negative persons in New York and Los Angeles (18,19). In the evaluation
of young, single men in New York City (presumably including HIV-infected individuals or
homosexual men at risk for HIV), stationary rates were documented, while an actual decrease in
HD among married men in New York State was observed at the same time (18).
In 1992, Hessol et al. (20) noted an increase in the standardized morbidity ratio for HD among
HIV-infected homosexual men from San Francisco. By use of data from 6704 homosexual men
enrolled in the San Francisco City Clinic HIV Cohort Study, cases of HD were ascertained
through the computer-matched identification of participants in the population-based Northern
California Cancer Center registry. Comparisons were made with rates determined in the general
population by use of the Surveillance, Epidemiology, and End Results (SEER)1 cancer registry.
A total of 90 cases of non-Hodgkin's lymphoma were identified, along with eight cases of HD.
The age-adjusted standardized morbidity ratio for HD among the HIV-infected men was 5.0
(95% confidence interval [CI] = 2.0-10.3), indicating a statistically significant increase.
Furthermore, when these data were compared with those from the SEER registry, the excess risk
of HD among HIV-infected homosexual men was 19.3 cases per 100 000 person-years, again
indicating a significant increase. While pathologic review was not performed, and while
diagnostic misclassification is known to occur, especially in lymphocyte-depleted HD (21,22),
the data did indicate that the incidence of HD may have increased in HIV-infected homosexual
men (20).
More recently, Lyter et al. (23) described an increase in HD among homosexual and bisexual
men, who were followed as part of the national Multicenter AIDS Cohort Study (MACS). Thus,
within the Pittsburgh MACS cohort, who were followed between 1984 and 1993, two cases of
HD were seen among 430 HIV-infected men (with 2344 person-years of follow-up) versus no
cases among 769 HIV-negative control subjects (followed for 5708 person-years). While
consisting of only two cases, the standardized incidence ratio for seropositives was increased
19.8-fold (95% CI = 2.4-71.5) when compared with that for seronegatives. Furthermore, when
these data were compared with those from the population-based SEER registry, the rate of HD
among HIV-positive men was 85 per 100 000 person-years versus 4.3 per 100 000 person-years
in the general population.
In an attempt to ascertain the full spectrum of malignant disease occurring in association with
HIV infection, Goedert and colleagues (24) performed a linkage analysis in which all cases of
cancer reported in over 98 000 cases of AIDS reported to the Centers for Disease Control and
Prevention were linked, case by case, to the population-based cancer registries in the United
States. AIDS-related cancers were defined as those that had increased statistically after an initial
AIDS diagnosis, with increasing prevalence from 5 years before the diagnosis of AIDS, through
2 years after the initial AIDS diagnosis. In this analysis, the risk of HD was increased 7.6-fold,
with the relative risk (RR) statistically increasing from the period prior to AIDS to that occurring
after the initial diagnosis of AIDS.
Significant increases in HD have also recently been documented in the National Cancer Institute
Hemophilia Cohort (RR = 5.6) (25); in injection drug users with AIDS in New Jersey (odds ratio
[OR] = 4.2; 95% CI = 1.4-14.7; P = .04) (26); in HIV-infected individuals from Denver, CO
(27); and in homosexual men from New South Wales, Australia (28). In the latter report, the RR
of HD was 18.3 (95% CI = 8.4-35), with the increase in risk confined to the 2 years immediately
before an AIDS diagnosis and the period after AIDS was diagnosed. These data would be
consistent with the concept that HD is a late manifestation of HIV disease, which may become
even more apparent as HIV-infected individuals live long enough to develop the disease.
HIV-Infected Populations at Risk for HD
Early studies from Europe indicated that HD did occur in HIV-infected individuals, although no
formal population-based comparisons were published at that time. However, Monfardini et al.
