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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 92 No. 4 (August 15), 1998:
pp. 1160-1164
Second Malignancies in Patients With Hairy Cell Leukemia in British
Columbia: A 20-Year Experience
By
Wing Y. Au,
Richard J. Klasa,
Richard Gallagher,
Nhu Le,
Randy D. Gascoyne, and
Joseph M. Connors
From the Divisions of Medical Oncology, Cancer Control Research, and
Pathology, British Columbia Cancer Agency and the University of British
Columbia, Vancouver, Canada.
 |
ABSTRACT |
The purpose of this study was to compare the relative
risk of second malignancies in a cohort of patients with hairy cell leukemia (HCL) against the normal population. Potential effects of type
of treatment and duration of follow-up and the site distribution of
cancer were also examined. Between 1976 and 1996, 117 patients were
diagnosed with HCL in British Columbia who were referred to the British
Columbia Cancer Agency (BCCA) for treatment. All additional
malignancies were traced using a provincial population-based cancer
registry and follow-up records from the BCCA. There were 90 men and 27 women. Median age at diagnosis was 53 years. The median follow-up time
was 68 months. Twenty-three patients underwent primary splenectomy, 65 received interferon alpha, 24 deoxycoformycin, and 67 cladribine
(2-chlorodeoxyadenosine). Thirty-six patients had an additional
malignancy (30.7%) with a total of 44 tumors. Six patients (5.1%) had
two or more malignancies. Twenty-five patients had malignancies
diagnosed after HCL (21.3%), three concurrent with HCL (2.6%), and 12 preceding HCL (10.2%). Second tumors (n = 28 tumors) occurred at a
median of 40 months after HCL (range, 3 to 167). The relative rate (RR)
of second malignancy among men and women was 2.91 (P < .001)
and 1.65 (P = .23), respectively, compared with age and
secular trend-matched controls. There were eight prostate cancers, nine
nonmelanoma skin cancers, two lung cancers, and four gastrointestinal
adenocarcinomas. The RR (90% confidence interval [CI]) in the
various treatment groups were: splenectomy (RR = 0.21 to 3.81),
purine analogues (RR = 0.60 to 5.69), interferon then purine
analogues (RR = 1.60 to 4.31), interferon alone (RR = 1.57 to
8.40). Cancer risk peaked at 2 years after HCL (RR = 4.13) and fell
steadily afterwards, reaching a RR of 1.82 at 6 years. Twenty patients
died, six due to HCL, 10 due to second malignancies, and four of
unrelated causes. HCL patients appear to be inherently prone to
malignancies. This appears to be more related to HCL tumor burden than
to genetic predisposition or treatment effect. RR tends to fall with
time after effective treatment. However, close monitoring for and
vigorous prevention of cancer in HCL patients is advisable.
© 1998 by The American Society of Hematology.
| |
INTRODUCTION |
HAIRY CELL LEUKEMIA (HCL) is a relatively
uncommon chronic lymphoid leukemia characterized by circulating
abnormal lymphocytes of distinctive morphology, immunophenotype, and
cytochemical properties.1 The treatment of HCL has been
revolutionized by the sequential introduction of
splenectomy,2 interferon (IFN),3
and purine analogues4 as the standards of treatment. With
the use of cladribine (2-chlorodeoxyadenosine, 2CDA) for treatment, a
sustained complete remission can be attained for over 90% of patients
and many may well be cured.5 2CDA has also been successful
as secondary treatment in patients relapsing from other forms of
treatment or earlier courses of 2CDA.6
With prolonged survival, it has been recognized that many HCL patients
have a tendency to develop further malignancies. Scattered case
reports7-10 and individual single center
series11-13 described the range of malignancies found.
However, inconsistent reporting policies and incomplete follow-up have
rendered it difficult to quantify the risk. The Lymphoma Tumor Group of
the British Columbia Cancer Agency (BCCA) is referred all cases of HCL
within the province for pathological review, tertiary oncology care,
and follow-up. All malignancies are required to be reported to a
provincial population-based cancer registry maintained by the BCCA.
