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Blood, Vol. 93 No. 11 (June 1), 1999:
pp. 3913-3921
Prognostic Significance of Anaplastic Lymphoma Kinase (ALK) Protein
Expression in Adults With Anaplastic Large Cell Lymphoma
By
Randy D. Gascoyne,
Patricia Aoun,
Daniel Wu,
Mukesh Chhanabhai,
Brian F. Skinnider,
Timothy C. Greiner,
Stephan W. Morris,
Joseph M. Connors,
Julie M. Vose,
David S. Viswanatha,
Andrew Coldman, and
Dennis D. Weisenburger
From the Departments of Pathology and Laboratory Medicine, Medical
Oncology, and Epidemiology, British Columbia Cancer Agency, University
of British Columbia, Vancouver, BC, Canada; the University of Nebraska
Medical Center, Omaha, NE; and the Department of Experimental Oncology,
St Jude Children's Research Hospital, Memphis, TN.
 |
ABSTRACT |
Anaplastic large cell lymphoma (ALCL) is an aggressive lymphoma that
is frequently associated with the t(2;5)(p23;q35), resulting in
expression of a fusion protein, nucleophosmin-anaplastic lymphoma kinase (NPM-ALK), which can be detected by either monoclonal or polyclonal antibodies to the ALK protein. The clinical features of
adults with ALCL are incompletely described, and the prognostic factors
that are useful for predicting survival remain unclear. This report
describes the clinical and laboratory findings in 70 adults with
systemic ALCL who were treated with curative intent. We attempted to
identify the clinical and pathological factors of prognostic
importance, including the International Prognostic Index (IPI),
immunophenotype, and expression of the ALK protein. The median age of
the patients was 49 years (range, 15 to 75). There were 26 women and 44 men with a median follow-up of 50 months for living patients. Advanced
stage was present in 56% and B symptoms were noted in 70% of the
patients. Immunostains showed that 46% of the cases had a T-cell
phenotype, 36% a null phenotype, and 18% a B-cell phenotype. The
expression of ALK protein was found in 51% of the cases. The IPI
factors were evenly distributed between the ALK+ and
ALK groups, except that the ALK+ patients
were younger (median age, 30 v 61 years; P < .002). The ALK+ cohort included cases with null (44%), T-cell
(42%), and B-cell (14%) phenotypes. All 10 cases with cytogenetic or
molecular evidence of a t(2;5) were ALK+. The 5-year
overall survival (OS) of the entire cohort was 65%. The 5-year OS of
the ALK+ and ALK cases was 79% and 46%,
respectively (P < .0003). Analysis of only the
T-cell/null cases (n = 57) showed a 5-year OS of 93% for the
ALK+ cases and only 37% for the ALK cases
(P < .00001). Univariate analysis of the clinical features showed that age  60 years (P < .007), a normal serum
lactate dehydrogenase (LDH) (P < .00001), a good performance
status (Eastern Cooperative Oncology Group [ECOG] <2) (P < .03), 1 extranodal site of disease (P < .012), and an IPI score 3 (P < .00001) were associated
with improved OS. Although a younger age correlated with ALK
positivity, multivariate analysis showed that only a normal serum LDH
(P < .00001), an IPI score of 3 (P < .0005), and
ALK protein expression (P < .005) predicted independently for
an improved OS. We conclude that ALCL is a heterogeneous disorder.
However, ALK protein expression is an independent predictor of survival
and serves as a useful biologic marker of a specific disease entity
within the spectrum of ALCL.
© 1999 by The American Society of Hematology.
