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Blood, Vol. 93 No. 8 (April 15), 1999:
pp. 2688-2696
Adverse Effects of Activated Cytotoxic T Lymphocytes on the Clinical
Outcome of Nodal Anaplastic Large Cell Lymphoma
By
Rosita L. ten Berge,
Danny F. Dukers,
Joost J. Oudejans,
Karen Pulford,
Gert J. Ossenkoppele,
Daphne de Jong,
Jo F.M.M. Miseré, and
Chris J.L.M. Meijer
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.
 |
ABSTRACT |
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,  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.
© 1999 by The American Society of Hematology.
| |
INTRODUCTION |
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).
| |
MATERIALS AND METHODS |
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 both GrB and TIA-1 was performed as described previously,
using a three-step staining technique.20,23,24 Moreover, to
identify the nature of the GrB+ cells, double-stainings
were performed for GrB and CD8 or CD3, as described
previously.14
Quantification of the percentage of GrB+ and
TIA-1+ CTLs in the reactive infiltrate was performed using
a commercially available interactive video overlay-based measuring
system (Q-PRODIT; Leica, Cambridge, UK), as described
previously.14,20 Per tumor slide, 100 to 150 fields of
vision were randomly selected using an automatic scanning stage.
Numbers of GrB+ and TIA-1+ lymphocytes were
expressed as percentages of all lymphocytes present in a tissue section
as judged by morphology. In cases where the activated CTLs were
difficult to distinguish from neoplastic cells with a cytotoxic
phenotype (n = 4), scoring of activated CTLs was performed with the aid
of sections double-stained for GrB and CD8, which helped to
differentiate between reactive lymphocytes and neoplastic cells, as the
latter were CD8 .
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  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).
| |
RESULTS |
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.
With the exception of two cases, all patients received comparable
polychemotherapy, consisting of CHOP (cyclophosphamide, doxorubicin,
vincristine, prednisone) regimens or variants, some receiving involved
field radiation. One patient (no. 1) died before therapy could be
administered; the other (no. 3) declined therapy on personal grounds.
In 33 of 42 cases (78.5%), complete remission was achieved; of these,
however, 12 patients (36%) experienced a relapse, with a median
progression-free survival time of 9.5 months (range, 2 to 105 months).
Analysis of overall survival time showed that the IPI has a strong
prognostic value (P < .001) (Fig
2A). This is in line with previous studies.5,33,34 As
expected, ALK expression defined a group with favorable clinical
outcome: none of 13 patients with ALK positive ALCL died, whereas 16 of
29 ALK negative patients died as a result of the disease (P < .01) (Fig 2B).
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| Fig 2.
(A) Comparison of overall survival time according to IPI.
(B) Comparison of overall survival time, according to ALK status.
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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
GrB expression by tumor cells was found in 23 of 42 cases (55%), with
the percentage of GrB+ tumor cells ranging from a few to
more than 90% of tumor cells (Table 1). In two additional cases, there
was TIA-1, but no GrB expression (data not shown).
In all cases tested, GrB+ reactive lymphocytes were found
interspersed between the tumor cells and displaying a granular
cytoplasmic staining pattern, which reflects the granular localization
of GrB (see Fig 3A and B). Numbers of
GrB+ CTLs ranged between 1% and 62% of reactive
lymphocytes, with approximately half of the patients having 15%
GrB+ CTLs (n = 21).
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| Fig 3.
