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Blood, Vol. 92 No. 10 (November 15), 1998:
pp. 3557-3561
Risk Factors for Adult T-Cell Leukemia Among Carriers of Human
T-Lymphotropic Virus Type I
By
Michie Hisada,
Akihiko Okayama,
Shigemasa Shioiri,
Donna L. Spiegelman,
Sherri O. Stuver, and
Nancy E. Mueller
From the Departments of Epidemiology and Biostatistics, Harvard
School of Public Health, Boston, MA; and the Second Department of
Internal Medicine, Miyazaki Medical School, Miyazaki, Japan.
 |
ABSTRACT |
The presence of circulating "flower cells" and a low
prevalence of antibody to Tax regulatory protein of human
T-lymphotropic virus type I (HTLV-I) are characteristics of adult
T-cell leukemia (ATL). To examine the predictability of levels of
HTLV-I antibodies and of flower cell-like abnormal lymphocytes (Ably)
for the risk of ATL among asymptomatic HTLV-I carriers, we
prospectively evaluated the levels of viral markers of five HTLV-I
carriers who developed ATL and 38 age-, sex-, and screen-matched
HTLV-I-positive controls in the Miyazaki Cohort Study. After
accounting for matching factors, Ably level was slightly, but not
significantly, higher among cases than among controls (P = .13). Anti-HTLV-I (odds ratio [OR] = 1.6 per twofold dilution;
95% confidence interval [CI] 0.94, 3.8) was associated with ATL
diagnosis, but antibody to Tax regulatory protein (anti-Tax) was not
(OR = 0.78; 95% CI 0.26, 1.7). Anti-Tax level was low for all ATL
cases for up to 10 years preceding their diagnosis, independent of the
level of anti-HTLV-I titer. HTLV-I carriers with a higher anti-HTLV-I
titer and a lower anti-Tax reactivity may be at greatest risk of ATL.
© 1998 by The American Society of Hematology.
| |
INTRODUCTION |
ADULT T-CELL LEUKEMIA (ATL) is caused by
human T-lymphotropic virus type I (HTLV-I) infection,1,2
generally many decades after initial infection.3-5 It is
believed that carriers who have acquired infection early in life are at
greatest risk of ATL.6 One of the features of ATL is the
unique morphology of leukemic cells with an indented or convoluted
nucleus ("flower cells"). The level of flower cells is a marker
to distinguish clinical subtypes of ATL and to monitor progression from
smoldering to overt ATL.7 Asymptomatic HTLV-I carriers
often have a very low, but detectable, level of circulating abnormal
lymphocytes (Ably) that closely resemble the flower cells.8
In the population-based Miyazaki Cohort Study, we have found that the
presence and levels of Ably is highly correlated with HTLV-I proviral
load.9,10 The presence of Ably also is associated with a
greater proportion of CD4+/CD25+ cells, a
predominant phenotype of ATL cells.11 Moreover, persistent proliferation of HTLV-I-infected clones has been shown primarily in
CD4+ cells in asymptomatic carriers with a high proviral
load.12 These data suggest that HTLV-I-infected T-cell
clones are likely expanding among Ably-positive carriers and that the
presence of Ably may correlate with the risk of ATL. High levels of
Ably in the presence of the symptoms of immune suppression has been
shown to predict the subsequent development of ATL.13
However, it is uncertain if low levels of Ably among asymptomatic
HTLV-I carriers predict the onset of ATL.
Although the precise mechanism of HTLV-I oncogenesis is unknown, the
enhanced expression of Tax regulatory protein, a viral gene product
that transactivates transcription of viral mRNA and other host genes
that control cell proliferation, is believed to play a central role in
HTLV-I oncogenesis.14,15 However, the level of Tax mRNA has
been shown to be low in ATL cells,16 which has led to the
hypothesis that a continuous expression of Tax gene product may not be
required for the maintenance of the malignant phenotype.17
This theory is supported by our observation of a lower prevalence of
antibody to the Tax regulatory protein (anti-Tax) among ATL cases
compared with asymptomatic HTLV-I carriers.18 A lower
prevalence of anti-Tax also has been found in the subset of HTLV-I
carriers with a detectable level of Ably (>0.6%) compared with those
without Ably,10 suggesting that anti-Tax reactivity may be
low among those at risk of ATL before their clinical diagnosis.