| |
INTRODUCTION |
ANAPLASTIC LARGE CELL lymphoma
(ALCL) was first described by Stein et al1 in 1985 as a
pleomorphic large cell non-Hodgkin's lymphoma (NHL) with sinus
infiltration and anaplastic cytomorphology. Many of these cases had
been previously diagnosed as malignant histiocytosis. The neoplastic
cells in ALCL express CD30 (Ki-1, Ber-H2) antigen and can be of T-cell,
B-cell, or null phenotype. ALCL of B- or T-cell type is recognized in
the revised Kiel classification.2 However, the Revised
European-American Lymphoma (REAL) classification includes B-cell ALCL
with all other diffuse large B-cell NHLs, whereas ALCL of T-cell or
null phenotype is considered a distinct disease entity.3
Although some investigators argue that a B-cell phenotype is
incompatible with the diagnosis of ALCL, a recent study of adults with
ALCL found the B-cell phenotype to be the most common (38%), in
contrast to the T-cell (34%) and null (22%) types.4
Numerous histologic subtypes of ALCL have now been described including
monomorphic, pleomorphic, small cell, lymphohistiocytic, sarcomatoid,
signet-ring, and neutrophil-rich variants.5-12 In a recent
series, the monomorphic variant was the most common type of
ALCL.12 Because CD30 expression is shared with many other NHL subtypes and with Hodgkin's disease, it does not on its own represent a definitive marker of ALCL.13-15 Therefore,
unique biologic markers that better define ALCL as a disease entity are
needed, analogous to cyclin D1 expression in mantle cell
lymphoma.16 Although it is not a common NHL, the recently
completed clinical evaluation of the International Lymphoma Study Group
(ILSG) proposal found that T-cell/null ALCL accounted for 2.4% of all
NHL.17
In 1989, the association of ALCL with a characteristic t(2;5)(p23;q35)
cytogenetic abnormality was first described.18-20 This was
followed 5 years later by the cloning of the translocation breakpoints
and the discovery that the chromosomal rearrangement fuses part of the
nucleophosmin (NPM) gene on chromosome 5q35 to a portion of the
anaplastic lymphoma kinase (ALK) gene on chromosome 2p23,
generating a chimeric mRNA molecule and a unique 80-kD
NPM-ALK fusion protein (also referred to as p80).21,22
Polyclonal and monoclonal antibodies specific for the ALK portion of
the molecule have been studied, and neither show any detectable
staining of normal or reactive lymphoid tissues.23,24 Thus,
a positive immunostain signal serves as a phenotypic marker of the
t(2;5). The sole exception reported to date is an uncommon diffuse
large B-cell lymphoma that expresses the full-length ALK protein
through unknown mechanisms and does not possess the (2;5)
translocation.25 The neoplastic cells in this entity have
characteristic plasmacytoid immunoblastic morphology, fail to express
CD30, and are frequently positive for cytoplasmic IgA. The association
of aberrant ALK expression with ALCL is well established, but the
frequency of its detection varies greatly, reflecting different
methodologies, variable case definition, and the ages of the particular
study population (ALCL in the pediatric age group being more frequently NPM-ALK+ than adult cases).26-28 The
association is further confounded by the lack of cytogenetic data in
many cases, as well as the fact that variant breakpoints such as the
t(1;2)(q25;p23) and inv(2)(p23;q35) also result in ALK expression, but
are not detected by the current reverse transcriptase-polymerase chain
reaction (RT-PCR) techniques used to identify the
t(2;5).29-31 The specificity of the t(2;5) has been
questioned after reports of NPM-ALK rearrangements in some
large B-cell lymphomas, as well as peripheral T-cell lymphomas (PTCL)
lacking the typical features of ALCL.26,27,32
Very few data are available concerning the clinical and pathological
features that are useful for predicting outcome in
ALCL.5,6,33-37 Interpretation of these data are further
confounded by the lack of precise critieria to distinguish primary
cutaneous ALCL from systemic ALCL.34 Even less is known
about the prognostic significance of NPM-ALK/p80 protein expression.
Although three reports have suggested that NPM-ALK/p80+
cases of ALCL are associated with a younger median age at diagnosis and
an improved survival, no treatment details were provided and, more
importantly, these studies did not perform multivariate
analysis.23,38,39 A single pediatric study of the
prognostic role of ALK immunostaining in diffuse large cell lymphoma
failed to show a significant difference in outcome between
ALK+ and ALK
cases.40
The purpose of this study was to investigate the frequency of ALK
expression in a series of adult ALCL patients diagnosed on the basis of
histopathologic features and CD30 expression. We also sought to
determine the prognostic relevance of ALK protein expression in this
cohort of patients who were treated with curative intent, and to
investigate whether this biologic variable has independent predictive
value for survival. Lastly, in a small subset of cases with cytogenetic
and/or molecular evidence of the t(2;5), we wished to determine the
frequency of ALK protein expression.
| |
MATERIALS AND METHODS |
Patients.
This study consists of 70 patients, including 50 from the British
Columbia Cancer Agency (BCCA) and 20 from the University of Nebraska
Medical Center in Omaha. All patients had a diagnosis of systemic ALCL,
and no cases of primary cutaneous ALCL or secondary ALCL were included.
Eligibility criteria included age from 15 to 75 years, a diagnosis of
systemic ALCL, therapy given with curative intent, and an available
diagnostic paraffin block for immunophenotyping. Lymphomas occurring in
the setting of acquired immunodeficiency syndrome or organ
transplantation were excluded. No patients had prior lymphoma therapy.
Eligible patients were treated with chemotherapy, radiotherapy, or
both, dependent on the stage of disease and the era in which the
patients were treated. Specific multiagent chemotherapy protocols
containing doxorubicin were used at each center, as previously
published.41-43
Histology and immunophenotyping.