(29) from the Italian Cooperative Group for AIDS-related Tumors sent 1962 questionnaires to
various professional groups of oncologists, infectious disease specialists, and others, in an
attempt to ascertain potential cases of HD among HIV-infected individuals. A total of 35 cases of
HD and 95 cases of lymphoma were identified. Of interest, 89% of the patients with HD had a
history of injection drug use, while an additional 9% were homosexual with a history of injection
drug use. In contrast, a history of injection drug use was present in 68% of the lymphoma
patients, while 5% had a history of both injection drug use and homosexuality. While
retrospective and biased by the method of case ascertainment, this study suggested the possibility
that injection drug use might be a specific risk factor for HIV-associated HD. Subsequent work
from France (30) confirmed this suggestion, with 38% of 45 HIV-infected patients with HD
providing a history of injection drug use, versus only 12.5% of 168 patients with non-Hodgkin's
lymphoma. Roithmann et al. (31) confirmed the increased likelihood of HD among injection
drug users versus homosexual men from France, while investigators from Spain (32) also
documented a similar relationship, with 85% of 46 cases of HD occurring in injection drug users
and 9% occurring in homosexual men. Furthermore, Ahmed et al. (33) also noted that the
incidence of HD was three to 10 times higher among prisoners in the United States who were
injection drug users, versus those who were not, although the overall incidence of HD had not
increased in these prison inmates.
While these earlier studies seemed to indicate an increased proclivity for HD among HIVinfected injection drug users, subsequent studies have not really confirmed this fact. Thus,
statistically significant increases in HD have now been described in HIV-infected hemophiliacs
(25) as well as in HIV-infected homosexual men (23,28). More time will be required to elucidate
the true increase in risk of HD among injection drug users, when compared to other HIV-infected
populations.
Relatively little is currently known about the precise level of immune dysfunction in patients
with HIV-related HD. Ames et al. (34) evaluated 23 such patients, whose median CD4 cell count
was 201/mm3, ranging from 7 to 882/mm3. In another report published in 1991 from Italy (35),
the median CD4 cell count in 38 patients was 254/mm3 (range, 27-1316/mm3). A study from
France published in 1993 (30) described 45 patients with HIV-related HD in whom the median
CD4 cell count was 306/mm3. More recently, CD4 cells were determined at baseline in a group
of 21 patients with HIV-related HD (36) who were treated prospectively as part of the AIDS
Clinical Trials Group (ACTG study #149). The median CD4 cell count was 128/mm3, ranging
from 2 to 972/mm3. The apparently lower median CD4 cell count seen in this latter series may
reflect simple chance alone, or it may be reflective of the fact that this series was accrued later in
the epidemic, at a time when patients are living longer, despite falling CD4 cell counts.
Most patients with HIV-related HD have not had an AIDS-defining diagnosis prior to the onset
of HD. Thus, in the group of 21 patients studied as part of ACTG study #149 (36), 20% had a
history of AIDS prior to HD, consisting of Mycobacterium avium-intracellulare in two,
Pneumocystis carinii pneumonia in two, and Kaposi's sarcoma in one. An additional 50% had
symptomatic HIV-related disease prior to the diagnosis of HD, consisting of oral candidiasis,
herpes zoster, and/or immune thrombocytopenic purpura. Of interest, although the majority of
patients have not had full-blown AIDS prior to HD, many have had a history of reactive
lymphadenopathy (persistent, generalized lymphadenopathy), which was reported in 36%-83% of
individuals (30,33,35).
In de novo HD in the United States and Europe, the majority of patients are diagnosed with
nodular sclerosis disease, described in 52%-62% of large series (37). Lymphocyte-predominant
disease accounts for 8%-21%, while mixed cellularity HD is seen in 24% and lymphocyte
depletion subtype in 3%-6% of patients (37). In contrast, the most common type of HD in
underdeveloped areas of the world (type 1 pattern) is mixed cellularity, while lymphocyte
depletion is the next most frequently diagnosed pathologic subtype of disease (8-10).
