acquired immunodeficiency syndrome-associated non-hodgkin ...€¦ · acquired immunodeficiency...

Acquired Immunodeficiency Syndrome-Associated Non-Hodgkin’s Lymphomas and Other Malignancies in Patients With Hemophilia

By Margaret V. Ragni, Steven H. Belle, Ronald A. Jaffe, Sandra L. Duerstein, Debra C. Bass, Campbell W. McMillan, E.W. Lovrien, Louis M. Aledort, C.T. Kisker, Sally P. Stabler, W. Keith Hoots, Margaret W. Hilgartner, Joan Cox-Gill,

George R. Buchanan, Natalie L. Sanders, Doreen B. Brettler, Lloyd E. Barron, Jonathan C. Goldsmith, Bruce Ewenstein, Kenneth J . Smith, David Green, Joseph E. Addiego, and Lawrence A. Kingsley

Non-Hodgkin’s lymphoma (NHL) is the most common human immunodeficiency virus (HIV)-associated malignancy in hemophiliacs. We studied the incidence and clinicopathologic features of NHL in 3,041 hemophiliacs followed at 18 US Hemophilia Centers between 1978 and 1989. Of the 1,295 (56.6%) who were HIV( + ), 253 (1 9.5%) developed acquired immunodeficiency syndrome (AIDS), of whom 14 (5.5%) developed NHL. Three NHL occurred in HIV( - ) hemophiliacs, for a 36.5-fold greater risk in HIV( + ) than HIV( - ) hemophiliacs (P < .001). The NHL incidence rate was 29-fold greater than in the US population by Sur- veillance, Epidemiology, and End Results (SEER) estimates (P < .OOl). Between 0 and 4 lymphomas have been ob- sewed per year between 1978 and 1989. At presentation 13 (92.9%) of the HIV( + ) NHL were extranodal. Ten were stage IV, 1 stage II, and 3 stage IE. Ten (71.4%) were high-

NE OF THE MOST common malignancies associated 0 with human immunodeficiency virus (HIV) infection is non-Hodgkin’s lymphoma (NHL), initially described in 1982,’ but not recognized as an acquired immunodeficiency syndrome (AIDS)-defining illness until 1985.2 Typically, lymphomas associated with HIV infection are aggressive-, high-, or intermediate-grade B-cell lymphomas, often with extranodal presentation involving the gastrointestinal tract, central nervous system, bone marrow (BM), and l i ~ e r . ~ . ~ The response to chemotherapy is poor, and the mortality rate is high.3*5 Similar to lymphomas occumng in other immunodeficiency states, Epstein-Barr virus (EBV) has been detected in one third to one half of AIDS-associated lymphoma^,^,^ although whether EBV plays a role in the pathogenesis of these lymphomas remains unknown.

The incidence of NHL in HIV-infected individuals has been increasing since the onset of the AIDS epidemic, with a fourfold increase in homosexual men in San Francisco 1975- 78 to 1982-85 by Surveillance, Epidemiology, and End Re- sults (SEER) temporal trends.’ Centers for Disease Control (CDC) estimates that 3% of reported AIDS-defining illnesses are NHL,8,9 a figure that likely underestimates the incidence of NHL because NHL was not an AIDS-defining illness until 19858 and because CDC reporting requires only the first AIDS diagnosis, thus potentially missing 25% of NHL occumng as a second or later AIDS diagnosis3 With the treatment ad- vances for HIV infection, including zidovudine and Pneu- mocystis carinii prophylaxis, and improved life expectancy of AIDS patients,1°-12 a marked increase in HIV-associated lymphomas has been observed,13 and projections suggest this trend will ~0ntinue.I~

AIDS-associated lymphomas have been studied primarily in homosexual men, with little known about lymphomas in HIV( +) hemophiliacs. NHLs have consistently represented a higher proportion of AIDS-defining illnesses in hemophiliacs than in homosexual men: in 1988, 4.7% versus 1.5%; in 1989, 4.6% versus 1.5%; and, in 1990, 4.6% versus 3.1%,

grade, 3 (21.4%) intermediate-grade, and 1 (7.1 %) was a low-grade B-cell lymphoma. Epstein-Barr virus (EBV) DNA was detected in 36% by in situ hybridization, including one central nervous system (CNS) lymphoma. The mean CD4 cell count at NHL diagnosis was 64/mm3, the mean latency from initial HIV infection was estimated to be 59 months, and the median survival was 7 months. The incidence of basal cell carcinoma in HIV( + ) hemophiliacs was 18.3- fold greater than in HIV( - ) hemophiliacs (P < .0001) and 11 .4-fold greater than in the US population (P < .OOl). In conclusion, incidence rates of NHL and basal cell carcinoma in HIV( + ) hemophiliacs are significantly increased over rates in HIV( - ) hemophiliacs and over rates in the US population. Clinicopathologic presentation of NHL in HIV( + ) hemophiliacs is similar to that in HIV( + ) homosexual men. 0 1993 by The American Society of Hematology.

respectively9 (John Murphy, MD, and Frank de Stefano, MD, Centers for Disease Control, personal communication, Au- gust 1988 and August 1990). Further, although there has been a reported doubling in NHLs as AIDS-defining illnesses from 1.5% to 3.1% over the last 3 years, this trend has not been reported in hemophiliacs. Although unsubstantiated, potential lymphoma incidence differences between homosexual and hemophilic men might relate to lifestyle and viral or antigenic exposure differences or differences in survival following AIDS diagnosis between these groups. The median survival after AIDS was 0.5 years in hemophiliacs receiving no antiviral therapy, and 2.1 years in those treated with antiviral therapy,I5 barely reaching the minimal 2-year survival on antiretroviral therapy, during which increased lymphoma incidence has been observed.”

As previous studies of AIDS-associated lymphomas and cancers have included few, if any, hemophiliacs, we studied the incidence and clinicopathologic features of NHL and other malignancies in 3,041 US hemophiliacs enrolled in the Hemophilia Malignancy Study (HMS), to characterize the epidemiology of HIV-associated cancers in hemophiliacs.

From the University of Pittsburgh School ofMedicine, Hemophilia Center of Western Pennsylvania, and the Graduate School of Public Health. Pittsburgh, PA, and the Hemophilia Malignancy Study Group.

Submitted June 4, 1992; accepted November 17, 1992. Supported by NCI Grant CA-50849, National Cancer Institute. Address reprint requests to Margaret V. Ragni, MD, University of

Pittsburgh, Hemophilia Center of W. PA, 812 Fifth Ave, Pittsburgh, PA 15219.