Detection of activated CTLs. (A) Biopsy specimen of an
ALCL patient with 15% activated CTLs, presenting with stage 1 disease who died 13 months later as a result of the disease. Brown
cytoplasmic staining indicates GrB expression. Tumor cells are negative
for GrB. (B) Biopsy specimen of an ALCL patient with a cytotoxic
phenotype of the tumor cells and 15% activated CTLs. Both
GrB+ tumor cells (arrowheads) and activated CTLs (thick
arrows) show brown cytoplasmic staining; thin arrow indicates
GrB reactive lymphocytes. (C) Double-staining for CD8
and GrB in a biopsy specimen of an ALCL patient. The majority of
activated CTLs express both CD8 (brown membranous staining) and GrB
(black cytoplasmic staining). Tumor cells are CD8 and
GrB. (D) Double-staining for CD8 and GrB in a biopsy
specimen of an ALCL patient with cytotoxic phenotype of the tumor
cells. Tumor cells (arrowheads) show expression of GrB (black
cytoplasmic staining), but not CD8, whereas activated CTLs (thick
arrows) show expression of both GrB (black cytoplasmic staining) and
CD8 (brown membranous staining).
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Double-staining showed that the large majority of GrB+
reactive lymphocytes are also positive for CD3 and CD8 and are thus in
majority activated CTLs. In all cases, except one, the tumor cells were
found to be negative for CD8 (Table 1). This predominantly CD8 phenotype of ALCL has been demonstrated before
by us and other groups.35-37 Thus, double-stainings helped
to differentiate between (GrB+/CD8+) reactive
lymphocytes and (GrB+/CD8) tumor cells
and were used as an aid in quantifying activated CTLs in cases where it
was difficult to distinguish tumor cells from reactive lymphocytes (Fig
3C and D). In our study, this was the case in four lymphomas, all ALK
positive (Table 2, cases 30, 32, 36, and
38).
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).
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| Fig 4.
Diagram depicting the relative risk (RR) for a fatal
outcome of ALCL as a function of the percentage of activated CTLs (Cox
regression).
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If patients were divided into a group with 15% and <15% activated
CTLs (the threshold leading to the lowest P value), the presence of 15% activated CTLs defined a group of patients with an
unfavorable prognosis: 13 of 21 patients with 15% activated CTLs
died during the follow-up period compared with three of 21 patients
with <15% activated CTLs (P < .001)
(Fig 5A).
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| Fig 5.
(A) Comparison of overall survival time according to
percentage activated CTLs. (B) Comparison of overall survival time
according to percentage activated CTLs combined with ALK status. (C)
Comparison of progression-free survival time according to percentage
activated CTLs combined with ALK status.
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The percentage of TIA-1+ CTLs (entered as a continuous
variable) was not related to progression-free and overall survival
time, as estimated by Cox regression analysis.
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 15% activated CTLs defined a group
with a very poor 2-year survival of less than 20%, as compared with
ALK negative patients with <15% activated CTLs, of whom more than
80% were still alive after 2 years (P < .0001, Fig 5B).
Similar results were obtained for progression-free survival time
(P < .0001, see Fig 5C).
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).
Thus, in this study, a high percentage of activated CTLs combined with
negative ALK status seems to be more sensitive as a marker of poor
prognosis in nodal ALCL than the high risk or high-intermediate risk
categories of the IPI.
| |
DISCUSSION |
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 IPI and other clinical risk factors are well established as
prognostic markers in ALCL. In this study, the IPI and our index
(percentage activated CTLs/ALK status) identify largely the same group
of patients. However, although the IPI is helpful in recognizing most
patients who will fail to respond well to therapy, some poorly
responding patients are not identified (see Table 1, cases 5 and 9 through 13). Our findings suggest that a biological prognostic marker,
as is the percentage of activated CTLs in combination with ALK status,
is at least as strong and probably more sensitive in identifying these
patients than established clinical markers as combined in the IPI. As
such, it may be very helpful in deciding to apply alternative treatment modalities.
However, some caution has to be expressed. Because our study was
performed on a relatively small number of patients, separate studies
involving larger numbers are indicated to confirm the predictive value
of our index.
In those cases where a high percentage of tumor cells show a cytotoxic
phenotype, distinction between activated CTLs and tumor cells can be
difficult. In our study, this was encountered in four cases, all ALK
positive (Table 2, cases 30, 32, 36, and 38). However, double-staining
for CD8 and GrB (Fig 3C and D) in these four cases helped to
differentiate between activated CTLs and neoplastic cells, as tumor
cells did not show CD8 expression (Table 2).
