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Blood, Vol. 93 No. 8 (April 15), 1999:
pp. 2688-2696
By
From the Departments of Pathology and Haematology, University
Hospital Vrije Universiteit, Amsterdam, The Netherlands; the Department
of Cellular Science, John Radcliffe Hospital, Oxford, United Kingdom;
the Department of Pathology, The Netherlands Cancer Institute,
Amsterdam, The Netherlands; and the Department of Pathology, St.
Elisabeth Hospital, Tilburg, The Netherlands.
Systemic (nodal) anaplastic large cell lymphoma (ALCL) is a subgroup
of T-cell non-Hodgkin's lymphomas with a relatively favorable clinical
outcome. Part of systemic ALCLs harbor a genetic aberration (usually
the t(2;5)(p23;q35) translocation) containing the anaplastic lymphoma
kinase (ALK) gene at 2p23, which results in aberrant expression of the
ALK protein. Recently, we have shown that the presence of high
percentages of activated cytotoxic T lymphocytes (CTLs) in tumor biopsy
specimens of Hodgkin's disease (HD) is associated with a poor
prognosis. In the present study, we investigated the prognostic value
of percentages of activated CTLs in combination with ALK expression in
primary nodal ALCL. Primary nodal biopsies of 42 patients with ALCL
were investigated for the percentage of activated CTLs (quantified
using Q-PRODIT) and the expression of ALK by
immunohistochemistry using monoclonal antibodies (MoAbs) directed
against T-cell antigen granzyme B (GrB) and ALK, respectively. These
parameters were evaluated for their predictive value regarding progression-free and overall survival time. The presence of a high
percentage of activated CTLs (ie,
ANAPLASTIC LARGE CELL lymphoma (ALCL) is
a group of non-Hodgkin's lymphomas characterized by large
CD30+ cells with multiple or single prominent nucleoli and
T-cell or null cell characteristics.1 Several histologic
subtypes have been described, eg, common type, lymphohistiocytic, giant
cell rich and small-cell variant.2 Clinically, two types
can be recognized: a systemic variant originating mainly from lymph
nodes with an intermediate prognosis; and a primary cutaneous variant with a very good prognosis.1,3,4,5
In part of the nodal ALCLs the t(2;5)(p23;q35) is detected, resulting
in the fusion of the nucleophosmin (NPM) gene at 5q35 and the
anaplastic lymphoma kinase (ALK) gene at 2p23.6 This results in expression of the 80-kD chimeric protein NPM-ALK. Recently, detection of the ALK portion in formalin fixed, paraffin embedded tumor
specimens by immunohistochemistry was made possible by the development
of the polyclonal antibody anti-p80NPM/ALK and the
monoclonal antibody (MoAb) ALK1, respectively.7,8 It was
shown that expression of ALK as detected by this ALK1 MoAb correlates
strongly with the presence of genetic aberrations in which the ALK
locus is involved, including the t(2;5)(p23;q35).8,9 Although its function is still unknown, expression of ALK and/or presence of the t(2;5) was found by several investigators to be related
to a more favorable clinical outcome10-13; ALK positive cases showing an 80% 5-year surivival rate, as compared with a rate of
30% for ALK negative cases.13
One of the issues to be resolved in the pathogenesis of lymphomas is
the fact that tumor cells apparently are not effectively killed by the
host's immune system. The presence of many reactive lymphocytes
surrounding the tumor cells in several types of lymphomas (especially
in Hodgkin's disease [HD] and ALCL) suggests that the neoplastic
cells are able to elicit an immune response, but that evasion of this
immune response is an important pathogenic factor.
Although ALCL and HD are considered to be separate clinicopathologic
entities, they have, besides CD30 expression, many morphologic features
in common and have a similar bimodal age distribution.1 Recently, we and others have shown that in HD different immune escape
mechanisms may be involved: downregulation of major histocompatability complex (MHC)-I expression by the tumor
cells,14-16 expression of immunomodulatory cytokines such
as interleukin-10 (IL-10) by the tumor cells inducing a local T-cell
anergy,17-19 and intrinsic resistance of the tumor cells to
apoptosis. The latter notion arose from our observation that HD
patients with tumor biopsies harboring high percentages of activated
cytotoxic T lymphocytes (CTLs), as demonstrated by the presence of
granzyme B+ cells, have a far worse prognosis as compared
with patients with low percentages of activated CTLs.20 We
postulated that one of the possibilities was that in cases with many
activated CTLs, this continuous immunogenic pressure selects for tumor
cells that are best equipped to resist or inhibit CTL-mediated killing.