The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. section 1734 solely to indicate this fact. 0 1993 by The American Society of Hematology. 0006-49 71/93/81 0 7-0021 $3.00/0

Blood, Vol 8 1, No 7 (April 1). 1993: pp 1889-1 897 1889

For personal use only.on October 3, 2017. by guest www.bloodjournal.orgFrom

http://www.bloodjournal.org/

http://www.bloodjournal.org/site/subscriptions/ToS.xhtml

1890 RAGNl ET AL

MATERIALS AND METHODS

The HMS is a multicenter study of over 3,041 individuals with hemophilia from 18 US Hemophilia Treatment Centers in the I O Health and Human Services geographic regions. Primary goals of this study are to determine the incidence, risk factors, clinicopathologic, and molecular-biologic characteristics of AIDS-associated malignancy in the hemophilia population. This report summarizes the findings of the Retrospective Study, which is a retrospective review of all past AIDS cases, malignancies, and deaths in HIV(+) and HIV(-) hemophiliacs between January I , 1978 and December 31, 1989. Data were collected by the nurse coordinator at each center through chart review and data abstraction. These data form the basis for determining the incidence of AIDS, lymphoma, and other cancers in HIV(+) and HIV(-) hemophiliacs. Data entry and management were performed by a Central Coordinating Center. Inconsistencies and missing data were tracked and reviewed with the nurse coordinator by the Pittsburgh project coordinator. Autopsy and pathologic biopsy slides and paraffin blocks from past AIDS or HIV(+)-related deaths were collected by each nurse coordinator and sent to the coordinating center, catalogued and coded, and histopathologically classified by independent pathologic review (R.A.J.). All death reports were corroborated by physician report, hospital record, health records, autopsy report, and slides from the autopsy.

Cut slides or paraffin blocks were received from 14 of the patients with lymphomas. Glass slides only were reviewed on the three others. In addition to the usual histochemical stains, hematoxylin/eosin, Pe- riodic acid Schiff, and giemsa stains, immunochemistry was performed using an avidin-Biotin detection system (PBC Elite; Vector, Burlin- game CA). The antibodies used were common leukocyte antigen (CLA, CD45), B cell (L-26, CD20), T cell (UCHL-I, CD45R0, and Leu 22, CD43), and a macrophage/monocyte marker (W-I, CD68). All were commercially obtained through Dako (Carpinteria, CA) ex- cept Leu 22 (Becton Dickinson, San Jose, CA) and KP-1 (a gift from Dr D. Mason, Oxford, England). Dilutions were titrated against known positive biologic controls, one of which was run with each batch, and the negative controls consisted of substitution of a mouse Ig isotype for each antibody.

EBV-DNA was detected in paraffin-embedded tissues after protease digestion using a commercial kit from Digene (Silver Spring, MD) following manufacturer’s directions and using a known positive control processed to paraffin in our own laboratory. A cytomegalovirus (CMV) probe, from the same source, was used as the probe control.

Dates of seroconversion were imputed as the midpoint between the date of the last negative HIV test and the first positive HIV test when both dates were known. These data were only available on 190 subjects. However, 17 had other risk factors or lapses in treatment, and thus only 173 were available for analysis. For the other 1,231 patients who either tested HIV positive, or were presumed positive, the date of seroconversion was estimated to be June IO, 1982 for individuals with hemophilia A, or October 11, 1983 for individuals with hemophilia B. These dates were based on the median date of seroconversion for hemophilia A and B, respectively, for the 173 with known dates of last negative and first positive HIV antibody test.

Cancer incidence in the cohort was compared with the general population, using SEER age-specific rates for all males 1984 to 1988.16 Age-specific incidence rates for basal cell cancers among males were obtained from the Mayo Clinic registry.” Expected numbers of cancers in the HIV(+) and HIV(-) cohorts, respectively, were obtained by applying these rates to the person-years of observation in each cohort. With the exception of a single case of Kaposi’s sarcoma, observed and expected numbers of malignancies are reported for all malignancies in which at least one case was reported.

For each malignancy the number of person-years of observation were calculated separately for the HIV(-) and HIV(+) cohorts. With a single exception, person-years for the HIV(-) cohort were accrued from the time of birth until whichever came first: diagnosis with the cancer, seroconversion, last visit to the hemophilia center, or death. The exception is one ofthe patients diagnosed with leukemia 2 years after his last visit to a hemophilia center. His person-years of observation are only included until the date of diagnosis of leukemia. Person-years in the HIV(+) cohort were accrued from the date of seroconversion to whichever came first: diagnosis with cancer, last visit to the hemophilia center, or death.

Observed and expected deaths were compared statistically using a test for the ratio of a Poisson variable to its expectation.’* Chi square analysis was used to compare lymphoma incidence differences and relative risks for cancers and lymphomas between HIV(+) and HIV(-) hemophiliacs. Kaplan-Meier time-limit estimates were con- structed for the proportion surviving following first AIDS diagnosis and for the proportion surviving following lymphoma diagnosis.

RESULTS

A total of 3,041 patients with hemophilia A or B, cared for at 18 US hemophilia-treatment centers, between January I , 1978 and December 31, 1989, were enrolled in the study. Of these, 2,420 (79.6%) had been tested for HIV antibody, of whom 1,295 (56.6%) were HIV antibody positive (1,198 or 92.5% Western blot confirmed) and 1,125 (37.0%) were HIV antibody negative. Of the 621 remaining patients, including 576 untested and 45 unknown if tested, a total of I26 were presumed positive because of a diagnosis of severe hemophilia A treated with factor VI11 concentrate between 1978 and 1986, the peak period of HIV transmission in hemophiliacs, and because over 90% of this group has become HIV infected.19 A total of 206 were presumed HIV negative, including 130 never exposed to any blood products and 76 exposed to blood products before 1978 or after 1986 and 289, the remainder, whose risk of HIV infection could not be accurately determined. The reasons given for lack of HIV testing in 576 untested hemophiliacs included: (1) testing was unavailable (before 1985) in 217 (37.7%); (2) patient was too young (birth or exposure after 1986) in 12 1 (2 1 .O%); (3) patient refused testing for confidentiality reasons in 94 ( 1 6.3%); (4) patient had no or little lifetime exposure (not related to young age) in 87 (15.1%); ( 5 ) no reason given in 39 (6.8%); and (6) limited follow-up of the patient precluded testing in 18 (3.1%). The median age in those presumed HIV positive was nearly identical to the age ofthose known HIV(+), while those presumed HIV(-) were much younger than those known HIV(-), reflecting the time of exposure (after 1986) and much lower presumed risk of HIV infection after 1986, related to availability of safer blood products.

Ofthe 1,295 HIV(+) hemophiliacs, 253 (19.5%) had developed AIDS by December 31, 1989, with the peak frequency in 1988 (1 in 1981, I in 1982,4 in 1983, 7 in 1984, 15 in 1985, 34 in 1986,47 in 1987, 75 in 1988, 64 in 1989, and 5 unknown). Fourteen (5.5%) developed NHL, 10 (7 1.4%) as a primary AIDS diagnosis and 4 (28.6%) in patients with a prior diagnosis of AIDS. Three HIV(-) individuals presented with NHL, at a median age of 63.0 years, compared with 3 1.9 years in HIV(+) patients with NHL. There was a 36.5-fold greater risk of NHL in HIV(+); 14 per 8,549.9 per-




AIDS-ASSOCIATED LYMPHOMAS IN HEMOPHILIACS 1891

severe disease (<0.01 U/mL factor activity), and 2 with mod- erate disease (0.01 to 0.04 U/mL) (Table 2). All had been treated with clotting-factor concentrates. Only three had received antiretroviral treatment for HIV infection. One of the latter and one additional HIV( +) patient were also treated with the antiviral acyclovir, one for concomitant oral herpes simplex virus infection. It should be clarified that patient nos. 1,2,3, 5,7,8, 10, 1 1, 13, and 14 are truly AIDS-defining, as they were systemic and occurred as a primary AIDS-defining illness: the remaining four, nos. 4, 6, 9, and 12, are HIV-related but not truly AIDS defining by the CDC definition.2 Ofthe 14 HIV(+) NHL, 10 (71.4%) were high-grade, 3 (21.4%) intermediate-grade, and 1 (7.1%) low-grade by the National Cancer Institute Working Formulation.” The high- grade NHL included nine diffuse large-cell immunoblastic and one diffuse undifferentiated Burkitt’s lymphomas. The intermediate-grade NHL included two diffuse, large cell noncleaved, and one diffuse, mixed small and large cell lymphoma. The single low-grade NHL was a follicular, small cell cleaved lymphoma.