Histologic sections were processed routinely from either buffered
formalin or B5-fixed paraffin blocks, cut at 3 µm and mounted on
slides. All cases were reviewed independently by three
hematopathologists (R.D.G., P.A., and D.D.W.), with consensus reached
using a multiheaded microscope. The diagnostic criteria for ALCL were
those of the original description by Stein et al.1 Cases
were also included if they showed the histologic features of the more
recently identified variants of ALCL.5-12 Cases were not
excluded based on lineage assignment, which was determined by paraffin
section immunperoxidase staining, flow cytometric analysis, and/or gene
rearrangement studies. All cases were stained with hematoxylin and
eosin (H&E), CD20 (L26), CD79a, CD3 (polyclonal), CD45RO
(UCHL-1), and CD30 (Ber-H2) (Dako, Carpenteria, CA). The majority of
the cases were also stained routinely in paraffin sections with CD45
(LCA) and epithelial membrane antigen (EMA; Dako). Microwave antigen
retrieval was used as required with appropriate controls. Cases were
assigned a B-cell lineage if they showed positive staining with either CD20 or CD79a and failed to stain with any T-cell markers. Cases were
also assigned to the B-cell lineage if they failed to express either
CD20 or CD79a, but expressed monotypic immunoglobulin light chain
and/or had a clonal immunoglobulin heavy-chain gene rearrangement without rearrangement of the T-cell receptor genes. A T-cell lineage was assigned if the tumor cells in a case stained with CD3 and/or CD45RO and failed to stain with either CD20 or CD79a. Cases were classified as null if all lineage markers were negative and/or molecular genetic studies were negative for either immunoglobulin heavy
chain or T-cell receptor gene rearrangements. All such cases had the
typical morphology of ALCL and expressed CD30. All B-cell cases with
available paraffin blocks were further immunostained for cytoplasmic
IgA, and kappa and lambda light chains, including both the
ALK+ and ALK groups. These data were
correlated with the cellular morphology and the results of EMA immunostaining.
All 70 cases were stained with both the polyclonal (ALK11) and
monoclonal (ALK1) antibodies to residues 419-520 of the NPM-ALK chimeric protein product of the t(2;5). The polyclonal antibody was
supplied by Stephan W. Morris and the monoclonal antibody kindly provided by Karen A.F. Pulford and David Y. Mason (Oxford, UK).
The details of the production and specificity of both these antibodies have been previously published.24,40,44 Staining was performed on sections from formalin and/or B5-fixed,
paraffin-embedded tissue using a standard avidin-biotin complex
technique. Briefly, paraffin sections were mounted on superfrost/plus
glass slides and deparaffinized. Antigen retrieval was performed by
heating the slides in 10 mmol sodium citrate buffer (pH 6.0) for
30 minutes in a 95°C waterbath. Slides were cooled for 15 minutes
and immunostaining was performed on a Ventana ES automated
immunohistochemistry stainer (Ventana, Tucson, AZ) using the polyclonal
ALK11 antibody at 1:200 and 1:400 dilutions, and the monoclonal ALK1
antibody at a 1:2 dilution. Cases were considered positive when there
was staining with either the polyclonal, monoclonal, or both antibodies.
Molecular genetics and cytogenetics.
Immunoglobulin heavy-chain and T-cell receptor beta gene Southern blot
analysis were performed in 13 cases using routine techniques, as
previously described.45 Immunoglobulin heavy chain and
T-cell receptor gamma gene polymerase chain reaction (PCR) studies were performed in 17 cases, as previously described.46 Reverse
transcriptase (RT)-PCR for the NPM-ALK rearrangement was
performed in 12 cases.47 Cytogenetic studies were performed
in 15 cases using routine techniques. Cells were cultured in vitro for
24 hours, harvested, and Giemsa-banded with karyotypes classified
according to the International System for Human Cytogenetic
Nomenclature (ISCN) (1995).48
Statistical analysis.
Overall survival (OS) was calculated from the date of diagnosis until
the patient's death or last follow-up. Failure-free survival (FFS) was
calculated as the interval between diagnosis and relapse, progression
if the patient had less than a complete response, or death due to any
cause. Survival curves were calculated by the method of Kaplan and
Meier.49 Statistical comparisons between curves were made
using the log-rank test.50 Significant differences in the
distribution of clinical prognostic factors between the
ALK+ and ALK groups were determined by
the Pearson  2 test. Univariate analysis was performed
with each of the individual clinical variables, the International
Prognostic Index (IPI) score, and ALK protein expression.51
Multivariate survival analysis was performed using the stepwise
proportional hazards model.52 Multivariate Cox analysis was
performed using all five of the clinical variables, the IPI score, and
ALK expression. The prognostic impact of ALK protein expression was
determined by adding ALK after the individual clinical variables or the
IPI score were included in the model.
| |
RESULTS |
A total of 70 patients with ALCL were included in this study. There
were 26 women and 44 men ranging in age from 15 to 75 years, with a
median age of 49 years at diagnosis (three patients were 19 years).