Similar to the pathologic spectrum in type 1 areas, patients with HIV-related HD tend to present
with either mixed cellularity or lymphocyte depletion HD, diagnosed in 41%-100% of patients
(29,32,34,38-41). Serrano et al. (40) compared the pathologic characteristics in 22 patients with
HIV-related HD with those in 125 uninfected control subjects with HD diagnosed in the same
time period, in the same institution in Spain. Mixed cellularity or lymphocyte depletion HD was
diagnosed in 68% of the HIV-infected group, versus 35% of the uninfected control subjects. Of
interest, when nodular sclerosis was diagnosed in the setting of HIV, it did not occur within the
mediastinum, in contrast to HIV-negative patients with nodular sclerosis, in whom mediastinal
involvement was documented in 74%.
Systemic B Symptoms
In general, fever, drenching night sweats, and/or weight loss occur more often in patients with
HIV-related HD than in patients with de novo disease. Thus, in a large series from the United
States or Europe, the prevalence of systemic B symptoms ranged from 30% (42) to 62%, the
latter described in U.S. patients from minority racial/ethnic backgrounds and lower
socioeconomic status (11). In contrast, between 70% and 100% of patients with HIV-related HD
have presented with B symptoms (29,30,32,34,38-41). In the series of HIV-positive versus HIVnegative cases of HD from Spain, Serrano et al. (40) noted B symptoms in 81% of 22 HIVinfected patients and in 57% of 125 HIV-negative patients.
While thus apparent that fever, night sweats, and/or weight loss may be commonly encountered
in the setting of HIV-related HD, it is important to recognize that these symptoms may also be
seen in Mycobacterium avium-intracellulare, cytomegalovirus disease, and other opportunistic
infections. Thus, the assignation of such symptoms to HD must be made only after a careful
evaluation has excluded the presence of underlying occult infection.
Clinical Stage of HIV-Related HD at Presentation
In de novo HD in the United States or Europe, stage III disease is diagnosed in approximately
27%, while stage IV is documented in 16%-26% (37). In contrast, widely disseminated HD is
expected in the majority of patients with HIV-related HD. Thus, in the study of HIV-positive
versus HIV-negative HD in Spain, Serrano et al. (40) noted stage III or IV disease in 91% of
HIV-infected patients, versus only 46% of those with de novo HD. In a similar comparative study
from France, Andrieu et al. (30) reported stage III or IV disease in 75% of 45 HIV-infected
patients and in 33% of 407 HIV-negative individuals. These data would indicate that HD
associated with HIV is clearly distinct in terms of the expectation of widely disseminated disease
at initial presentation. This is very similar to the expectation in AIDS-related lymphoma, which is
distinct from de novo lymphomatous disease (1).
The most common site of extranodal HD in HIV-infected patients is the bone marrow, which is
involved in approximately 41%-50% of all reported patients (32,34,39,40,43). Of interest, bone
marrow involvement may be the first presentation of HIV-related HD, with patients seeking
medical attention because of systemic B symptoms and/or signs or symptoms of pancytopenia.
The primary diagnosis of HD within bone marrow may be difficult, revealing lymphohistiocytic
aggregates and large atypical mononuclear cells that are suggestive but not diagnostic of HD
(44). The rather common occurrence of HD within the bone marrow of HIV-infected individuals
is in sharp contrast to de novo HD, in which Colby et al. (45) described such involvement in only
3.5% of 659 patients. While bone marrow involvement is distinctly unusual in de novo HD in the
United States, when one considers only those patients with mixed cellularity or lymphocyte
depletion HD, the prevalence of bone marrow involvement is much higher, at 20%-30%, as
reported by O'Carrol et al. (46). Even when one considers only mixed cellularity and lymphocyte
depletion disease, however, bone marrow involvement by HD is still more likely in the setting of
HIV infection. Thus, Serrano et al. (40) described bone marrow involvement by HD in 50% of
HIV-positive patients from Spain and in only 10% of 125 HIV-negative patients who were
diagnosed and evaluated in the same institution.