Ten of the HIV-associated lymphomas (7 1.4%) were stage IV at presentation; the remaining four included three stage IE and one stage 11. All but 1 HIV-associated NHL were extranodal at presentation, including 4 gastrointestinal, 4 in- traabdominal (including 3 occumng in the liver and 1 occurring in the spleen with an associated abdominal mass), 2 central nervous system (CNS), and 1 each BM, parotid gland, and subcutaneous skin of the thigh. The single nodal NHL was located in the axilla, bilaterally: the latter was the only stage I1 NHL. Ten of 10 tumors (100%) tested showed reac- tivity with the L-26 B-cell marker, and were unreactive with the UCHL- I and Leu 22 T-cell markers. Immune phenotype, determined on three, showed IgMk in two and IgMX in one. EBV was detected in 4 of 11 (36.4%) lymphomas tested by DNA probe, while one CNS lymphoma (no. 2) was EBV(+) by DNA probe and showed c-myc gene rearrangement. The mean latency ofthe 14 HIV(+) lymphomas was 59.0 months from the date of known or estimated seroconversion (range 20 to 122, median 60.5 months). The median CD4 at NHL diagnosis was 39/mm3, or 41/mm3 in the seven systemic

% S U

1 I

0 6 12 18 24 30 36 42 46

Months Following Diagnosis

Fig 1. Survival trends in the hemophilia cohort following a diagnosis of AIDS. Kaplan-Meier estimates are shown for the proportion remaining alive from the time of first AIDS diagnosis, in years (*), and for the proportion remaining alive from the time of AIDS-associated lymphoma diagnosis (-). The median survival is 16 months for AIDS and 7 months for AIDS-associated lymphoma.

son-years (163.7 per 100,000 person-years) as compared with HIV(-) hemophiliacs; 3 per 66,789.4 person-years (4.5 per 100,000 person-years) (P < .001). The mean CD4 at lymphoma diagnosis was 64/mm3 (range 9 to 269). The median survival following an AIDS diagnosis by Kaplan-Meier time limit estimates was 16 months, and the median survival following lymphoma diagnosis was 7 months (Fig I).

Geographically, there were significant differences in the proportion of patients tested for HIV antibody, 82.8% versus 79.6% versus 74.0% in the eastern, mid-western, and western states, respectively, X 2 = 12.50 (P < .005), which may reflect, in part, geographic differences in HIV reporting requirements in the late 1980s and early 1990~~’ (see Appendix for list of centers in each geographic region). There were significant differences in the proportion HIV(+), 59.4% versus 46.6% versus 5 1.4%, respectively, from eastern, mid-western, and western states, X 2 = 13.82 (P < .OOI). The rates of AIDS in the eastern, mid-western, and western states were 2.9 per 100 person-years, 3.0 per 100 person-years, and 2.9 per 100 person-years, respectively, following seroconversion (P > .05). The rates of lymphoma in the HIV(+) cohort were 183.6 per 100,000 person-years, 175.8 per 100,000 person-years, and 100.8 per 100,000 person-years in the eastern, mid-western, and western states, respectively, following seroconversion (P > .05).

When compared with SEER incidence rates from 1984 to 1988, the observed rate of NHL in hemophilic men was 29- fold greater than expected in the US population (P < .001) (Table I ) . The incidence rate of NHL in hemophilic men, although increased over expected, has remained relatively constant with 0 to 4 new cases of AIDS-associated lymphoma per year between 1984 and 1989. The incidence of NHL in HIV(+) hemophiliacs was 163.7 per 100,000 person-years, as compared with 4.5 per 100,000 person-years in HIV(-) hemophiliacs.

The 14 HIV-associated NHL occurred in 13 hemophilia A patients and 1 hemophilia B patient, including 12 with

Table 1. Age-Adjusted Lymphoma Rates in HIV( + ) and HIV( - ) Hemophilic Men

HIV (+) HIV (-)

Age Person- Person- (yr) yrs Expected Observed yrs Expected Observed

0-9 991.2 .01 0 26,289.7 0.23 0 10-19 2,381.4 .04 4 18,246.9 0.32 0 20-29 2,627.7 .08 3 11,217.8 0.34 0 30-39 1,581.7 .13 3 5.972.8 0.49 1 40-49 623.7 .10 2 2,908.4 0.45 0 50-59 238.2 .06 0 1,458.1 0.39 0 60-69 83.2 .04 2 553.3 0.26 0 70-79 15.6 .01 0 127.9 0.10 1 280 7.3 - 0 14.7 - 0.02 - 1

8,549.9 0.48 14’ 66,789.4 2.60 3

The observed to expected ratio in HIV(+) hemophiliacs is 14/0.48 or 29.1 2 and for HIV(-) hemophiliacs is 3/2.60 or 1.1 5.




A

Tab

le 2

. C

linic

opat

holo

gic

Cha

ract

eris

tics

of

Lym

phom

as in

Hem

ophi

liacs

m

(D

N

Tr

eatm

ent

DN

A P

robe

s Ty

pe/S

ever

ity

CDI

at D

X

1 ' or

2"

L-26

H

isto

path

olog

y (E

Cel

l) E

BV

LM

P

CH

IR

A

V

Sur

viva

lt N

o.

Age

Ivr

) H

emop

hilia

N

o./m

m3

AID

S D

X

Late

ncy'

S

ite

Gra

de

HIV

(+)

1.

38

A,

Sev

ere

9 10

46

CN

S

Hig

h D

iffus

e la

rge

cell

imm

unob

last

ic,

plas

mac

ytoi

d D

iffus

e la

rge

cell

non-

cl

eave

d D

iffus

e la

rge

cell

imm

unob

last

ic

Diff

use

larg

e ce

ll im

mun

obla

stic

, pl

asm

acyt

oid

Diff

use

larg

e ce

ll im

mun

obla

stic

, pl

asm

acyt

oid

Diff

use

larg

e ce

ll im

mun

obla

stic

l D

iffus

e la

rge

cell

imm

unob

last

ic

Diff

use

undi

ffere

ntia

ted

Bur

kitt

'sl

Diff

use

mix

ed, s

mal

l &

larg

e ce

ll D

iffus

e la

rge

cell

imm

unob

last

ic,

pleo

mor

phic

D

iffus

e la

rge

cell

imm

unob

last

ic

Diff

use

larg

e ce

ll im

mun

obla

stic

, pl

eom

orph

ic

clea

ved

clea

vedl

Diff

use

larg

e ce

ll, n

on-

Folli

cula

r sm

all c

ell

+ +

+ +

4

2.