Here we report on 117 patients with HCL diagnosed over a 20-year period
and followed prospectively. The analysis takes advantage of the cancer
registry data from within our stable geographically defined at risk
population. This allowed us to quantify relative risks for male and
female cancer incidence compared with the general provincial population over a defined period of observation.
| |
MATERIALS AND METHODS |
The clinical records of 117 patients with HCL were reviewed for
clinical, family, and smoking history. All pathologic material was
reviewed by an experienced hematopathologist at BCCA. Cases were
included only if they demonstrated characteristic morphology in
peripheral blood or bone marrow smears, typical bone marrow biopsy
histology, positivity for CD11c, CD25, and CD103 by flow cytometric
immunophenotyping (when available) and cytochemical positivity for
tartrate resistant acid phosphatase (TRAP). Corresponding computerized
files of all malignancies among the 117 HCL patients were requested
from the Cancer Registry for cross-reference to the date and nature of
the other malignancies. Mortality data on all deceased cases were also
obtained.
Standardized cancer incidence ratios (SIRs) were used to compare the
cancer incidence of the HCL patients with those of the BC general
population. Cancer incidence rates in BC were calculated by 5-year age
groups and 5-year calendar periods dating back to 1969, using rates
derived from the population-based BC Cancer Registry.14
Tests of significance for the SIRs were calculated assuming the
observed number of second malignancies followed a Poisson distribution
with mean given by the expected number of second malignancies based on
BC population rates.15 One sided t-test and 90%
confidence intervals (CI) corresponding to a 5% significance level
were used. Actuarial proportion of patients without a second malignancy
was also calculated.16
| |
RESULTS |
Between 1976 and 1996, 117 patients presented to BCCA with HCL. There
were 90 men and 27 women (77% v 23%). Taking the mean male
and female population of BC between 1975 and 1991 as 1.42 and 1.45 million, respectively, the crude incidence rate was 3.16 and 0.93 per
million per year for men and women. Median age was 53 years (range, 23 to 85). The median follow-up time was 68 months (range, 1 to 212).
Three patients were lost to follow-up and not available for complete
analysis.
The study group included patients enrolled in four clinical trials: a
phase I study of lymphoblastoid IFN,17 a phase III trial of
IFN alpha at two different doses,18 a trial of splenectomy versus IFN alpha,19 and a trial of IFN alpha versus
2-deoxycoformycin (DCF).20 From 1976 to 1981, 23 patients
(19.7%) had splenectomy as part of the primary treatment, 14 as part
of combination treatment. From 1979 to 1992, 65 patients (55.5%)
received IFN (0.2 MU/m2 to 2 MU/m2 three times
weekly) as part of first line treatment. Twenty-one of these were
subsequently treated with 2CDA for disease persistence or relapse. From
1984 to 1991, 24 cases (20.5%) were treated with DCF (4 mg/m2 every 2 weeks). From 1991, 46 cases were initially
treated with 2CDA (0.1 mg/kg/day for 7 days). In total, 67 cases (57.2%) received 2CDA at some time. Three cases were not
treated. Fifty-six patients (47.8%) received more than one treatment
modality.
Thirty-six patients had an additional malignancy (30.7%) with a total
of 44 separate neoplasms (Table 1). Six
patients (5.1%) had two or more malignancies in addition to HCL.
Twenty-five cases (21.3%) presented after HCL, three cases (2.6%)
concurrent with HCL, and 12 cases (10.2%) preceded HCL. The preceding
tumors (n = 13) occurred at a median of 85 months before HCL (range, 1 to 336). Antineoplastic treatments given before the diagnosis of HCL
included chemotherapy in five cases, radiotherapy in two cases, and
excision in six cases. Second tumors (n = 28) occurred at a median of
40 months after HCL (range, 3 to 167). There were seven prostate
cancers, nine nonmelanoma skin cancers, two lung cancers, and four
gastrointestinal adenocarcinomas after HCL. Eleven patients had a
history of cancer in first degree relatives. Three patients were
smokers (including the two who developed lung cancers) and 13 were
ex-smokers.