Aside from bone marrow, other sites of extranodal HD have included rectum (34,47), tongue
(34), and skin (43,49). Involvement of the brain by HD is extremely unusual in de novo disease,
but it has been described in the setting of HIV (49) in an injection drug user who presented with a
seizure and was found to have a 3-cm, partially enhancing lesion in the left parietal lobe. Spinal
fluid was negative, and the diagnosis of mixed cellularity HD was made after stereotaxic brain
biopsy.
More usual sites of extranodal HD have been described in patients with HIV-related disease, but
even in this circumstance, the disease is distinct from that expected. Thus, HD in the lung has
been described in the absence of mediastinal lymphadenopathy (43,50). Furthermore, hepatic HD
has been diagnosed in the absence of splenic involvement (43).
The majority of all patients with de novo HD experience long-term disease-free survival, with
probable cure of disease expected in approximately 70%. When one considers results of
radiotherapy for localized stage I or II disease, complete remission is expected in 80%-95%, with
80% of responders in continuous complete remission at 7 years (51). In patients with stage III or
IV disease, ABVD chemotherapy (i.e., chemotherapy with doxorubicin, bleomycin, vinblastine,
and dacarbazine) is associated with complete remission in 70%-80% of patients, with relapsefree survival in approximately 60%-70% of responders (52).
Results of Retrospective Therapeutic Trials for HIV-Related HD
Prognosis in patients with HIV-related HD is distinctly poorer than that expected in patients with
de novo disease. Thus, median survival has been in the range of only 8-18 months
(30,32,34,35,40,41,53). In the series of HIV-positive versus HIV-negative HD patients reported
from Spain (40), 5-year survival was achieved in 80% of 125 HIV-negative patients and in none
of 22 HIV-infected patients.
The potential causes of decreased survival in HIV-related HD patients could include early
demise as a result of other AIDS-related disorders, decreased efficacy of standard therapy, and/or
increased toxicity of treatment. Of interest, while no large prospective series of uniformly treated
patients has yet been published, preliminary data would suggest that the results of multiagent
chemotherapy may be somewhat less optimal than expected in de novo disease. Thus, the
comparative study by Serrano et al. (40) documented a complete remission in 54% of HIVinfected patients with HD, versus an 84% complete remission rate in those with de novo disease.
As depicted in Table 1, complete remission rates have ranged from 44% to 100% in patients
with HIV-related HD after being treated with a variety of regimens (32,35,38,40,54,55).
Prospective Treatment Trials
When one considers prospective therapeutic trials, Errante et al. (53) treated 17 patients with
epirubicin, vinblastine, and bleomycin. Patients with poor prognostic disease (Eastern
Cooperative Oncology Group performance status 3 or a history of opportunistic infection)
received 50% of planned epirubicin and vinblastine dosing. In addition, these patients received
zidovudine at the initiation of chemotherapy, while the others received full-dose chemotherapy
with zidovudine initiated only after cycle 3. In patients with good prognosis disease, a complete
remission rate of 67% was achieved, while complete remission was achieved in only one (20%)
of five patients with poor prognosis HIV-related HD. Overall median survival in the 17 patients
was 11 months.
Tirelli et al. (56) used a similar regimen in 29 patients with HIV-related HD; they employed
epirubicin (70 mg/m2), bleomycin (10 mg/m2), and vinblastine (6 mg/m2) given intravenously on
day 1, with prednisone (40 mg/m2) given orally on days 1 through 5. Cycles were given every 21
days. Zidovudine (500 mg/day) was given to all patients who had not taken this drug before,
while didanosine was given to the other patients. Granulocyte colony-stimulating factor was
given at 5 µg/kg per day subcutaneously from day 6 to day 20 in all cycles. The median CD4 cell
count at study entry was 219/mm3 (range, 6-812/mm3). Stage III or IV disease was present in
80% of the patients, while 90% had systemic B symptoms. Pathologic evaluation revealed either
mixed cellularity or lymphocyte depletion HD in 69% of the patients. The complete remission
rate was 69%, with 58% of these patients (i.e., 40% of all patients showing complete remission)
remaining disease free at 2 years. Relapse of HD was documented in 30% of patients who had
shown complete remission. Opportunistic infections occurred in 28% during therapy. Grade 3 or
4 leukopenia was documented in 34%. Median survival for the group was 14 months. HD was
the cause of death in 50% of these patients; HD and opportunistic infection were the causes of
death in an additional 5%.