3.

4.

12

42

18

A,

Sev

ere

A,

Sev

ere

A,

Sev

ere

20

269

ND

1"

1"

20

76

122 88

Live

r

Par

otid

CN

S

Inte

rmed

iate

Hig

h

Hig

h

+ + -

+ + -

+ + -

+ + +*

-

-

ND

5.

23

B, S

ever

e N

D

1"

23

GI

Hig

h +

ND

+$

80

+ +

6.

7.

8.

9.

10.

44

15

17

34

21

A,

Sev

ere

A,

Sev

ere

A,

Sev

ere

A,

Sev

ere

A,

Sev

ere

ND

41

37

74

41

2"

1"

10

2"

10

51

27

66

37

69

Live

r

GI

BM

LN

Ski

n

Hig

h

Hig

h

Hig

h

Inte

rmed

iate

Hig

h

ND

+ ND

ND

+

ND

-

ND

ND

-

3 50

<1 30

7

+ +

+ + +

11.

12.

34

60

A,

Sev

ere

A,

Mod

erat

e

ND

ND

1"

2"

20

64

Abd

omin

al m

ass/

sp

leen

G

I

Hig

h

Hig

h

+ + 14

5

+ +

13.

14.

29

60

31.9 4.2

(mea

n)

A,

Mod

erat

e

A,

Sev

ere

ND

21

39fm

m3

(med

ian)

1"

1"

57

79

58.9 f 7.5

(mea

n)

GI

Live

r

Inte

rmed

iate

Low

+ ND

9/10

il 9

15.6 f 6.1

(mea

n)

- ND

411

1

- -

5/14

ND

If8

+ 10114

+ 8/14

HIV

(-)

15.

16.

17.

33

75

81

63.0 t 15.1

(mea

n)

A,

Sev

ere

A, M

ild

B, M

ild

CN

S

LN

BM

Inte

rmed

iate

Low

Lo

w

Diff

use

larg

e ce

ll,

Folli

cula

r sm

all c

ell

Folli

cula

r mix

ed, s

mal

l

clea

ved

& la

rge

cell

+ 1

36

10

15.7 f 10.5

(mea

n)

+

+ + + +

Of 3

013

013

EBV

is E

pste

in-B

arr v

irus

DN

A in

-situ

; LM

P is

late

nt m

embr

ane

prot

ein,

imm

unol

ogic

; C

H =

che

mot

hera

py;

IR =

irra

diat

ion;

AV

= a

ntiv

iral t

hera

py

Late

ncy

indi

cate

s tim

e in

mon

ths

from

kno

wn

or im

pute

d se

roco

nver

sion

to th

e de

velo

pmen

t of t

he ly

mph

oma.

t

Sur

viva

l is

indi

cate

d in

mon

ths.

* Zi

dovi

dine

. 5

Tiss

ue u

nava

ilabl

e or

insu

ffici

ent f

or p

atho

logy

revi

ew. D

iagn

osis

giv

en is

that

of l

ocal

pat

holo

gist

s.

1) Acy

clov

ir.

n D 0 z

For

per

sona

l use

onl

y.on

Oct

ober

3, 2

017.

by

gue

st

w

ww

.blo

odjo

urna

l.org

Fro

m




NHL. The median survival for the 14 lymphomas in HIV(+) hemophiliacs was 7 months: by contrast, the median survival after AIDS diagnosis in this cohort (n = 253) was 16 months (Fig I) . The longest survivals in HIV-associated NHL, 80 and 50 months, occurred in patients receiving both chemotherapy and antiretroviral treatment: these were also among the younger patients developing lymphoma (age 23 and 15 years, respectively). The three CNS lymphomas (2 of which were HIV(+)) showed a median survival of 1 month.

The three HIV(-) lymphomas (Table 2) occurred in a 33- year-old patient with severe hemophilia A in 1978, likely before exposure to HIV, and in 2 older patients with mild hemophilia, 1 a 75-year-old with mild hemophilia A, treated only with cryoprecipitate, and the other an 8 1-year-old with mild hemophilia B, never treated with blood products. The former was a high-grade lymphoma of the CNS, and the latter 2, 1 intermediate-grade diffuse lymphocytic poorly differ- entiated lymphomas, stage 11, presenting in axillary lymph nodes and the other a low-grade nodular mixed small- and large-cell lymphoma, stage IV, presenting in the BM. All three were L-26 positive, B-cell tumors. All three were EBV negative by DNA probe. The median survival in HIV(-) NHL was 10 months. None of these three were known to be farmers or had a history of chemical exposure.

Basal cell carcinoma was the next most common malignancy occurring in hemophilic men (Table 3). There was an 1~8.3-fold greater incidence of basal cell carcinoma in HIV(+), 7 per 8534.1 person-years, (82.0 per 100,000 person-years), as compared with HIV(-) hemophiliacs, 3 in 66,777.0 person- years (4.0 per 100,000 person-years), P < .0001. The mean age at which basal cell carcinoma occurred in HIV(+) men was 40 years, as compared with 55 years in HIV(-) hemophilic men. When compared with the US population incidence rates as per Mayo Clinic estimates,I7 (Christopher Chute, MD, MPH, Mayo Clinic, personal communication, November 199 l), there was an 1 1 .4-fold greater incidence in basal cell carcinoma in HIV(+) hemophiliacs (P < .001). The age-adjusted basal-cell carcinoma incidence was significantly lower in HIV(-) hemophiliacs than the US population (P < .01). The incidence rates of all other observed cancers were not significantly different from expected using SEER estimates (P > .05)16: the only exception was the significantly lower incidence of lung carcinoma in HIV( -) hemophiliacs than in the US population (P < .OO 1) (Table 4).

Two cancers were diagnosed at autopsy. These occult cancers included one hepatocellular carcinoma and one prostatic carcinoma. The incidence of hepatocellular carcinoma was less than 1% among hemophiliacs overall, and not significantly different between HIV(+) and HIV(-), with 1 per 8554.8 person-years compared with one per 66,789.4 person- years, respectively. The only case of Kaposi’s sarcoma occurred in an HIV(+) hemophilic man who was also homosexual. Overall, cancers occurred a mean I3 years earlier in HIV(+) than HIV(-) hemophiliacs.

A total of 226 deaths occurred in this cohort through De- cember 31, 1989. Data were obtained by medical records in 174 (77.0’%), by physician in 52 (23.0%), by family or next of kin in 38 (1 8.6%), and/or by death certificate in 42 (1 8.6%). The three leading causes of death were AIDS in 12 1 (56%),

bleeding in 43 (19%), and liver disease in 22 (10%). Autopsies were obtained in 18 (8%) with the detection of two occult malignancies ( 1 1 Yo), as noted above.