In this prospective study, we describe changes in prediagnostic viral
markers of ATL cases and examine risk factors for ATL in a matched
case-control study nested within the Miyazaki Cohort Study.
| |
MATERIALS AND METHODS |
Study subjects.
The Miyazaki Cohort Study was established in 1984 in two HTLV-I endemic
villages in Miyazaki Prefecture, Japan. Nearly 27% of 1,960 cohort
members enrolled as of August 1996 are HTLV-I seropositive at
baseline.19 The cohort has been followed in the context of
free health examinations offered annually by the government for those
aged 40 or older. Those younger than 40 years who come to these
examinations also are enrolled in the study. The annual screens consist
of a physical examination, other routine health examinations, and blood
tests. A detailed baseline questionnaire collects demographic data, as
well as information on alcohol and smoking status. A shorter
instrument completed at each follow-up screening updates
information on interval health history and symptoms and current alcohol
and smoking behavior. The study protocol was approved by the
Institutional Review Boards of the Miyazaki Medical School and the
Harvard School of Public Health. Informed consent was obtained from all
study subjects.
The subjects of this analysis are the five HTLV-I carriers who
developed ATL during the follow-up through December, 1995, and 38 HTLV-I-positive controls. ATL cases were identified through annual
census or reports from next-of-kin. The diagnosis was confirmed by
medical records for three of the five cases; two others were confirmed
by reports from the local government nurses. Using a nested
case-control sampling,20 the controls were selected from within the cohort among HTLV-I carriers who were alive and free of ATL
diagnosis when the case died and were matched to the cases by age
(± 5 years), sex, and study screens attended. The number of
controls selected per case varied based on availability of eligible
controls (Table 1).
Laboratory methods.
For each serum sample, positivity of anti-HTLV-I was tested by passive
particle agglutination assay (Serodia-HTLV, Fujirebio, Tokyo, Japan) at
a dilution of 1:16. Positive sera were titered by serial twofold
dilution. Anti-Tax reactivity was measured by a Western blot
assay using a recombinant Tax gene product as the antigen.21-23 Reactivity to recombinant-Tax protein was
quantified by comparison with anti-Tax positive control sera at
dilutions of 1:100, 1:500, 1:2500, or higher (+++, ++, +, or ±),
where a lower dilution corresponds to a higher anti-Tax
reactivity. Multiple measurements of viral markers were available
for subjects who attended more than one screening during the follow-up.
Because the standard method of viral marker measurement has changed
over time, all sera from the screens selected for case-control
comparison in the present study were retested for anti-HTLV-I titer
and anti-Tax reactivity in 1996 to attain internal consistency.
Peripheral blood smears were obtained from either the ear lobe or a
finger prick, by smearing one drop onto a glass slide. The slides were
fixed by methanol and stained with Giemsa. All blood smears were read
blinded to ATL diagnosis. The identification of Ably followed the
criteria by Kondo et al.8 The number of Ably among 500 leukocytes was recorded in percent.
Statistical analysis.
The mean age, leukocyte count, Ably level, and geometric mean of
anti-HTLV-I titer were compared between cases and controls using
Wilcoxon signed-rank test. The prevalence of smoking and the presence
of anti-Tax reactivity were compared using McNemar's test. The odds
ratio (OR) and 95% confidence interval (CI) for the association of ATL
diagnosis with viral markers and Ably level were estimated from exact
conditional logistic regression (LOGXACT, 1996, Cytel, Cambridge, MA).
For cases with multiple observations, the first measurement of HTLV-I
viral markers, Ably, and smoking status were used for calculation of
the ORs. In the logistic regression models, anti-HTLV-I titer by
serial twofold dilution and anti-Tax reactivity were treated as
ordinal categorical variables with 10 and five levels, respectively.