Levine et al. (36) have recently reported results from the AIDS Clinical Trials Group, employing
standard-dose doxorubicin, bleomycin, vinblastine, and dacarbazine (52) in patients with newly
diagnosed HIV-related HD. Cycles were repeated every 28 days, and therapy was continued until
two cycles beyond complete remission, until six cycles had been given, or until toxicity or
progressive disease. Granulocyte colony-stimulating factor was given subcutaneously at a dose
of 5 µg/kg per day from days 2 through 14 and days 16 through 28 of each cycle. Antiretroviral
agents were withheld during the first two cycles and then initiated with subsequent therapy.
Doses of doxorubicin and vinblastine were reduced 75% in the presence of initial bone marrow
involvement. A total of 21 patients were accrued, of whom 16 are currently assessable for
response. The median age of the patients was 34 years, and 75% were male. The majority (91%)
had no history of injection drug use. Median CD4 cell count at study entry was 128/mm3 (range,
2-972/mm3), and 20% had a history of AIDS prior to the diagnosis of HD. Systemic B symptoms
were present in 86%. Stage IV HD was detected in 62%, while 14% had stage III disease. Sites
of extranodal disease included bone marrow in 25%, while kidney, liver, brain, spinal cord, lung,
and muscle involvement was also documented. A median of six cycles of ABVD chemotherapy
was given (1-8). Complete remission was attained in 56% of the patients, and an additional 25%
attained a partial response. Toxicity was significant, with grade 4 neutropenia in 48%, despite the
use of granulocyte colony-stimulating factor. Hepatic toxicity was also observed; it was detected
in 52% of the patients and consisted of grade 4 transaminasemia in four of 21. Other toxic effects
were rather mild. The median survival for the group is 19.5 months, and eight patients have now
died, as a result of opportunistic infection in three, liver failure due to reactivation of hepatitis B
in one, sepsis in one, bacterial pneumonia in one, and HD in two.
It is apparent from these studies that complete remission may be achieved in the majority of
patients with HIV-related HD. However, toxicity from chemotherapy is substantial and is related
especially to bone marrow compromise, even when hematopoietic growth factors are routinely
employed. Furthermore, the median survival is significantly shorter than that described in
patients with de novo HD, with the majority of deaths due to AIDS-related complications and
other bacterial infections. It is clear that alternative therapeutic strategies must be explored in
HIV-infected patients with HD.
(1) Levine AM. AIDS-associated malignant lymphoma [review]. Blood 1992;80:8-20.[Medline]
(2) Penn I. The occurrence of malignant tumors in immunosuppressed states. Prog Allergy
1986;37:259-300.[Medline]
(3) Penn I. The incidence of malignancies in transplant recipients. Transplant Proc 1975;7:3236.[Medline]
(4) Swinnen LJ, Costanzo-Nordin MR, Fisher SG, O'Sullivan EJ, Johnson MR, Heroux AL, et
al. Increased incidence of lymphoproliferative disorder after immunosuppression with the
monoclonal antibody OKT3 in cardiac-transplant recipients. N Engl J Med 1990;323:17238.[Abstract]
(5) Penn I. Kaposi's sarcoma in organ transplant recipients: report of 20 cases. Transplantation
1979;27:8-11.[Medline]
(6) Penn I. Depressed immunity and the development of cancer. Clin Exp Immunol 1981;46:45974.[Medline]
(7) Spector BD, Perry GS 3d, Kersey JH. Genetically determined immunodeficiency disease
(GDID) and malignancy: report from the immunodeficiency—cancer registry. Clin Immunol
Immunopathol 1978;11:12-29.[Medline]
(8) Correa P, O'Conor GT, Berard CW, Axtell LM, Myers MH. International comparability and
reproducibility in histologic subclassification of Hodgkin's disease. J Natl Cancer Inst
1973;50:1429-35.[Medline]
(9) MacMahon B. Epidemiology of Hodgkin's disease. Cancer Res 1966;26:1189-200.[Medline]
(10) Grufferman S, Delzell E. Epidemiology of Hodgkin's disease. Epidemiol Rev 1984;6:76106.[Medline]
(11) Hu E, Hufford S, Lukes R, Bernstein-Singer M, Sobel G, Gill P, et al. Third-World
Hodgkin's disease at the Los Angeles County-University of Southern California Medical Center.