The median follow-up of living patients was 50 months (range, 2 to
240). Details of the clinical features and immunophenotypes of the
cases are shown in Table 1. The
ALK+ patients were significantly younger than the
ALK patients (30 v 61 years; P < .002). Additionally, the ALK+ patients had less frequent
involvement of multiple extranodal sites (P < .047), but
otherwise the clinical variables were evenly distributed between the
ALK+ and ALK groups. There were seven
cases with primary extranodal presentations, including three involving
soft tissue and one each of lung, bone, stomach, and tonsil, all of
which also had nodal sites of involvement.
The majority of cases had the typical pleomorphic cytology and
sinusoidal infiltration of ALCL. Zonal necrosis was also a frequent
finding. So-called hallmark cells with eccentric horseshoe or
kidney-shaped nuclei were present in all cases, including both ALK+ and ALK cases.12 Most
of the cases also had scattered neoplastic cells with multiple nuclei
and a prominent perinuclear eosinophilic inclusion that appeared to
represent the Golgi apparatus. One case each of a small cell variant of
ALCL and a Hodgkin's-like variant were included in this study. The
most frequent histologic subtype was the common type, including six
monomorphic cases and 62 with pleomorphic features. The frequency of
histologic subtypes reflects the study design, whereby the majority of
cases enrolled from the 1980s and early 1990s were the pleomorphic
subtype. These cases fulfilled the diagnostic criteria of Stein et
al and were diagnosed before the description of most of
the histologic variants of ALCL.1 Nonetheless, a similar
study of 83 peripheral T-cell lymphomas during the same era at the BCCA
failed to disclose any additional ALK+ cases, with or
without CD30 expression (R.D.G., unpublished data, August 1998).
Immunophenotypic analysis showed that 32 of the 70 cases (46%) were of
T-cell type, 25 (36%) were of null type, and 13 (18%) were of B-cell
type. CD30 expression was present in 67 of the 70 cases (96%). CD45
and EMA were studied in a subset of the cases and were positive in 27 of 41 (68%) and 40 of 53 cases (75%), respectively. ALK protein
expression was determined using both polyclonal and monoclonal
antibodies. Cases were considered to be positive if tumor cells stained
with either antibody. A total of 36 cases were positively stained using
the polyclonal ALK11, and 32 were positive with monoclonal ALK1.
Typical staining was seen within both the nucleus and the cytoplasm in
the majority of positive cases. Representative examples of T-cell and
B-cell cases, including ALK stains, are shown in
Fig 1. In total, 36 of the 70 cases (51%)
were ALK protein-positive, and included 15 (42%) T-cell, 16 (44%)
null, and five (14%) B-cell cases. Interestingly, of the
ALK+ cases also stained for EMA, 26 of the 31 (84%) were
EMA+. All B-cell cases with sufficient tissue remaining in
the block (10 of 13) were also stained for cytoplasmic IgA, and kappa
and lambda light chains using paraffin section immunoperoxidase
techniques. Of the five ALK+ cases analyzed, only one case
expressed cytoplasmic IgA, and none of these cases had the morphology
of immunoblasts that was previously described in the rare B-cell
lymphoma expressing full-length ALK protein.25 Details of
the five ALK+ B-cell cases are shown in
Table 2. The remaining eight
ALK B-cell cases all failed to express cytoplasmic
IgA, kappa, or lambda light chains.
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| Fig 1.
Representative photomicrographs of a T-cell ALCL case
stained with H&E (A) and polyclonal anti-ALK antibody ALK11 (B) and a
B-cell case stained with H&E (C) and polyclonal anti-ALK antibody ALK11
(D). Original magnification × 400.
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Of the 70 cases included in this series, cytogenetic and/or molecular
genetic data concerning the presence of the t(2;5) were available for
15 cases. Ten of the 15 cases had evidence of the characteristic t(2;5)
of ALCL, and all 10 cases were positive for ALK protein expression.
Clonal karyotypes of the five t(2;5)-negative cases are shown in
Table
3.
The OS of all 70 patients is shown in Fig 2 (median
survival, 133 months). The 5-year OS and FFS of the entire cohort was 65% and 63%, respectively. The 5-year OS for the entire cohort and
the subgroup of T-cell/null cases based on the IPI score is shown in
Table 4. The 5-year OS was not significantly affected by
immunophenotype (B-cell v T-cell v null; 55% v
56% v 83%, P = .38) or monomorphic versus pleomorphic
cytology (P = .54). Figure 3 shows the OS for
all 70 patients based on the expression of ALK protein. The 5-year OS
of the ALK+ cases was 79% versus only 46% for the
ALK cases (P < .0003). The 5-year FFS for
ALK+ and ALK cases was 82% and 45%,
respectively (P < .001). Figure 4 shows the OS
for those cases with either a T-cell or null phenotype. The 5-year OS
of the ALK+ cases was 93% versus only 37% for the ALK
negative cases (P < .00001). The corresponding 5-year FFS was
88% for ALK+ cases and 37% for ALK
cases (P < .0001). The 5-year OS of B-cell cases (n = 13)
when comparing the ALK+ and ALK groups
showed a trend in favor of the ALK+ group, but was not
statistically different (75% v 20%, P = .15); similarly, FFS for B-cell cases was not significantly different (P
= .34). However, the number of cases included in this analysis is
small (n = 13).