This acquired resistance to CTL-mediated cytotoxicity might also result in resistance to therapy-induced apoptosis, thus explaining the poor
treatment outcome. Indeed, we could show that, to a certain extent, in
HD cases with high percentages of activated CTLs, the neoplastic cells
expressed the apoptosis inhibiting gene bcl-2, in contrast to HD cases
with low percentages of activated CTLs.21
In the present study, we investigated whether the presence of high
percentages of activated CTLs in the diagnostic biopsies of patients
with primary nodal ALCL is related to poor clinical outcome. Because
ALK expression is a strong prognostic marker in ALCL, this was done in
relation to ALK expression. Furthermore, we compared its prognostic
value with that of the International Prognostic Index (IPI).
Patients.
Patients with primary nodal ALCL (n = 42) were selected from the files
of the Comprehensive Cancer Center Amsterdam (diagnosed between 1985 and 1997) and the Department of Pathology of the St. Elisabeth
Hospital, Tilburg, The Netherlands (diagnosed between 1991 and 1994).
If during this period a patient presented with recurrent ALCL, the
lymph node biopsy was retrieved on which the initial diagnosis of ALCL
was made. In our group, one primary tumor was retrieved in this way.
Cases were classified according to the Revised European-American
Classification of Lymphoid Neoplasms1 and subtyped as
described by Benharroch et al.2 Staging at first
presentation was determined by physical examination, full blood count,
serum lactate dehydrogenase (LDH) concentration, bone marrow aspirate
and biopsy, and radiologic imaging of chest and abdomen. Patient and
tumor characteristics are summarized in Tables 1 and 2.
Detection of activated cytotoxic T cells.
At present, accurate detection of cytotoxic cells is possible using
MoAbs, which react specifically with granzyme B (GrB)22,23 and T-cell intracytoplasmic antigen (TIA-1).24 GrB is
exclusively expressed in the activated form of CTLs, whereas TIA-1
expression is found in both resting and activated CTLs.25
Upon activation, CTLs acquire cytotoxic granules in their cytoplasm.
These granules contain, among other, the pore forming protein
"perforin" and a family of highly homologous serine proteases,
one of them being granzyme B,26-29which is involved in
target cell DNA fragmentation and apoptosis. MoAb GrB7 was raised
against recombinant human granzyme B protein.22 This
antibody detects activated CTLs and natural killer (NK) cells in
routinely formalin fixed, paraffin embedded tissue sections by immunohistochemistry.
Detection of ALK positive cases.
Expression of ALK was detected in biopsy specimens by
immunohistochemistry using the MoAb ALK1, as described
previously,8 with minor modifications. Slides were
incubated overnight using a 1:75 dilution, and staining was enhanced by
the catalyzed reporter deposition (CARD) method, which
amplifies biotinylated sites.30 Cases were considered
positive if tumor cells showed positive labelling, irrespective of
their number.
Analysis of clinical data.
For each patient, the following characteristics were noted from the
medical records: age at diagnosis, sex, Ann Arbor stage at
presentation, the presence or absence of B symptoms, erythrocyte sedimentation rate (ESR), serum LDH concentration, therapy, response, the occurrence of relapses, and cause of death. Performance status was
assessed according to the Eastern Cooperative Oncology Group (ECOG)
scale (0 to 4). For each patient, the IPI was determined as described
previously.31 The median follow-up time was 25 months
(range, 0 to 207 months). Survival time was measured from time of
initial diagnosis until death due to ALCL or until end of follow-up.
Patients who died of causes unrelated to the disease were censored at
the time of death. Progression-free survival time was measured from
time of initial diagnosis until time of disease relapse. Patients who
did not enter complete remission were assigned a progression-free
survival time of zero in the analysis.
Statistical methods.
Survival curves were constructed with the Kaplan-Meier method.
Differences between the curves were analyzed using the Log-rank test.
Multivariate analysis was performed using the Cox-proportional hazards
model32 (enter and remove limits 0.1). Qualitative
variables were analyzed by Pearson Patient characteristics.
Age distribution showed a bimodal pattern, as has been described for
ALCL,1 with one peak between 20 and 30 years and another between 60 and 70 years (Fig 1). ALK
expression was found in 31% of all cases (13 of 42) and showed a
predilection for the younger age groups (Fig 1 and
Table 1). About half of the patients
presented with stage III or IV disease, showing either multiple organ
involvement or bone marrow dissemination.
Tumor characteristics and GrB expression.