J Clin Oncol 1988;6:1285-93.[Abstract]
(12) Eltringham JR, Kaplan HS. Impaired delayed-hypersensitivity responses in 154 patients
with untreated Hodgkin's disease. Natl Cancer Inst Monogr 1973;36:107-15.[Medline]
(13) Kumar RK, Penny R. Cell-mediated immune deficiency in Hodgkin's disease. Immunol
Today 1982;3:269-73.
(14) Levy R, Kaplan HS. Impaired lymphocyte function in untreated Hodgkin's disease. N Engl J
Med 1974;290:181-6.[Medline]
(15) Posner MR, Reinherz EL, Breard J, Nadler LM, Rosenthal DS, Schlossman SF. Lymphoid
subpopulations of peripheral blood and spleen in untreated Hodgkin's disease. Cancer
1981;48:1170-6.[Medline]
(16) Ewing J. Neoplastic diseases. Philadelphia: Saunders, 1928.
(17) Notter DT, Grossman PL, Rosenberg SA, Remington JS. Infections in patients with
Hodgkin's disease: a clinical study of 300 consecutive adult patients. Rev Infect Disease
1980;2:761-800.[Medline]
(18) Biggar RJ, Horm J, Goedert JJ, Melbye M. Cancer in a group at risk of acquired
immunodeficiency syndrome (AIDS) through 1984. Am J Epidemiol 1987;126:57886.[Abstract]
(19) Bernstein L, Levin D, Menck H, Ross RK. AIDS-related secular trends in cancer in Los
Angeles County men: a comparison by marital status. Cancer Res 1989;49:466-70.[Abstract]
(20) Hessol NA, Katz MH, Liu JY, Buchbinder SP, Rubino CJ, Holmberg SD. Increased
incidence of Hodgkin disease in homosexual men with HIV infection. Ann Intern Med
1992;117:309-11.[Medline]
(21) Glaser SL, Swartz WG. Time trends in Hodgkin's disease incidence. The role of diagnostic
accuracy.Cancer 1990;66:2196-204.[Medline]
(22) Kant JA, Hubbard SM, Longo DL, Simon RM, DeVita VT Jr, Jaffe ES, et al. The
pathologic and clinical heterogeneity of lymphocyte-depleted Hodgkin's disease. J Clin Oncol
1986;4:284-94.[Abstract]
(23) Lyter DW, Bryant J, Thackeray R, Rinaldo CR, Kingsley LA. Incidence of human
immunodeficiency virus-related and nonrelated malignancies in a large cohort of homosexual
men. J Clin Oncol 1995;13:2540-6.[Abstract]
(24) Cote TR, Biggar RJ, Rosenberg PS, DeVesa SS, Percy C, Yellin FJ, et al. Non-Hodgkin's
lymphoma among people with AIDS: incidence presentation and public health burden. Int J
Cancer 1997;73:645-50.[CrossRef][Medline]
(25) Rabkin CS, Hilgartner MW, Hedberg KW, Aledort LM, Hatzakis A, Eichinger S, et al.