Leukocyte count, Ably level, and age were treated as continuous
variables. Smoking status was dichotomized, with current- and
ex-smokers combined as ever-smokers. Statistical significance was based
on two-sided tests.
| |
RESULTS |
Five ATL cases (3 men, 2 women) developed during the study period. One
additional patient was diagnosed with ATL before his enrollment in the
study. The characteristics of these ATL cases are summarized in
Table 1. The mean age at death of these six cases was 73 years. Samples had been taken from these cases up to 10 years preceding their death. Four of the five incident cases had
multiple measurements of prediagnostic viral markers, which showed
virtually no change in level over time. Anti-Tax reactivity was
relatively low or undetectable for all cases. Only one case (case 3)
had detectable level of Ably (>0.6%) before diagnosis. All male
cases were long-term smokers, whereas both female cases were
never-smokers.
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Table 1.
Prediagnostic Changes in Viral Markers, Ably, and
Leukocyte Count Among the Six ATL Cases in the Miyazaki Cohort
Study
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Because ongoing therapy may have modified the levels of Ably and of
viral markers, the prevalent ATL case (case 1) was excluded from
further analysis. The characteristics of the five ATL cases as compared
with the 38 controls are summarized in
Table 2. After accounting for the matching
factors, neither the geometric mean of anti-HTLV-I titer (1,782 v 467, P = .31) nor prevalence of anti-Tax reactivity
(20% v 32%, P = .57) was different between cases and
controls. The prevalence of ever-smokers and the mean leukocyte count
were also similar for cases and controls. The mean Ably level was
slightly, but not significantly, higher among cases compared with
controls (0.36% v 0.24%, P = .13).
Table 3 shows the distribution of anti-Tax
reactivity among cases and controls by their anti-HTLV-I titer. Among
controls, the proportion of anti-Tax positivity increased with
anti-HTLV-I titer level. The positive correlation between the levels
of anti-HTLV-I titer and anti-Tax reactivity were comparable to those
in the entire study cohort of HTLV-I carriers (Table 3). In contrast,
there was no apparent correlation between these two viral markers among ATL cases.
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Table 2.
Comparison of Demographic Characteristics and HTLV-I
Viral Markers Between Five ATL Cases and 38 Age-, Sex-, and
Screen-Matched Controls in the Miyazaki Cohort Study, Adjusted for the
Matching Factors
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Table 3.
Distribution of Anti-Tax Reactivity by the Level of
Anti-HTLV-I Titer Among Cases, Controls, and All HTLV-I Carriers
in the Study Cohort
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Anti-HTLV-I titer was associated with ATL diagnosis (OR = 1.6 per twofold dilution; 95% CI 0.95, 3.8), albeit not to a
statistically significant degree (P = .09)
(Table 4). Anti-Tax was not predictive (OR = 0.78; 95% CI 0.26, 1.7). With mutual adjustment for anti-HTLV-I titer and anti-Tax reactivity, the OR for anti-HTLV-I titer and anti-Tax reactivity was 1.6 (95% CI 0.95, 3.5) and 0.74 (95% CI 0.21, 1.8), respectively. Smoking and leukocyte counts were not significant
predictors of ATL. We were unable to obtain a stable estimate for the
association of Ably level and the risk of ATL in the logistic
regression analysis due to sparse data.
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Table 4.
Univariate Association of ATL With Viral Markers,
Smoking, and Leukocyte Count Using Exact Conditional Logistic
Regression
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| |
DISCUSSION |
The rare occurrence and long latency period of ATL has posed
substantial difficulties in community-based, prospective studies of
this malignancy. The present study examined the characteristics of ATL
cases in a well-defined adult population endemic for HTLV-I infection.
The mean age of ATL mortality, 73 years, was much higher than the
national average of 57 years among the general Japanese population,24 reflecting the high average age (60 years) of the HTLV-I-positive cohort members in the Miyazaki Cohort.
Our analysis found a 1.6-fold increase in the risk of ATL per twofold
increase in anti-HTLV-I titer, indicating that those carriers with the
highest titer ( 1:8,192) will have an approximately 70-fold risk of
developing ATL relative to those with the lowest titer level (1:16).