DISCUSSION

NHL is over 36 times more common in HIV(+) than HIV(-) hemophilic men. Although only IO of the 14 HIV(+) hemophilia patients with NHL were truly AIDS-defining by the CDC definitioq2 for purposes of this discussion, we have included all NHL in HIV(+) hemophiliacs. The lymphoma incidence among AIDS cases is 5.5%, which is similar to the proportion in San Francisco AIDS cases (7%)’* and to the proportion of AIDS-associated lymphoma reported to the CDC (3%).” Compared with the US population by SEER rates, the observed age-adjusted incidence rates of NHL in HIV(+) hemophiliacs is 29-fold greater. This figure is some- what lower than the 60-fold risk estimated by Beral et a18 in a CDC study of primarily homosexual men or the 100-fold risk estimated by Rabkin et a123 from the San Francisco SEER registry. However, unlike the CDC and SEER registry data, the source of our data was the comprehensive medical records from hemophilia treatment centers, which contain both in- patient and outpatient outcome information, as well as the results of HIV testing. Seroconversion data were available, thereby providing an estimate of whether observed NHL were HIV-related or unrelated. With this method, there was a ten- dency to be more conservative, as seen in one patient (no. 15) who developed NHL in 1978, 4 years before the 1982 imputed seroconversion date; thus, his lymphoma was des- ignated HIV-unrelated, although his severe hemophilia A and chronic factor-concentrate exposure put him at great risk for early HIV infection. However, if we were to assume his lymphoma was HIV-related, we would have to make two assumptions, each of which alone is unlikely. First, we would have to assume he became infected at least 2 years earlier than the other hemophiliacs in the United States, and specifically other hemophiliacs in his state of residence, Penn- sylvania, where the earliest seroconversions in hemophiliacs occurred in 1978 and 1979.’’ This seems very unlikely. We

Table 3. Age-Adjusted Basal Cell Carcinoma Rates in HIV( + ) and HlVl- 1 HemoDhilic Men

HIV (+) HIV I-) Age Person- Person- (yr) yrs Expected Observed yrs Expected Observed

0-9 991.2 .OO 0 26,289.7 .OO 0 10-19 2,383.8 .06 0 18,246.9 .40 0 20-29 2,628.8 .36 0 11,217.8 1.44 0 30-39 1,582.1 .89 2 5,968.6 3.36 1 40-49 616.3 .83 1 2,901.0 3.91 1 50-59 228.1 .64 3 1.457.3 4.03 0 60-69 81.0 .38 1 553.3 2.60 0 70-79 15.6 .I2 0 127.9 0.97 1 280 7.3 .18 0 14.7 0.23 Q

8,534.1 3.46 7” 66.777.0 16.94 3

The observed to expected ratio for basal cell carcinoma in HIV(+) hemophiliacs is 7/3.46 or 2.03 and for basal cell carcinoma in HIV(-) hemophiliacs is 3/16.94 or 0.18.




1894 RAGNl ET AL

Table 4. Age-Adjusted Cancer Incidence Rates in HIV( + 1 and HIV( - ) Hemophilic Men ~ ~

HIV(+) HIV(-1

Person-yrs' Expected Observed Person-yrst Expected Observed

Cancer Lymphoma Basal cell CA Testicular CA Melanoma Leukemia11 Head & neck CA Prostate CA Hepatocellular CA Hodgkin's disease Lung CA Colon CA Bladder CA All cancers

8,549.9 8,534.1 8,553.4 8,551.5 8,552.6 8,553.4 8,553.4 8,553.4 8,553.4 8,553.4 8,553.4 8,553.4

0.48 3.46 0.52 0.46 0.35 0.36 0.64 0.06 0.30 1.05 0.47 0.33

14$ 7* 0 1 1 0 0 1 0 0 0 0

24 -

66,789.4 66.777.0 66,762.8 66,785.2 66,787.1 66,755.1 66,785.6 66,787.1 66,784.9 66,783.4 66,781.6 66.787.1

2.60 16.94 2.26 2.17 3.18 1.92 3.94 0.43 1.51 6.17 2.63 1.89

3 31 5 3 2 4 2 1 1 1T 1 1

27

Includes time from seroconversion t o whichever event came first: diagnosis of cancer, last clinic visit, or death. t Includes time from birth t o whichever event came first: diagnosis of cancer, HIV seroconversion. last clinic visit, or death t P < ,001. § P < .01. 11 Includes one case diagnosed subsequent t o last clinic visit. CA is carcinoma. ll P < .05

would also have to assume that the incubation period, between initial HIV seroconversion and development of lymphoma, occurred at the extreme minimum duration of infection, 2 years.15 This also seems very unlikely, and thus we believe that his lymphoma occurred as an incidental HIV( -) lymphoma, rather than an HIV-related lymphoma. If our assumptions are incorrect, at worst this would suggest the 29-fold risk of lymphoma in HIV(+) hemophiliacs may be an underestimate. Alternatively, another patient (no. 6) developed NHL at age 15, within the HIV-related time frame and 27 months after seroconversion, but his greater than 6- year survival is distinctly unusual for HIV-related NHL. Thus, given his known HIV infection and date of development of NHL, we believe his lymphoma was an HIV-related lymphoma.

Although Rabkin et al noted in their study of hemophili- a c ~ ~ ~ that the risk of NHL increases with age, our data show a similar risk throughout all age groups. Further, as so few of the patients had received antiretroviral therapy before the development of NHL, it is unlikely that antiretroviral therapy played a major role in the development of NHL in this study group.

The lack of an increase in the rate of NHL since 1984 in HIV( +) hemophiliacs is distinctly different from that observed in homosexual men. 13,24 If factors, such as prior antiretroviral therapy or survival greater than 2 years with immunodeficiency, play a role in the development of lymphoma as pro- posed by Pluda et aI,l3 then the small proportion of lymphoma patients receiving antiretroviral treatment and the short survival (16 months) after an AIDS diagnosis in this group may explain the lack of increase in the rate of development of NHL in this population. However, it should be noted that the study of Pluda et all3 may be limited by the small number of cases and, in scope, with primarily CNS lymphomas. De- spite this, there are clear lifestyle and antigenic exposure dif-

ferences between hemophiliacs and homosexual men; whether these factors account for any potential differences in rates of development of lymphomas between hemophiliac and homosexual men remains unknown.

Lymphomas were primarily intermediate- or high-grade in the HIV(+) hemophiliacs, although we also noted one low-grade lymphoma, similar to that described by McGrath et al.25 Unlike Rabkin et a124 who found no cases of CNS lymphoma, we observed three CNS lymphomas and, as noted by ~ t h e r s , ~ these lymphomas were associated with an extremely short survival. The mean CD, at presentation of NHL was extremely low, similar to patients previously r e p ~ r t e d , ~ . ~ ~ including those treated with antiretroviral therapy,26 but lower than a series reported by Levine et al.27 Although CD4 level has been related to the site of tumor presentation and his- tology in nonhemophilic patients, it is possible that CD4 number in hemophilia patients at NHL presentation may reflect not only the result of underlying HIV infection with the quantitative decrease in CD4, but also may be related to the chronic immunosuppression associated with chronic for- eign protein and antigenic exposure with chronic blood t r a n s f ~ s i o n . ' ~ ~ ~ ~ - ~ ~ For instance, it is well known that depressed CD4 number and natural killer activity occurs in hemophiliacs and other transfusion recipients, even in the absence of HIV

Using DNA probes, only one third of the HIV-associated NHL had detectable EBV. This technique is relatively insen- sitive under the best conditions. EBV PCR or EBV probes with greater expression3' may improve detection of EBV in lymphoma tissue, provide a basis for comparison with tumors in homosexual men, and potentially clarify the role of this virus in HIV-related lymphomagenesis. The Prospective Study of lymphomas in the Hemophilia Malignancy Study, currently underway, is addressing this question.





