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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 93 No. 8 (April 15), 1999:
pp. 2697-2706
ALK+ Lymphoma: Clinico-Pathological Findings and Outcome
By
Brunangelo Falini,
Stefano Pileri,
Pier Luigi Zinzani,
Antonino Carbone,
Vittorina Zagonel,
Chris Wolf-Peeters,
Gregor Verhoef,
Fabio Menestrina,
Giuseppe Todeschini,
Marco Paulli,
Mario Lazzarino,
Roberto Giardini,
Antonella Aiello,
Hans-Dieter Foss,
Iguacyra Araujo,
Marco Fizzotti,
Pier-Giuseppe Pelicci,
Leonardo Flenghi,
Massimo F. Martelli, and
Antonella Santucci
From the Institute of Hematology, University of Perugia, Perugia,
Italy; the Institutes of Pathology and Hematology, University of
Bologna, Bologna, Italy; the Institutes of Pathology and Clinical
Oncology, Centro di Riferimento Oncologico, Istituto Nazionale Tumori,
Aviano, Italy; the Institutes of Pathology and Hematology, University
of Leuven, Leuven, Belgium; the Institutes of Pathology and Hematology,
University of Verona, Verona, Italy; the Institutes of Pathology and
Hematology, University of Pavia, Pavia, Italy; the Institute of
Pathology, Istituto Nazionale Tumori of Milan, Milan, Italy; the
Institutes of Pathology and Hematology, Benjamin Franklin University,
Berlin, Germany; and the European Institute of Oncology, Milan, Italy.
 |
ABSTRACT |
A distinct pathologic entity (ALK+ lymphoma) that is
characterized by expression of the anaplastic lymphoma kinase (ALK)
protein has recently emerged within the heterogeneous group of
CD30+ anaplastic large-cell lymphomas. Information on
clinical findings and treatment outcome of ALK+ lymphoma
is still limited, and no data are available concerning the value of the
International Prognostic Index when applied to this homogeneous disease
entity. To clarify these issues, a recently developed monoclonal
antibody ALKc (directed against the cytoplasmic portion of ALK) was
used to detect expression of the ALK protein in paraffin-embedded
biopsies from 96 primary, systemic T/null anaplastic large-cell
lymphomas, and the ALK staining pattern was correlated with
morphological features, clinical findings, risk factors (as defined by
the International Prognostic Index), and outcome in 78 patients (53 ALK+ and 25 ALK ). Strong cytoplasmic
and/or nuclear ALK positivity was detected in 58 of 96 ALCL cases
(60.4%), and it was associated with a morphological spectrum (common
type, 82.7%; giant cell, 3.5%; lymphohistiocytic, 8.6%; and small
cell, 5.2%) that reflected the ratio of large anaplastic elements
(usually showing cytoplasmic and nuclear ALK positivity) to small
neoplastic cells (usually characterized by nucleus-restricted ALK
expression). Clinically, ALK+ lymphoma mostly occurred in
children and young adults (mean age, 22.01 ± 10.87 years) with a male
predominance (male/female [M/F] ratio, 3.0) that was particularly
striking in the second-third decades of life (M/F ratio, 6.5) and
usually presented as an aggressive, stage III-IV disease, frequently
associated with systemic symptoms (75%) and extranodal involvement
(60%), especially skin (21%), bone (17%), and soft tissues (17%).
As compared with ALK+ lymphoma, ALK cases
occurred in older individuals (mean age, 43.33 ± 16.15 years) and
showed a lower M/F ratio (0.9) as well as lower incidence of stage
III-IV disease and extranodal involvement at presentation. Overall
survival of ALK+ lymphoma was far better than that of
ALK anaplastic large-cell lymphoma (71% ± 6%
v 15% ± 11%, respectively). However, within the good
prognostic category of ALK+ lymphoma, survival was 94% ± 5% for the low/low intermediate risk group (age-adjusted
International Prognostic Index, 0 to 1) and 41% ± 12% for the
high/high intermediate risk group (age-adjusted International
Prognostic Index,  2). Multivariate analysis identified ALK
expression and the International Prognostic Index as independent variables that were able to predict survival among T/null primary, systemic anaplastic large-cell lymphoma. Thus, we suggest that such
parameters should be taken into consideration for the design of future
clinical trials.
© 1999 by The American Society of Hematology.
| |
INTRODUCTION |
CD30+ ANAPLASTIC large-cell
lymphoma is a widely recognized clinico-pathological entity that is
characterized by frequent occurrence in children (~40% of all
large-cell lymphomas),1,2 preferential paracortical and
intrasinusoidal lymph node involvement by large anaplastic tumor cells
expressing the CD30 molecule (previously named Ki-1),3,4
and highly aggressive clinical course usually associated with systemic
symptoms and extranodal involvement, especially skin and
bone.1,2,4-13 Anaplastic large-cell lymphomas of B- and
T-cell type were initially recognized in the updated Kiel
Classification.14 The recently proposed Revised
European-American Lymphoma (REAL) classification15 included
the B-cell type anaplastic large-cell lymphoma among the morphological
variants of diffuse large B-cell lymphoma, limiting the term of
anaplastic large-cell lymphoma only to cases with T and null phenotype.