Given a strong positive correlation between anti-HTLV-I and proviral
load among asymptomatic carriers in our cohort,25 the
observed association of anti-HTLV-I with ATL diagnosis may imply a
similar association of proviral load with this malignancy.
As would be predicted from our previous finding of a lower prevalence
of anti-Tax reactivity among ATL cases,18 the analysis of
prediagnostic sera of the ATL cases in the present study showed that
anti-Tax reactivity was low or undetectable for all cases for up to 10 years preceding their diagnosis. Given the observed higher anti-HTLV-I
titer among the ATL cases compared with asymptomatic carriers, as well
as our previous report of a strong correlation between anti-HTLV-I
titer and anti-Tax positivity among asymptomatic carriers,21 it seems possible that a loss of anti-Tax
occurs in the process of ATL development. Those carriers at risk of ATL also may be inherently more likely to have low anti-Tax reactivity.
ATL cells are less likely to express detectable level of Tax
mRNA.26 Because Tax protein is a known target of cytotoxic T-lymphocyte (CTL) immunity,16,27 it seems plausible that
ATL cells that do not express Tax are likely to escape cell lysis mediated by the CTL.2 Thus, one explanation for the
observed low anti-Tax reactivity among ATL cases may be their low CTL
response against HTLV-I. Determinants of CTL response, such as the
human leukocyte antigens, may play a role in determining the host's susceptibility to ATL.28-30 In addition, a large proportion
of ATL cells has been found to carry deleted HTLV-I genomes, raising the possibility that genetic events that render an altered
immunogenecity to the Tax protein may be crucial in the development of
ATL.31 Mutations in the Tax gene that lead to an altered
CTL response against Tax protein32 or changes in viral
transcription and translation33 also could result in the
loss of anti-Tax reactivity. We were unable to evaluate these
possibilities due to the lack of preserved lymphocyte specimens.
Ably level has been shown to spontaneously fluctuate in ATL
patients.13 Because of the large amount of
within-individual variability, there have been arguments for and
against the use of Ably level as a marker for risk of
ATL.9,34 In the present study, the mean level of
prediagnostic Ably of the ATL cases was only slightly higher than that
of their matched controls. The possibility exists that the
predictability of Ably depends on clinical ATL diagnosis. However, due
to small number of cases, no further analysis could be conducted. Thus,
our findings must be interpreted with caution.
Although the use of population-based controls allowed the comparison of
characteristics between cases and controls with minimal selection bias,
there are several important limitations to the present study. A few
eligible controls could not be included in the analysis because one or
more serum samples were no longer available. However, exclusion of
these subjects is unlikely to have affected the ORs substantially, as
unavailability of specimens was random. Any misclassification of
explanatory variables such as Ably measurement and smoking history
would be unrelated to ATL diagnosis and thus have biased the estimates
only towards the null. We were unable to evaluate our data with
additional adjustment for proviral load and Tax mRNA level in
multivariate analysis because preserved lymphocyte specimens were
unavailable for the majority of ATL cases and controls. Statistical
power to detect significant differences was clearly limited by the
relatively small number of observations.
In sum, the present analysis suggests that HTLV-I carriers with a
higher anti-HTLV-I titer are at greatest risk of ATL and that the
level of anti-HTLV-I and anti-Tax reactivity is discorrelated before
diagnosis. Additional analysis of Tax mRNA expression, proviral load,
HTLV-I clonality, as well as direct measurement of CTL response is
needed to provide further insights into the oncogenic process of this
virus infection. Investigation of correlates of the host immune
response in this population in relation to HTLV-I viral markers may be
useful to shed light on the association between host factors and the
risk of ATL.
| |
FOOTNOTES |
Submitted April 23, 1998;
accepted July 3, 1998.
Supported by Public Health Service Grant No. 2RO1-CA38450 (National
Cancer Institute), National Institutes of Health, Department of Health
and Human Services.
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.
Address reprint requests to Michie Hisada, MD, MPH, ScD, Viral
Epidemiology Branch, Division of Cancer Epidemiology and Genetics,
National Cancer Institute, 6130 Executive Blvd, EPN434, Rockville, MD
20852; e-mail: mh280i{at}nih.gov.
| |
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Abstract
Introduction