Unlike findings in homosexual men,26 there appeared to be no association of NHL development and the occurrence of opportunistic malignancies or viral infections: none of our 14 HIV(+) patients with NHL experienced a second malignancy nor any acute viral infection at the onset of NHL.

Of the 3 lymphomas developing in HIV(-) hemophiliacs, 2 occurred in the midwestern United States. However, none of the latter HIV(-) hemophiliacs were farmers nor was there any history of herbicide exposure, a suspected risk factor for lymphoma noted in several s t ~ d i e s . ~ ~ , ~ ~

Basal cell carcinomas were significantly more common in HIV(+) hemophiliacs than HIV(-) and occurred at an earlier age in HIV(+) as compared with HIV(-). There are no figures for comparison, although McGrath et al have reported an increase in basal cell cancers in men under 60 in San Fran- c i s ~ ~ . ~ ~ Using the Mayo Clinic registry,17 the age-adjusted incidence of basal cell cancers in HIV(+) hemophiliacs was significantly greater than the incidence in the US population. Therefore, we believe that these findings suggest a significantly increased risk of basal cell cancers in association with HIV infection in the hemophilia population. Moreover, this find- h g suggests that the immunosuppression associated with HIV plays a role in the earlier predisposition to development of basal cell cancers in HIV(+) hemophiliacs. By comparison, studies of other immunosuppressed patients, including congenital immunodeficiency d i~orde r s~ ’*~~ and acquired immunodeficiency, for example, associated with transplanta- t i ~ n ~ ~ have shown increased incidence of lymphomas but no increase in basal cell cancers. It is important to recognize that this study is a retrospective study and that incidence figures may underestimate the malignancy incidence, and specifically the low incidence of basal cell cancers in HIV(-) hemophiliacs. However, it is also likely that basal cell cancers in HIV( +) hemophiliacs are underestimated. Longer follow- up in our Prospective Study will be necessary to verify this hypothesis.

The single case of Kaposi’s sarcoma occurred in a hemophiliac who was also homosexual. It is likely related to his homosexual behavior, given the much greater incidence of this tumor in that risk group. Kaposi’s sarcoma has been reported only rarely as an AIDS-defining illness in hemophiliacs, mostly in homosexual hemophiliacs (John Murphy, MD, Centers for Disease Control, personal communication, August 1 990).24 Some investigators have postulated that the occurrence of Kaposi’s sarcoma in HIV(+) individuals is related to the effects ofgrowth factors, cytokines, viral infections and elaborated factors, or sexually transmitted diseases. Findings in our study continue to support the concept that patients with hemophilia were either not exposed or not sus- ceptible to whatever agent or factors cause Kaposi’s sarcoma. By comparison, although there has been some increase in the incidence of Kaposi’s sarcoma in transplant recipient^,^' there has been no such increase noted in congenital immunodeficiency state^.^^.^'

The incidence of hepatocellular carcinoma, which has been associated with chronic hepatitis B and C infections, was not increased in HIV(+) or HIV(-) hemophiliacs. Despite the high proportion of hemophiliacs with chronic hepatitis B and chronic hepatitis C infection, there appears to be no increase

in the frequency of this tumor. This is in concordance with findings of a survey by Colombo et aI3’ and is similar to the lack of any increase in hepatocellular cancer in either transplant recipients or congenital immunodeficiency state^.^^.^^ With the increasing duration of HIV immunosuppression and improving survival in HIV( +) hemophiliacs treated with antiretroviral drugs,’’ the incidence of hepatocellular cancer, given their chronic hepatitis B and C exposure, could potentially increase.

Of all cancers in HIV( -) hemophiliacs, lymphomas were the only cancer similar in incidence to the US population, with the remaining cancer incidence much lower than US population by SEER rates. The incidence of both basal cell cancer and lung cancer in HIV(-) hemophiliacs were significantly lower than the US population. We are not aware of sun exposure or cigarette exposure data in this population, but these might be of help in understanding the above figures. One could postulate that hemophiliacs, in general, because of the morbidity and disability of their disease, and periodic requirements for braces, casts, and immobilization, likely work or spend less time outdoors or in the sun. Life expectancy before the 1970s and the introduction of clotting factor concentrates was lower than the general population and therefore could have contributed to lower cancer incidence, but our study spans the years from 1978 through 1989, a time during which longevity in this population approached that of the normal population, at least before AIDS.

In summary, the risk of NHL in HIV(+) hemophiliacs is greatly increased over that in HIV( -) hemophiliacs and in the general US population. No increase in the rate of lymphomas has been observed since 1984, distinctly different from the findings in homosexual men. This may relate to: ( I ) lack of further HIV exposure or re-exposure through newer, safer blood products; (2) decrease in the total number of hemophiliacs who are HIV(+) and who have AIDS; (3) shorter survival after AIDS diagnosis; and/or (4) lifestyle differences including that monogamy is typical, and sexually transmitted diseases and parenteral drug use are rare. Basal cell carcinomas also appear to be significantly increased in HIV(+) as compared with HIV( -) hemophiliacs, and occur at an earlier age. It is likely that the observed rates of lymphoma and cancers in this group are conservative for several reasons. First, in this series there was an 11% occult malignancy rate noted at autopsy. Moreover, in autopsy series of patients with AIDS, as many as 20% have been found to have NHL, 40% of which were not detected antemortem.39240 Thus, it is likely that a significant number of NHL may have been missed. Finally, the risk factors associated with the development of these cancers are unknown, but the subject of our ongoing Prospective Study.

ACKNOWLEDGMENT

We thank Barbara Dianne Toth for preparation of the manuscript, Karen Sahan and Cheryl Pistoruis for secretarial support, Iris Ohrams, MD, PhD and Daniella Seminara, PhD, for helpful discussions, and the nurses at the 18 hemophilia centers who, despite their many clinical responsibilities, willingly gave their time and energy to ac- complish this study.