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| Fig 3.
Overall survival curve of all 70 patients with ALCL
studied for the expression of ALK protein, including 36 ALK+ and 34 ALK cases.
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| Fig 4.
Overall survival curve of the T-cell/null ALCL cases (n
= 57) studied for expression of ALK protein, including 31 ALK+ and 26 ALK cases.
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The results of univariate analysis of the various prognostic factors
for the entire cohort are given in Table 5. Of note, stage was not found to be prognostically important. Factors associated with improved OS included age 60 years, a normal serum lactate dehydrogenase (LDH), good performance status, none or only one extranodal site of disease, an IPI score 3, and ALK protein
expression. Multivariate analysis was performed using two different
models. First, using the individual clinical variables in the model
showed that a normal serum LDH (P < .0001) and age 60 years
(P < .007) were associated with improved survival. In the
second model, analysis of the five clinical variables as an IPI score
showed that an IPI score of 3 was also associated with improved OS
(P < .00001). When ALK protein expression was added to either
model, age was no longer a significant predictor of outcome, but normal
serum LDH (P < .00001), an IPI score of 3 (P < .0005) and ALK positivity (P < .005) remained highly
significant. Thus, although ALK protein expression tended to be
associated with a younger age, ALK expression was the more powerful
independent variable. Of the patients less than or equal to 35 years of
age, 19 of 26 (73%) were ALK+. The multivariate analysis
was repeated on the subset of patients with a T-cell/null
immunophenotype (n = 57). Without ALK expression in the models, only a
normal serum LDH (P = .0001), age 60 years (P =
.0026), and an IPI score of 3 (P = .0008) were significant predictors of a favorable outcome. When ALK was added to the model, age
was no longer significant, but a normal serum LDH (P < .00001), an IPI score of 3 (P = .023), and ALK protein
expression (P = .0007) were associated with improved survival.
| |
DISCUSSION |
This study shows for the first time that a combination of clinical and
biological factors can be used to predict survival in ALCL. A normal
serum LDH at diagnosis, an IPI score of 3 or less, and expression of
the ALK protein are associated with a favorable clinical outcome and
have been shown in this study to be independent prognostic variables.
Stage was not a predictor of outcome unlike previous
studies.33,53 However, we did not include cases of primary
cutaneous ALCL, an entity known to be associated with a favorable
outcome.34 It is likely that some of the previous studies
that have identified limited stage as a favorable prognostic factor
have included cases of primary cutaneous ALCL and related
CD30+ lymphoproliferative disorders.33,53
Moreover, age was a predictor of outcome in both univariate and
multivariate analysis when ALK expression was not included in the
model, it was not a significant variable following multivariate
analysis that included all factors. There is a relationship between
young age and ALK protein expression, but the latter was the more
important prognostic factor in this patient cohort. Although ALK
expression has previously been associated with patient age, these
variables have not been subjected to multivariate analysis. Shiota et
al23 first reported the association of NPM-ALK/p80 expression and patient outcome in 1995. In a study of 105 patients with
ALCL, they found NPM-ALK/p80 expression in 30 patients (29%) and
reported an association with younger age and improved 5-year OS.
However, their study included pediatric cases and did not provide
details regarding either clinical features or treatment. Multivariate
analysis was performed only in relation to those factors associated
with NPM-ALK/p80 expression, but not the factors usually predictive of
survival in NHL.23,38 In a follow-up report from the same
group, 67 cases of ALCL were analyzed for NPM-ALK/p80 expression with
64% being positive. An association of NPM-ALK/p80 with both younger
age and improved 5-year survival was again found.39 Twenty
of the cases analyzed were common to both studies.23,38,39
Although some treatment details were provided in the more recent study,
multivariate analysis was not performed and, as before, many of the
patients were in the pediatric age group. In 1997, Hutchison et
al40 reported a study of 44 cases of diffuse large cell
lymphoma in children including 20 CD30+ cases, 16 of which
had morphology consistent with ALCL. Nineteen of the 20 CD30+ cases were ALK+. Interestingly, 5 of the
24 CD30 cases were also ALK+, but
survival analysis failed to show a difference in event-free survival
for ALK+ versus ALK cases and
multivariate analysis was not performed. Of note, this study included
one ALK+ B-cell case. To our knowledge, no other studies of
the clinical significance of ALK expression in ALCL have been published.