Incidence of lymphomas and other cancers in HIV-infected and HIV-uninfected patients with
hemophilia. JAMA 1992;267:1090-4.[Abstract]
(26) Weiss SH, Karcnik T, Patel S, Skurnick JH, Fromowitz F, Schwartz RA, et al. The ten-year
cancer and HIV experience of the UMDNJ-University Hospital cancer registry: excess
proportions of Hodgkin's lymphoma and lung cancer. J AIDS Human Retrovirol 1997;14:A18.
(27) Myers AM, Toi M, Muldrow M, Rajan G, Kane M, Curiel T, et al. Non AIDS-defining
malignancies in HIV positive individuals. J AIDS Human Retrovirol 1997;14:A31.
(28) Grulich A, Wan X, Law M, Coates M, Kaldor J. Rates of non-AIDS defining cancers in
people with AIDS.J AIDS Human Retrovirol 1997;14:A18.
(29) Monfardini S, Tirelli U, Vaccher E, Ambrosini A, Andriani A, Silvestroni IB, et al.
Malignant lymphomas in patients with or at risk for AIDS: a report of 50 cases observed in Italy.
Cancer Detect Prev 1988;12:237-41.[Medline]
(30) Andrieu JM, Roithmann S, Tourani JM, Levy R, Desablens B, le Maignan C, et al.
Hodgkin's disease during HIV1 infection: the French registry experience. French registry of
HIV-associated tumors.Ann Oncol1993 ;4:635-41.[Abstract]
(31) Roithmann S, Tourani JM, Andrieu JM. Hodgkin's disease in HIV-infected intravenous
drug abusers. N Engl J Med 1990;323:275-6.[Medline]
(32) Rubio R. Hodgkin's disease associated with human immunodeficiency virus infection. A
clinical study of 46 cases. Cooperative Study Group of Malignancies Associated with HIV
Infection of Madrid. Cancer 1994;73:2400-7.[Medline]
(33) Ahmed T, Wormser GP, Stahl RE, Mamtani R, Cimino J, Glasser M, et al. Malignant
lymphomas in a population at risk for acquired immune deficiency syndrome. Cancer
1987;60:719-23.[Medline]
(34) Ames ED, Conjalka MS, Goldberg AF, Hirschman R, Jain S, Distenfeld A, et al. Hodgkin's
disease and AIDS. Twenty-three new cases and a review of the literature.Hematol Oncol Clin
North Am 1991;5:343-56.[Medline]
(35) Monfardini S, Tirelli U, Vaccher E, Foa R, Gavosto F. Hodgkin's disease in 63 intravenous
drug users infected with human immunodeficiency virus. Gruppo Italiano Cooperativo AIDS &
Tumori (GICAT).Ann Oncol 1991;2(suppl 2):201-5.[Medline]
(36) Levine AM, Cheung T, Tulpule A, Huang J, Testa M. Preliminary results of AIDS Clinical
Trials Group (ACTG) study #149: phase II trial of ABVD chemotherapy with G-CSF in HIVinfected patients with Hodgkin's disease. J AIDS Human Retrovirol 1997;14:A12.
(37) Davis S, Dahlberg S, Myers MH, Chen A, Steinhorn SC. Hodgkin's disease in the United
States: a comparison of patient characteristics and survival in the Centralized Cancer Patient
Data System and the Surveillance, Epidemiology, and End Results Program. J Natl Cancer Inst
1987;78:471-8.[Medline]
(38) Gold JE, Altarac D, Ree HJ, Khan A, Sordillo PP, Zalusky R. HIV-associated Hodgkin
disease: a clinical study of 18 cases and review of the literature. Am J Hematol 1991;36:939.[Medline]
(39) Ree HJ, Strauchen JA, Khan AA, Gold JE, Crowley JP, Kahn H, et al. Human
immunodeficiency virus-associated Hodgkin's disease. Clinicopathologic studies of 24 cases and
preponderance of mixed cellularity type characterized by the occurrence of fibrohistiocytoid
stromal cells. Cancer 1991;67:1614-21.[Medline]
(40) Serrano M, Bellas C, Campo E, Ribera J, Martin C, Rubio R, et al. Hodgkin's disease in
patients with antibodies to human immunodeficiency virus. A study of 22 patients. Cancer
1990;65:2248-54.[Medline]
(41) Tirelli U, Errante D, Vaccher E, Repetto L, Rizzardini G, Spina M, et al. Hodgkin's disease
in 92 patients with HIV infection: the Italian experience. GICAT (Italian Cooperative Group on
AIDS & Tumors). Ann Oncol 1992;3(suppl 4):69-72.[Medline]
(42) Kaplan HS. Hodgkin's disease. 2nd ed. Cambridge, MA: Harvard University Press, 1980.