1896 AAGNI ET AL

APPENDIX: PARTICIPATING HEMOPHILIA MALIGNANCY STUDY INVESTIGATORS

The participants in the Hemophilia Malignancy Study are as fol- lows: Participating Institutions and Investigators: Eastern Hemophilia Treatment Centers: Worcester Memorial Hospital, Worcester, MA, D. Brettler, MD, A. Forsberg, RN; Brigham & Women’s Hospital, Boston, MA, B. Ewenstein, MD, H. Mahoney West, PNP; Mt Sinai School of Medicine, New York, NY, L. Aledort, MD, J. McCarthy, RN; Cornell, New York Hospital, New York, NY, M. Hilgartner, MD, M. Cahill-Bordas, RN; University of Pittsburgh School of Med- icine, Pittsburgh, PA, M.V. Ragni, MD, M. Kratofil, RN, Hemophilia Treatment Center, Allentown, PA, L. Barron, MD, A. Odenwelder, RN; University of North Carolina, Chapel Hill, C. McMillan, MD, A. Schlaudecker, RN. Midwestern Hemophilia Treatment Centers included: Great Lakes Hemophilia Foundation, Wauwatosa, WI, J. C. Gill, MD, P. Tim- mons, RN; Northwestern University, Chicago, IL, D. Green, MD, J. Deutsche, RN; Gulf States Hemophilia Center, Houston, TX, W.K. Hoots, MD, M. Canthi, RN; University of Texas School of Medicine Hemophilia Center, North Texas Group, Dallas, G. Buchanan, MD, C. Wozniak, RN and A. Johnson, RN; University of Nebraska Med- ical Center, Omaha, J. Goldsmith, MD, S. Matecko, R N University of Iowa Hospitals, Iowa City, C.T. Kisker, MD, J. McKillip, RN. Western Hemophilia Treatment Centers included: Mountain States Hemophilia Center, University Colorado Health Science Center, Denver, S. Stabler, MD, B. Riske, RN; University of New Mexico, Albuquerque, K. Smith, MD, T.J. Gribble, MD, M. Schwartz, RN; S. California Hemophilia Center, Pasadena, N. Sanders, MD, K. Jackson, RN; Children’s Hospital, Oakland, Oakland, CA, J. Addiego, MD, M.A. Dragone, RN, M.S.; Oregon Health Science University Hemophilia Center, Portland, E.W. Lovrien, MD, R. Ingram, RN.

Pathologists participating in the Hemophilia Malignancy Study included Mt Sinai School of Medicine, New York, NY, A. Schiller, M D St Lukes Hospital, Bethlehem, PA, S. Longo, MD; Children’s Hospital of Wisconsin, Milwaukee, R. Franciosi, MD, Northwestern University, Chicago, IL, S. Rao, MD; University of Nebraska Medical Center, NE Omaha, D. Purtillo, MD; University of Iowa Hospitals, Iowa City, C. Platz, MD; Rocky Mountain Health Care Systems, Denver, CO, P. Stoffel, MD; Children’s Hospital, Los Angeles, CA, T. Triche, MD.

Members of the coordinating center for the Hemophilia Malignancy Study, University of Pittsburgh, PA, include S. Duerstein, RN, Project Coordinator, D. Bass, MS, Project Data Manager and Statistician, R. Jaffe, MBBCh, Project Pathologist, S. Belle, PhD, Project Statis- tician, L. Kingsley, DrPH, Project Epidemiologist, and M. Ragni, MD, Project Director.

REFERENCES

1. Ziegler JL, Drew WL, Miner RC, Rosenbaum E, Lennette ET, Shillitoe E, Cassavant C, Mintz L, Gershow J, Greenspan J, Beckstead J, Yamamoto K. Outbreak of Burkitt’s-like lymphoma in homosexual men. Lancet 2:631, 1982

2. Centers for Disease Control: Revision of the case definition of acquired immunodeficiency syndrome for national reporting-U.S. MMWR 34:373, 1985

3. Ziegler JL, Beckstead JA, Volberding PA, Abrams DI, Levine AM, Lukes RJ, Gill PS, Burkes RL, Meyer PR, Metroka CE, Mou- radian J, Moore A, Riggs SA, Butler JJ, Cabanillas FC, Hersh E, Newell GR, Laubenstein LJ, Knowles D, Odajnyk C, Raphael B, Koziner B, Urmacher C, Clarkson B D Non-Hodgkin’s lymphoma in 90 homosexual men: Relation to generalized lymphadenopathy and the acquired immunodeficiency syndrome (AIDS). N Engl J Med 31 1:565, 1984

4. Knowles DM, Chamulak G, Subar M, Burke JS, Dugan M, Wernz J, Slywotzky C, Pelicci PG, Dalla-Favera R, Raphael B Lym- phoma neoplasia associated with the acquired immunodeficiency syndrome (AIDS). Ann Intern Med 108:744, 1988

5. Kaplan LD, Abrams DI, Feigal L, McGrath M, Kahn J, Neville P, Ziegler J, Volberding PA: AIDS-associated non-Hodgkin’s lymphoma in San Francisco. JAMA 261:719, 1989

6. Subar M, Nen A, Inghirami G, Knowles DM, Dalla-Favera R: Frequent c-myc oncogene activation and infrequent presence of Ep- stein-Barr virus genome in AIDS-associated lymphomas. Blood 72: 667. 1988

7. Harnley ME, Swan SH, Holly EA, Ketter A, Padian N: Tem- poral trends in the incidence of non-Hodgkin’s Lymphoma and se- lected malignancies in a population with a high incidence of acquired immunodeficiency syndrome (AIDS). Am J Epidemiol 128:261, 1988

8. Beral V, Peterman T, Berkelman R, Jaffe H: AIDS-associated non-Hodgkin’s lymphoma. Lancet 337:805, 199 I

9. Centers for Disease Control: HIV/AIDS Surveillance Report. US. Department Health and Human Services, August 1-18, 1991

IO. Fischl M, Richman DD, Grieco MH, Gottlieb MS, Volberding PA, Laskin OL, Leedom JM, Groupman JE, Mildvan D, Schooley RT, Jackson GG, Durack DT, King D The efficacy ofazidothymidine (AZT) in the treatment of patients with AIDS or AIDS-related com- plex. N Engl J Med 317:185, 1987

1 I . Volberding PA, Logakos SW, Koch MA, Pettinelli C, Myers MW, Booth DK, Balfour HH, Reichman RC, Bartlett JA, Hirsch MS, Murphy RL, Hardy WD, Soeiro R, Fischl MA, Bartlett JG, Merigan TC, Hyslop NE, Richman DD, Valentine FT, Corey LC: Zidovudine in asymptomatic human immunodeficiency virus infection: A controlled trial in persons with fewer than 500 CD4-positive cells per cubic millimeter. N Engl J Med 322:94 1, 1990

12. Golden JA, Chernoff D, Hollander H, Feigal D, Conte JE: Prevention of Pneumocystis carinii pneumonia by inhaled pent- amidine. Lancet 1:654, 1989

13. Pluda JM, Yarchoan R, Jaffe ES, Feuerstein IM, Solomon D, Steinberg SM, Wyvill KM, Raubitschek A, Katz D, Broder S: De- velopment of non-Hodgkin’s lymphoma in a cohort of patients with severe HIV infection on long-term antiretroviral therapy. Ann Intern Med 113:276, 1990

14. Gail MH, Pluda JM, Rabkin CS, Biggar RJ, Goedert JJ, Horm JW, Sondik EJ, Yarchoan R, Broder S: Projections of the incidence of non-Hodgkin’s lymphoma related to acquired immunodeficiency syndrome. J Natl Cancer Inst 83:695, 1991