A recent study from the Groupe d'Etudes des Lymphomes de l'Adulte
reported on 146 patients with ALCL, defined on the basis of morphology
and CD30 expression.4 These cases were compared with a
large cohort of similarly treated nonanaplastic diffuse large cell
lymphomas, with the ALCL patients showing a superior survival. This
study found that patients with ALCL were more likely to be male,
younger, to have B symptoms, as well as skin and lung involvement, in
comparison with the non-ALCL cases. The tumor immunophenotype of the
ALCL cases was predominantly B-cell, but the event-free survival and OS
of the B-cell cases was similar to those of the T-cell and null cases
of ALCL. Importantly, all ALCL patients, independent of
immunophenotype, had superior responses to chemotherapy,
event-free survival, and OS as compared with non-ALCL
patients, suggesting that recognition of ALCL based on morphology and
CD30 expression was important. ALK protein expression was not analyzed
in this study.
At present, ALCL remains a heterogeneous disorder using standard
morphologic and immunophenotypic criteria. Since its original description, the morphologic spectrum of ALCL has been greatly expanded, now including at least eight different histologic
variants5,7-12 Not surprisingly, there is little agreement
as to what constitutes the important criteria for defining ALCL as a
disease entity. Unfortunately, histologic definitions alone result in
significant immunologic and molecular genetic heterogeneity. However,
biologic definitions allow for substantial morphologic variability,
including the possibility of numerous histologic subtypes. This is
clearly the case for ALCL. From its inception, the definition of ALCL has been fraught with controversy.54 Many initially
advocated use of the term "Ki-1 lymphoma," because of the
presumed unique expression of the Ki-1 (CD30, Ber-H2) antigen by these
tumors. Subsequently, it has been shown that CD30 is an activation
antigen that can be expressed by normal lymphoid cells and the
neoplastic cells of many lymphoproliferative disorders in addition to
ALCL.55 Thus, CD30 antigen does not constitute a unique
phenotypic marker of ALCL, and indeed may be negative in bona fide
cases.40 Unfortunately, the term "anaplastic" is no
longer helpful in defining ALCL as an entity, as many cases do not show
the cytologic atypia usually reserved for the term
"anaplastic."12 Rather, the monomorphic subtype of
the "common" variant appears to be a frequent form of the
disease, although the architectural features of sinusoidal infiltration
and cohesive growth are often retained. Thus, without the use of
biologic criteria, resolving the heterogeneity of ALCL would be a
difficult task.
A recent publication from Benharroch et al12 appears to
have brought some clarity to this problem. These investigators studied 123 cases from the consultative files of one of the authors. The cases
were selected from a larger group of 145 cases with a diagnosis of
ALCL. By definition, the cases expressed both CD30 and EMA, and cases
expressing B-cell antigens were specifically excluded. Using these
criteria, 123 of the 145 cases (85%) expressed ALK protein and were
the subject of the report. Key morphologic features of the
ALK+ cases were highlighted including the presence of
so-called hallmark cells with eccentric, horseshoe-shaped nuclei and a
characteristic prominent Golgi apparatus in some of the tumor cells,
and a typical perivascular infiltration pattern seen in almost half of
the cases.12 It was concluded, based on these results, that
the diverse histologic subtypes observed in ALK+ ALCL are
part of the spectrum of a single disease entity, all sharing a common
molecular pathogenesis, ie, expression of a constitutively activated
abnormal ALK protein. Based on these observations, the investigators
suggested the term "ALKoma" to refer to these lymphomas. Although
we would agree that the expression of ALK is important in further
defining ALCL, our data do not agree completely with theirs. For
example, they claim that the hallmark cells are only seen in
ALK+ ALCL, whereas we found these cells with equal
frequency in our ALK cases, indicating that these
cells are not specific for ALK+ ALCL. Moreover, not all of
the ALK+ cases in our series expressed EMA.
Our study identified a small number of ALK+ B-cell ALCLs
and, importantly, none of these cases had the morphology and
immunophenotype of the rare cases reported to express full-length
ALK.25 Specifically, our five cases lacked immunoblastic
morphology, failed to express cytoplasmic IgA except in one case, and
three of the five expressed CD30. Additionally, the case expressing IgA
was found to have a t(2;5) by classical cytogenetics and express ALK
protein. These observations, together with other data from the
literature, indicate that "true" B-cell ALK+ ALCL
cases do exist.4,26,40 However, our results differ from
those of Tilly et al4 in several respects. B-cell ALCL was
the least frequent immunophenotypic subgroup in our study and the
5-year OS and FFS were similar to that of nonanaplastic diffuse large
B-cell lymphoma. The addition of ALK immunostaining in our study did
not delineate clinically distinct subgroups, as we were unable to show
a statistically significant survival difference when comparing the
ALK+ versus ALK cases. Only 13 B-cell
ALCL (18%) cases were identified in this study of 70 adult patients
based on histologic and phenotypic criteria, and this small number of
cases precludes definitive conclusions regarding the clinical
implications of ALK protein expression in this cohort. Although the
ALK+ cases showed a trend toward improved OS, we urge
caution in the interpretation of these data based on a small number of
events. Therefore, we believe that insufficient data are currently
available to warrant the exclusion of B-cell cases from the disease
entity presently classified as ALCL, and that additional studies are clearly needed.