Two previous studies on ALCL with the MoAb ALK1 have shown ALK
expression in 39 of 73 (53%) and 13 of 30 (43%) cases,
respectively.8,9 The fact that we found less ALK positive
cases (31%) is probably due to the relatively high number of elderly
patients as compared with the above-mentioned studies. However, our
patient group showed a pattern of age distribution consistent with the
literature1 and confirmed previous studies with regard to
prognostic significance of the IPI and ALK
status.5,10-13,33,34 ALK positive ALCL has been uniformly
shown to be related to a good prognosis. Thus, the relevance of our
study lies in providing a prognostic marker for the ALK negative ALCL,
which has not been described in the literature before.
The question remains why primary nodal ALCL patients with a high
percentage of activated CTLs and lack of ALK expression show such a
highly unfavorable clinical outcome (Fig 5B and C). The following
explanations can be given.
(1) Assuming that CTLs are directed against the tumor cells, it is
conceivable that in cases with many activated CTLs, only those tumor
cells will survive that are best equipped to resist or inhibit
CTL-mediated apoptosis. The poor clinical outcome in patients with a
high percentage of activated CTLs may then be explained by assuming
that resistance to CTL-induced apoptosis also results in resistance to
therapy-induced apoptosis due to blockade of the final common apoptosis
pathway. Indeed, several independent routes to apoptosis appear to
converge on a final common pathway.38,39 CTL-mediated
apoptosis is achieved by at least two pathways: the function of
perforins and granzymes26-29 and activation of Fas
(CD95/APO-1) on target cells,40-42 which induces apoptosis
by activation of downstream "caspases".43 The Fas
system was shown also to be involved in drug-induced apoptosis in
leukemia cells.44 The downstream antiapoptosis gene, bcl-2, has been shown to reduce sensitivity to both chemotherapy and CTL-induced apoptosis,39,45-47 in the latter case by
blocking the apoptosis pathway before caspase activation.48
Indeed, in a recent study on HD by our group, cases with a high
percentage of activated CTLs (predisposing for poor prognosis) showed
bcl-2 expression by tumor cells.21
(2) A possible immune escape mechanism, other than apoptosis
resistance, is downregulation of MHC class I expression on the membrane
of the tumor cells, preventing recognition of tumor-associated antigens
by CTLs. However, in our study, no downregulation of MHC-I expression
was found (data not shown).
In addition, tumor cells might circumvent CTL-mediated killing
through induction of a local T-cell anergy by expressing certain cytokines. For instance, IL-10 (which has been shown to have
direct suppressive effects on cytotoxic T
lymphocytes)17-19,49,50 was recently demonstrated in
ALCL.51
Finally, tumor cells might escape CTL-mediated killing by neutralizing
the function of granzymes. Recently, a serine protease inhibitor
(serpin) designated PI-9 was cloned and shown to be a potent inhibitor
of GrB-mediated apoptosis.52 Expression of such inhibitory
proteins by the tumor cells would also render them resistant to
CTL-mediated lysis. However, these mechanisms of immune evasion (MHC I
downregulation, local T-cell anergy, and expression of serpins by tumor
cells) cannot account for the poor response to therapy.
We conclude that a high percentage of activated CTLs present in biopsy
material of patients with ALK negative ALCL is a strong indicator for
an unfavorable clinical outcome. In combination with negative ALK
status, the presence of high numbers of activated CTLs is a very strong
prognostic marker, even more sensitive than the IPI, in identifying a
group of ALCL patients with a highly unfavorable clinical outcome. We
advise studies with larger numbers of cases to validate the predictive
value of our index as described here. Furthermore, studies are
indicated to elucidate the putative role of apoptosis resistance as a
pathogenic mechanism in ALCL.
| |
ACKNOWLEDGMENT |
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.
| |
FOOTNOTES |
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