15. Ragni MV, Kingsley LA, Chou SJ: The effect ofantiviral therapy on the natural history of human immunodeficiency virus infection in a cohort of hemophiliacs. J AIDS 5:120, 1992

16. Ries LAG, Hankey BF, Miller BA, Hartman AM, Edwards BK: Cancer Statistics Review 1973-1 988. National Cancer Institute. NIH Publication No. 91-2789, 1991

17. Chuang TY, Popescu A, Su WPD, Chute CG: Basal cell cancer: A population-based incidence study in Rochester, Minnesota. J Am Acad Dermatol 22:4 13, 1990

18. Bailer JC, Ederer F Significance factors for the ratio of a Pois- son variable to its expectation. Biometrics 20:639, 1964

19. Ragni MV, Winkelstein A, Kingsley LA, Spero JA, Lewis JH: 1986 Update of HIV seroprevalence, seroconversion, AIDS incidence, and immunologic correlates of HIV infection in patients with hemophilia A and B. Blood 70:786, 1987

20. Centers for Disease Control: HIV Infection Reporting-United States MMWR 38:496, 1989

2 1. The Non-Hodgkin’s Lymphoma Classification Project: Na- tional Cancer Institute Sponsored Study of Classification of non- Hodgkin’s lymphomas: Summary and description of a working formulation for clinical usage. Cancer 49:2112, 1982





22. Cremer KJ, Spring SB, Gruber J: Role of human immunodeficiency of virus type I and other viruses in malignancies associated with acquired immunodeficiency syndrome. J Natl Cancer Inst 82: 1016, 1990

23. Rabkin CS, Biggar RJ, Horm JW: Increasing incidence of cancers associated with the human immunodeficiency virus epidemic. Int J Cancer 47:692, I99 I

24. Rabkin CS, Hilgartner MW, Hedberg K, Aledort LM, Hatzakis A, Eichinger S, Eyster E, White GC, Kessler CM, Lederman MM, de Moerloose P, Bray GL, Cohen AR, Andes WA, Manco-Johnson M, Schramm W, Kroner BL, Blattner WA, Goedert JJ: Incidence of lymphomas and other cancers in HIV-infected patients with hemophilia. JAMA 267:1090, 1992

25. McGrath MS, Ng VL: Human retrovirus associated malignancy, in Benz C, Lin E, (eds): Oncogenes. Norwell, MA, Kluwer Acad Publ, 1989, p 267

26. Moore RD, Kessler H, Richman DD, Flexner C, Chaisson RE: Non-Hodgkin’s lymphoma in patients with advanced HIV infection treated with zidovudine. JAMA 265:2208, 1991

27. Levine AM, Sullivan-Halley J, Pike MC, Rarick MU, Loureiro C, Bernstein-Singer M, Willson E, Brynes R, Parker J, Rasheed S, Gill PS: Human immunodeficiency virus-related lymphoma: Prog- nostic factors predictive of survival. Cancer 68:2466, 199 1

28. Gascon P, Zoumbos NC, Young NS: Immunologic abnormalities in patients receiving multiple blood transfusions. Ann Intern Med 100:173, 1984

29. Kaplan J, Sarnaik J, Gitlin J, Lusher J: Diminished helper/ suppressor lymphocyte ratios and natural killer activity in recipients of repeated blood transfusions. Blood 64:308, 1984

30. Kaplan J, Sarnaik J, Levy J: Transfusion-induced immunologic abnormalities not related to AIDS virus. N Engl J Med 313:1227, 1985

31. Ludlam CA, Tucker J, Steel CM, Tedder RS, Cheingsong- Popov R, Weiss RA, McClelland DBL, Philip I, Prescott RJ: Human T-lymphotropic virus type 111 (HTLV-111) infection in seronegative hemophiliacs after transfusion of factor VIII. Lancet 2:233, 1985

32. MacMahon EME, Glass JD, Hayward SD, Mann RB, Becker PS, Charache P, McArthur JC, Ambinder RF: Epstein-Barr virus in AIDS-related primary central nervous system lymphoma. Lancet 338: 969, 1991

33. Wide DT, Semenciw RM, Wilkins K, Riedel D, Ritter L, Morrison HI, Mao Y: Mortality study of Canadian male farm op- erators: Non-Hodgkin’s lymphoma mortality and agricultural prac- tices in Saskatchewan. J Natl Cancer Inst 82575, 1990

34. Hoar SK, Blair A, Holmes FF, Boysen CD, Robe1 RJ, Hoover R, Fraumeni JF: Agricultural herbicide use and risk of lymphoma and soft-tissue sarcoma. JAMA 256:1141, 1986

35. Penn I: The changing pattern of post-transplant malignancies. Transplant Proc 23: 1 I O I , I99 1

36. Stingini P, Carobbi S, Sansone R, Lombard0 C, Santi L Mo- lecular epidemiology of cancer in immune deficiency. Cancer Detect Prev 15:115, 1991

37. SwiR M, Chase CL, Morrell D: Cancer predisposition of ataxia- telangiectasia. Cancer Genet Cytogenet 46:21, 1990

38. Colombo M, Mannucci PM, Brettler DB, Girolami A, Lian ECY, Rodeghiero F, Sharrer I, Smith PS, White G C Hepatocellular carcinoma in hemophilia. Am J Hematol 37:243, 1991

39. Loureiro C, Gill PS, Meyer PR, Rhodes R, Rarick MU, Levine AM: Autopsy findings in AIDS-related lymphoma. Cancer 62:735, 1988

40. Reichert CM, OLeary TJ, Levens DL, Simrell CR. Macher AM: Autopsy pathology in the acquired immune deficiency syndrome. Am J Pathol 112:357, 1983




1993 81: 1889-1897

Kisker and SP StablerMV Ragni, SH Belle, RA Jaffe, SL Duerstein, DC Bass, CW McMillan, EW Lovrien, LM Aledort, CT lymphomas and other malignancies in patients with hemophiliaAcquired immunodeficiency syndrome-associated non-Hodgkin's

http://www.bloodjournal.org/content/81/7/1889.full.htmlUpdated information and services can be found at:

Articles on similar topics can be found in the following Blood collections

http://www.bloodjournal.org/site/misc/rights.xhtml#repub_requestsInformation about reproducing this article in parts or in its entirety may be found online at:

http://www.bloodjournal.org/site/misc/rights.xhtml#reprintsInformation about ordering reprints may be found online at:

http://www.bloodjournal.org/site/subscriptions/index.xhtmlInformation about subscriptions and ASH membership may be found online at:

Copyright 2011 by The American Society of Hematology; all rights reserved.Society of Hematology, 2021 L St, NW, Suite 900, Washington DC 20036.Blood (print ISSN 0006-4971, online ISSN 1528-0020), is published weekly by the American


http://www.bloodjournal.org/content/81/7/1889.full.html

http://www.bloodjournal.org/site/misc/rights.xhtml#repub_requests

http://www.bloodjournal.org/site/misc/rights.xhtml#reprints

http://www.bloodjournal.org/site/subscriptions/index.xhtml





acquired immunodeficiency syndrome-associated non-hodgkin ...€¦ · acquired immunodeficiency...

Documents