The association of the t(2;5) with ALCL is widely
recognized.27 Nonetheless, estimates of the frequency of
the t(2;5), using either classical cytogenetics or RT-PCR, vary from
15% to 80% of cases.28 Moreover, the translocation has
been detected in some peripheral T-cell lymphomas other than classical
ALCL and in some diffuse large cell lymphomas of
B-lineage.26,27,32 In our series of ALCL, one half of the
cases expressed ALK. Certainly, some of this apparent heterogeneity
results from changing diagnostic criteria for ALCL, but it is likely
that some of these findings represent true biologic heterogeneity.
Additionally, variant translocations have been identified that result
in aberrant ALK expression and can only be detected by classical
cytogenetics.29,30 More recently, a cryptic cytogenetic
abnormality has been descibed that is most easily recognized using
fluorescence in situ hybridization, inv(2)(p23q35), resulting in a
distinct pattern of ALK protein expression restricted to the cytoplasm
of the neoplastic cells.31 The report of rare diffuse large
B-cell lymphomas expressing full-length ALK is a further testament to
the present lack of understanding of the various molecular mechanisms
responsible for dysregulation of this novel tyrosine
kinase.25
In summary, in this series of 70 adults with ALCL, we have shown that,
in addition to such well-known factors as a normal serum LDH and an IPI
score of 3, ALK protein expression by the tumor cells is an
independent prognostic factor that predicts a favorable clinical
outcome. We conclude that aberrant ALK expression is critical in the
definition of ALCL as a disease entity, and we believe that the
inclusion of this biologic marker as a diagnostic criterion further
refines this heterogeneous category. We recommend that more cases be
surveyed to further define the morphologic and immunophenotypic
spectrum of this disease entity, with emphasis on clinical correlations
including patient outcome. Moreover, we recognize the need for more
studies that examine potential alternative molecular mechanisms that
may result in overexpression of ALK protein in NHL.
| |
ACKNOWLEDGMENT |
The authors thank Yulia D'yachkova for assistance with statistical
analysis and our clinical colleagues in medical and radiation oncology
for inclusion of patients treated under their care. We also thank
Dr Warren Sanger for providing the karyotypes listed in Table
3.
| |
FOOTNOTES |
Submitted September 3, 1998; accepted January 19, 1999.
Supported in part by National Cancer Institute Grants No. CA 69129 (to
S.W.M.) and Cancer Center Support (CORE) CA 21765, and by the American
Lebanese Syrian Associated Charities (ALSAC), St Jude Children's
Research Hospital.
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 Randy D. Gascoyne, MD, Department of
Pathology, British Columbia Cancer Agency, 600 W 10th Ave, Vancouver,
BC, Canada V5Z 4E6; e-mail: rgascoyn{at}bccancer.bc.ca.
| |
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Elevated serum-soluble interleukin-2 receptor levels in patients with anaplastic large cell lymphoma
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[Abstract]
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J. O. Armitage, J. M. Vose, and D. D. Weisenburger
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K. J. Savage, M. Chhanabhai, R. D. Gascoyne, and J. M. Connors
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October 1, 2004;
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E. J. Schlette, L. J. Medeiros, A. Goy, R. Lai, and G. Z. Rassidakis
Survivin Expression Predicts Poorer Prognosis in Anaplastic Large-Cell Lymphoma
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September 1, 2003;
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June 1, 2003;
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N. S. Reading, S. D. Jenson, J. K. Smith, M. S. Lim, and K. S. J. Elenitoba-Johnson
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Blood,
May 29, 2002;
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L. Passoni, A. Scardino, C. Bertazzoli, B. Gallo, A. M. L. Coluccia, F. A. Lemonnier, K. Kosmatopoulos, and C. Gambacorti-Passerini
ALK as a novel lymphoma-associated tumor antigen: identification of 2 HLA-A2.1-restricted CD8+ T-cell epitopes
Blood,
March 15, 2002;
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B. Falini and D. Y. Mason
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Blood,
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Q. Zhang, P. N. Raghunath, L. Xue, M. Majewski, D. F. Carpentieri, N. Odum, S. Morris, T. Skorski, and M. A. Wasik
Multilevel Dysregulation of STAT3 Activation in Anaplastic Lymphoma Kinase-Positive T/Null-Cell Lymphoma
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R L Ten Berge, F G M Snijdewint, S von Mensdorff-Pouilly, R J J Poort-Keesom, J J Oudejans, J W R Meijer, R Willemze, J Hilgers, and C J L M Meijer
MUC1 (EMA) is preferentially expressed by ALK positive anaplastic large cell lymphoma, in the normally glycosylated or only partly hypoglycosylated form
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December 1, 2001;
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G. Z. Rassidakis, A. H. Sarris, M. Herling, R. J. Ford, F. Cabanillas, T. J. McDonnell, and L. J. Medeiros
Differential Expression of BCL-2 Family Proteins in ALK-Positive and ALK-Negative Anaplastic Large Cell Lymphoma of T/Null-Cell Lineage
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August 1, 2001;
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J. P. Greer, M. C. Kinney, and T. P. Loughran Jr.