Among 87 men, the actuarial time to a 50% risk of developing a second
cancer was 150 months (Fig 1). The
corresponding risk at 150 months was 15% in the 27 women. Among cases
with a subsequent malignancy, 10 had been treated with splenectomy,
seven with IFN, seven with 2CDA, and four with DCF. Twenty patients
died, 10 (50%) due to second cancer, six due to HCL, and four of
unrelated causes.
View larger version (15K):
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| Fig 1.
Kaplan Meier actuarial analysis of the time to
development of a second malignancy in male and female patients with
HCL.
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The increased risks for second malignancies were calculated including
and excluding skin malignancies and results were similar (Table 2). Among 87 men, there was an
increased relative rate (RR) of 2.91 for all cancers (P < .001, 90% CI 1.97 to 4.15). The RR in 27 women was 1.65, but did not
reach statistical significance. Taking all patients into consideration,
the RR is 2.60 times that of an age, geographical, and secular period
matched background population (P < .001). When nonmelanoma
skin cancers and carcinoma in situ were excluded, the RRs were similar
(men RR = 3.03; women RR = 2.30, overall RR = 2.86). Among the subtypes
of cancers, the RR for prostate cancer and colon cancer were 3.95 (P < .001) and 5.83 (P = .016), respectively. The
number of events in the other cancer groups was too low for accurate
estimation of relative risks. The RR varied with time (Table 2). The
increased risk of second malignancy peaked between 1 and 2 years after
diagnosis (RR = 4.13; P = .001; CI 2.05 to 7.45). It then fell
steadily to a level of RR = 1.82 at 6 years and beyond. An increase in relative risk is found with all four types and combinations of treatment (RR 1.25 to 4.80) (Table 2). The increase in risk was highest
and statistically significant in the groups treated with IFN (90% CI
RR = 1.57 to 8.40 ) or IFN and purine analogues (90% CI RR = 1.60 to
4.31). However, the different groups have been followed up for variable
times and the 90% CIs for RR of all four groups overlapped
extensively.
View this table:
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Table 2.
Increased Risk in Second Malignancy in HCL Patients by
Sex, Cancer Subtype, Time After Diagnosis and Treatment Type
|
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| |
DISCUSSION |
We report a series of HCL patients from a stable geographically defined
population treated sequentially according to different protocols over a
period of 20 years. The age, sex ratio, and overall outcome were not
different from previous large reported series. However, we find one of
the highest rates (22%) of further malignancies among these patients.
Previous series have reported an incidence varying from 2% to 19%
(Table
3).11-13,21-29 Our ability to detect a high
incidence may be attributed to a long and complete follow-up for most
cases. The published literature is, however, heterogeneous in many
ways. Follow-up periods varied and some series excluded skin
malignancies.13,24 In several series, second
cancers were reported only as part of mortality data.25-27
Four studies compared the treatment population with SIRs from national
cancer registries and either did12 or did
not13,28,29 demonstrate significantly increased risk. Our
study is based on a stable geographically defined population with a
matched control population both from a single Canadian province. The
only other population-based epidemiological study conducted in Los
Angeles county showed similar results, reporting an annual incidence of
HCL of 2.9 and 0.6 per million among men and women.24 The
incidence of multiple primary cancers within the study period was 14%,
twice that of other cancer subtypes in the study. However, the absolute
values of the RR were not reported. Incidence was again highest
immediately around the time of HCL diagnosis.