(43) Schoeppel SL, Hoppe RT, Dorfman RF, Horning SJ, Chew TG, Weiss LM, et al. AIDS and
Hodgkin's disease. Front Radiat Ther Oncol 1985;19:66-73.[Medline]
(44) Karcher DS. Clinically unsuspected Hodgkin disease presenting initially in the bone marrow
of patients infected with the human immunodeficiency virus. Cancer 1993;71:1235-8.[Medline]
(45) Colby TV, Hoppe RT, Warnke RA. Hodgkin's disease at autopsy: 1972-1977. Cancer
1982;49:1848-58.[Medline]
(46) O'Carrol DI, McKenna RW, Brunning RD. Bone marrow manifestations of Hodgkin's
disease. Cancer 1976;38:1717-28.[Medline]
(47) Picard O, de Gramont A, Krulik M, Gonzalez G, Debray J, Cady J. Rectal Hodgkin disease
and the acquired immunodeficiency syndrome. Ann Intern Med1987 ;106:775.
(48) Shaw MT, Jacobs SR. Cutaneous Hodgkin's disease in a patient with human
immunodeficiency virus infection. Cancer 1989;64:2585-7.[Medline]
(49) Hair LS, Rogers JD, Chadburn A, Sisti MB, Knowles DM, Powers JM. Intracerebral
Hodgkin's disease in a human immunodeficiency virus-seropositive patient. Cancer
1991;67:2931-4.[Medline]
(50) Schieb RG, Siegel RS. Atypical Hodgkin's disease and the acquired immunodeficiency
syndrome. Ann Intern Med 1985;102:554.
(51) Hoppe RT, Hanlon AL, Hanks GE, Owen JB. Progress in the treatment of Hodgkin's disease
in the United States, 1973 versus 1983. The Patterns of Care Study.Cancer 1994;74:3198203.[Medline]
(52) Canellos GP, Anderson JR, Propert KJ, Nissen N, Cooper MR, Henderson ES, et al.
Chemotherapy of advanced Hodgkin's disease with MOPP, ABVD, or MOPP alternating with
ABVD. N Engl J Med 1992;327:1478-84.[Abstract]
(53) Errante D, Tirelli U, Gastaldi R, Milo D, Nosari AM, Rossi G, et al. Combined
antineoplastic and antiretroviral therapy for patients with Hodgkin's disease and human
immunodeficiency virus infection. A prospective study of 17 patients. The Italian Cooperative
Group on AIDS and Tumors (GICAT). Cancer 1994;73:437-44.[Medline]
(54) Tirelli U, Vaccher E, Rezza G, Broccia G, Fassio PG, Gobbi M, et al. Hodgkin disease and
infection with the human immunodeficiency virus in Italy. Ann Intern Med 1988;108:309-10.
(55) Newcom SR, Ward M, Napoli VM, Kutner M. Treatment of human immunodeficiency
virus-associated Hodgkin disease. Is there a clue regarding the cause of Hodgkin disease?Cancer
1993;71:3138-45.[Medline]
(56) Tirelli U, Errante D, Santarossa S, Spina M, Gisselbrecht C, Marolleau P, et al. Epirubicin,
bleomycin, vinblastine, and prednisone chemotherapy in combination with antiretroviral therapy
and primary use of G-CSF for patients with Hodgkin's disease and HIV infection. J AIDS and
Human Retrovirol 1997;14:A32.