Neoplastic cells showed CD30 expression and either a T-cell or
null-cell phenotype, as defined by the REAL
classification.1 Most cases (30 of 42, 71%) belonged to
the common type of ALCL, whereas eight cases (19%) were considered
lymphohistiocytic type, one case (2%) as mixed (lymphohistiocytic and
giant cell rich), and the remaining three (7%) as giant cell rich
variant.2
Prognostic value of percentage activated CTLs.
The influence of the percentage of activated CTLs on overall survival
time was estimated by Cox regression analysis; the prognosis declined with increasing percentages of activated CTLs (see
Fig 4).
Multivariate analysis of biological and clinical parameters.
As shown in Table 3, other factors than
those mentioned until now were related to survival in univariate
analysis: presence of B symptoms, LDH level, and performance status. A
multivariate Cox regression analysis was performed using the factors
listed in Table 3. Of these, percentage of activated CTLs (P < .001), ALK expression (P < .001) and the IPI (P < .0001) remained independently significant as prognostic markers of
overall survival. The other included variables (presence of B symptoms,
age, stage, number of extranodal sites, LDH level, and performance
status) gave no additional prognostic information.
Prognostic value of percentage of activated CTLs combined with ALK
expression.
The two variables, percentage of activated CTLs and ALK expression,
were combined (see Table 4). In ALK
negative cases, the presence of
Comparison of the prognostic value of percentages activated CTLs/ALK
status with the IPI.
As shown above, both indices (percentages of activated CTLs/ALK status
and the IPI) were independent, strong prognostic markers in a
univariate analysis of overall survival time. In retrospect, both
prognostic markers identify largely the same group of patients (see
Table 1). However, in a second multivariate analysis of overall
survival time using the Cox-proportional hazards model, the percentage
of activated CTLs combined with ALK status was a stronger prognostic
marker than the IPI. This combination identified six patients who died
of the disease within 2 years, although they were at low or
low-intermediate risk according to the IPI (nos. 5, 9-13). Using this
combined percentage of activated CTLs and ALK status index, only two
patients with rapid fatal disease progression were missed (nos. 17 and
18). In contrast to the IPI, our index was also able to identify
patients with poor prognosis presenting with low stage disease (nos. 11 through 13).
In this study, we have shown that the percentage of activated
(GrB+) CTLs is a strong prognostic marker in patients with
primary nodal ALCL. The same effect has been shown for percentages of activated CTLs in HD.20 Furthermore, we have shown that the expression of ALK is related to a favorable clinical outcome, as was
also shown by previous studies.10-13 By combining
percentage of activated CTLs with ALK status, it was possible
(retrospectively) to accurately identify a group of patients who run a
very high risk of dying within 2 years as a result of the disease. In
this group, 13 of 16 patients died. In a multivariate analysis of
overall survival time, the combination of percentage of activated CTLs and ALK status appeared to be a better prognostic marker than the IPI.
The authors thank the following persons for their help in collecting
tumor material and clinical data: Dr P. van Heerde, Dr J.J.A.M. ten
Velden, Dr W.S. Kwee, Dr A.P. Willig, and Dr H. van den Berg. We thank
Elly Fieret for her excellent technical assistance.
Submitted March 16, 1998; accepted November 24, 1998.
R.L.T.B. and D.F.D. contributed equally to this study.
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 Chris J.L.M. Meijer, MD, PhD, Department of
Pathology, University Hospital Vrije Universiteit, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands.
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TOP
ABSTRACT
INTRODUCTION
15%) was found to be an unfavorable prognostic marker. In combination with a lack of ALK expression, it was possible to identify a group of patients with a very
poor prognosis. In this group, 13 of 16 patients died within 2 years as
a result of the disease. Of the remaining 26 patients, only three (all
ALK negative) died (P < .0001). Furthermore, the percentage
of activated CTLs combined with ALK status appeared to be of stronger
prognostic value than the International Prognostic Index (IPI). We
conclude that a high percentage of activated CTLs present in biopsy
material of patients with primary nodal ALCL is a strong indicator for
an unfavorable clinical outcome. The combination of ALK expression and
percentage of activated CTLs appears to be more sensitive than the IPI
in identifying a group of patients with a highly unfavorable clinical
outcome who may be eligible for alternative (high dose) therapy schemes.
.
2 test or by the
Kruskal-Wallis test, when appropriate. All P values are based
on two-tailed statistical analysis. P values below .05 were
considered significant. All analyses were performed using the SPSS
statistical software (SPSS Inc, Chicago, IL).
analysis of the HLA class I processing pathway and the effects of interleukin-10 on Epstein Barr Virus-specific cytotoxic T-cell recognition.
Blood
92:1020, 1998