T Cell and NK Cell Lymphoproliferative Disorders
Hematology,
January 1, 2001;
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[Abstract]
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B. F. Skinnider, A. J. Elia, R. D. Gascoyne, L. H. Trumper, F. von Bonin, U. Kapp, B. Patterson, B. E. Snow, and T. W. Mak
Interleukin 13 and interleukin 13 receptor are frequently expressed by Hodgkin and Reed-Sternberg cells of Hodgkin lymphoma
Blood,
January 1, 2001;
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[Abstract]
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H. Stein, H.-D. Foss, H. Durkop, T. Marafioti, G. Delsol, K. Pulford, S. Pileri, and B. Falini
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[Abstract]
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D. A. Arber
Molecular Diagnostic Approach to Non-Hodgkin's Lymphoma
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R. Suzuki, Y. Kagami, K. Takeuchi, M. Kami, M. Okamoto, R. Ichinohasama, N. Mori, M. Kojima, T. Yoshino, H. Yamabe, et al.
Prognostic significance of CD56 expression for ALK-positive and ALK-negative anaplastic large-cell lymphoma of T/null cell phenotype
Blood,
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[Abstract]
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K. Pulford, B. Falini, A. H. Banham, D. Codrington, H. Roberton, C. Hatton, and D. Y. Mason
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Aberrant ALK Tyrosine Kinase Signaling : Different Cellular Lineages, Common Oncogenic Mechanisms?
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B. Lawrence, A. Perez-Atayde, M. K. Hibbard, B. P. Rubin, P. Dal Cin, J. L. Pinkus, G. S. Pinkus, S. Xiao, E. S. Yi, C. D. M. Fletcher, et al.
TPM3-ALK and TPM4-ALK Oncogenes in Inflammatory Myofibroblastic Tumors
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A. Wellmann, C. Thieblemont, S. Pittaluga, A. Sakai, E. S. Jaffe, P. Siebert, and M. Raffeld
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[Abstract]
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M. W. Bekkenk, F. A. M. J. Geelen, P. C. v. V. Vader, F. Heule, M.-L. Geerts, W. A. van Vloten, C. J. L. M. Meijer, and R. Willemze
Primary and secondary cutaneous CD30+ lymphoproliferative disorders: a report from the Dutch Cutaneous Lymphoma Group on the long-term follow-up data of 219 patients and guidelines for diagnosis and treatment
Blood,
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[Abstract]
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R. L t. Berge, J. J Oudejans, G.-J. Ossenkoppele, K. Pulford, R. Willemze, B. Falini, A. Chott, and C. J L M Meijer
ALK expression in extranodal anaplastic large cell lymphoma favours systemic disease with (primary) nodal involvement and a good prognosis and occurs before dissemination
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C. Touriol, C. Greenland, L. Lamant, K. Pulford, F. Bernard, T. Rousset, D. Y. Mason, and G. Delsol
Further demonstration of the diversity of chromosomal changes involving 2p23 in ALK-positive lymphoma: 2 cases expressing ALK kinase fused to CLTCL (clathrin chain polypeptide-like)
Blood,
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[Abstract]
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Z. Ma, J. Cools, P. Marynen, X. Cui, R. Siebert, S. Gesk, B. Schlegelberger, B. Peeters, C. De Wolf-Peeters, I. Wlodarska, et al.
Inv(2)(p23q35) in anaplastic large-cell lymphoma induces constitutive anaplastic lymphoma kinase (ALK) tyrosine kinase activation by fusion to ATIC, an enzyme involved in purine nucleotide biosynthesis
Blood,
March 15, 2000;
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[Abstract]
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G. W. B. Colleoni, J. A. Bridge, B. Garicochea, J. Liu, D. A. Filippa, and M. Ladanyi
ATIC-ALK: A Novel Variant ALK Gene Fusion in Anaplastic Large Cell Lymphoma Resulting from the Recurrent Cryptic Chromosomal Inversion, inv(2)(p23q35)
Am. J. Pathol.,
March 1, 2000;
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TOP
ABSTRACT
INTRODUCTION