Our results show that the incidence of malignancy is high both before
and after the diagnosis of HCL. A comparison with the provincial
population shows that this is neither due to local screening or
referral bias, nor due to the increasing age of the cohort or extended
follow-up. Increase in incidence of second cancers has also been noted
in other lymphoproliferative disorders such as chronic lymphocytic
leukemia (CLL), but with a much lower relative risk (RR
1.32 to 1.40).30 The increased cancer risk in HCL patients
may be related to immunosuppression due to HCL31 or its
treatment.32,33 It has been proposed previously that better
treatment may have allowed time for more secondary malignancies to
develop in an aging population.34 However, the development of second malignancies is highest in the period up to 2 years after
diagnosis. Taking into account the lag time for a neoplasm from
initiation to reach a clinically detectable level, these data support the theory that the cancer risk could at least
be partly related to immunosuppression or some other effect associated with the HCL clone itself. A residual risk persisted for up to 6 years
posttreatment. The steady fall in RR, however, suggests that the risk
is reduced by effective treatment. The high incidence of malignancy
occurring before (10.2%) and concurrent (2.6%) with HCL also
suggests some pretreatment predisposition to cancer. High incidence
of malignancies preceding and concurrent with HCL has also been noted
in another population-based study.24 Five of our patients
had a total of three to five separate malignancies in their clinical
histories. Such cases have also been noted in previous series (2 of 13 in Kampmeier et al12 and seven of 26 in Kurzrock et
al13). The combined data argue strongly for an inherent
predisposition to malignancies due to the HCL clone itself.
In previous studies, IFN and purine analogues have not been shown to
cause more cancers compared with splenectomy.13,28 Our
results showed an increased risk of second malignancies associated with
all types and combinations of treatments (Table 2), including splenectomy alone. This risk reached statistical significance only in
the groups treated with IFN alone or IFN and purine analogues. This may
have been influenced by differences in the follow-up time and numbers
of patients in the groups. The 90% CI of all four groups overlapped,
so our data do not provide evidence that IFN or purine analogue caused
more malignancies compared with splenectomy. However, it is interesting
to note that the least effective treatment of HCL, that is, IFN, was
associated in our data with the highest residual risk of second
neoplasm. More effective treatment with purine analogues, and longer
time from that effective treatment, both correlated with lowered risk
of second cancer, suggesting that it is the HCL itself that increases
predisposition to second cancers.
The distribution of various types of cancer followed that of the
general population. Previous reports of preferential increase in
leukemia12 and lymphoma13 were not supported by
our data. The large number of case reports of secondary lymphomas after HCL may be largely due to reporting bias due to availability of clonality analyses.35-39 The high incidence of
adenocarcinomas of the gastrointestinal tract and lung-based carcinomas
has been previously recognized (Table 3). The incidence of prostate
cancers (seven secondary cases, one concurrent case; median age, 68) is also significantly higher than the control population. A high incidence
of skin malignancies has been reported from series that included data
on skin cancers (Table 3). Our data further show that the RR for second
cancer is increased by the same extent whether or not skin malignancies
are included.
HCL is one of the few highly treatable disseminated cancers and only
six (5.1%) of our patients died of complications related to the
disease. However, more than twice that number died of second malignancies. The observation that the incidence of second neoplasms is
highest near and immediately after the diagnosis of HCL is intriguing.
Given the indolent course of HCL, it is conceivable that the disease
causes a progressive impact that increases with the leukemia burden.
This peaks near diagnosis when the burden is highest and diminishes
after the elimination of HCL. If this is true, longer follow-up of
cured patients should show a continuous decline in RR of secondary
cancer to control levels. Such an observation would have important
implications for the relationship between the lymphoid system and the
development of other neoplasms and carcinogenesis in general. It is
also important in a clinical sense in that meticulous follow-up,
vigorous prevention, and early detection of malignancy in HCL patients
may improve their survival outcome.
| |
FOOTNOTES |
Submitted March 3, 1998;
accepted April 1, 1998.
W.Y.A. is supported by a Croucher Foundation Fellowship.
Address reprint requests to Joseph M. Connors, MD, British Columbia
Cancer Agency, 600 W 10th Ave, Vancouver, BC V5Z 4E6, Canada.
The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" is accordance with 18 U.S.C. section 1734 solely to indicate this fact.
| |
ACKNOWLEDGMENT |
The authors thank Colleen Wong, Lisa Dykman, and Sherry Malsbury for
data management and their colleagues in the Lymphoma Tumor Group, BCCA,
for the clinical management of the patients.
| |
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Abstract
Introduction
Abstract