Anaplastic large-cell lymphoma is associated with a t(2;5)(p23;q35)
chromosome translocation16 that causes the anaplastic lymphoma kinase (ALK) gene on chromosome 2 to fuse with the
NPM (nucleophosmin) gene on chromosome 5.17 The
NPM-ALK fusion gene encodes for a 80-kD NPM-ALK chimeric
protein17-19 that consists of the N-terminal portion of the
NPM molecule (aminoacids 1-117)17,18 linked to the entire
cytoplasmic domain of the neural-specific receptor tyrosine kinase
ALK.20,21 The NPM-ALK hybrid protein is thought to play a
key role in lymphomagenesis by aberrant phosphorylation of
intracellular substrates.17,18,22-25
Polyclonal26,27 and monoclonal antibodies
(MoAbs)28,29 directed against the cytoplasmic portion of
the ALK protein have been recently used to detect in tumor biopsies the
NPM-ALK fusion protein [generated by the t(2;5)
translocation]28,29 or full-length ALK.30 In
two large studies,29,31 expression of the ALK protein was
demonstrated in approximately 60% of anaplastic large-cell lymphomas.
These cases occurred most frequently in the first three decades of life
and consistently showed a T/null phenotype associated with a
morphological spectrum, ranging from the common type to the
lymphohistiocytic or small-cell variant.29,31 For these tumors, we and others have recently proposed the term of
ALK+ lymphoma29,31 and Nakamura et
al32 proposed that of primary classical anaplastic
large-cell lymphoma. This lymphoma is more likely to represent a single
homogeneous disease (based on the presence of the genetic abnormality)
than are neoplasms selected on the basis of morphologic and phenotypic
features, eg, CD30 expression.
In recent years there has been growing interest to identify specific
molecular features that, in addition to histologic type and clinical
status, may help to define prognosis in patients with aggressive
lymphomas. One example includes the rearrangement of the BCL-6 gene
that has been associated with a favorable outcome in diffuse large
B-cell lymphomas.33 More recently, Shiota et al34,35 reported for the first time that CD30+
anaplastic large-cell lymphoma expressing the p80 (NPM-ALK) protein (as
defined by an anti-p80 polyclonal antibody) has a better prognosis than
p80 anaplastic large-cell lymphoma.
The role of the International Prognostic Index36,37 for
predicting outcome of CD30+ anaplastic large-cell lymphoma
is matter of debate.12,13 Reasons for these conflicting
results may lie in the lack of reliable morphologic and
immunophenotypic criteria for defining anaplastic large-cell lymphoma,
as reflected by the description in literature of at least eight
putative subtypes.38-41 This points to the importance of
assessing prognostic factors in the context of a more homogeneous disease entity, eg, ALK+ lymphoma.
In this study, routinely processed biopsies from 96 cases of primary,
systemic CD30+ anaplastic large-cell lymphomas with proven
T/null phenotype were investigated for expression of the ALK protein
using a highly specific MoAb ALKc that we recently generated against a
fixative-resistant epitope on the cytoplasmic portion of
ALK.29 The ALK immunostaining pattern was then correlated
with the histological features of the tumor as well as with the
clinical findings, risk factors, and outcome to assess whether ALK
expression and the International Prognostic Index may identify
different prognostic groups among CD30+ anaplastic
large-cell lymphomas.
| |
MATERIALS AND METHODS |
Selection of cases.
Pathological samples from 96 patients with CD30+ anaplastic
large-cell lymphoma were retrieved from the files of the Hemopathology Section, Institute of Hematology, University of Perugia (Perugia, Italy); the Hemopathology Section, Institute of Hematology "Lorenzo & Ariosto Seragnoli", University of Bologna (Bologna, Italy); and
the Institutes of Pathology at the following Institutions: Centro di
Riferimento Oncologico (Aviano, Italy), University of Pavia (Pavia,
Italy), University of Verona (Verona, Italy), the Istituto Nazionale
Tumori (Milan, Italy), the University of Leuven (Leuven, Belgium), and
the Free University of Berlin (Berlin, Germany). The material included
60 cases of T/null anaplastic large-cell lymphoma that had been
reported in a previous study.29 Most tissue samples were
fixed in 10% buffered formalin, while a percentage of them were fixed
in B5 or Bouin. Slides from routinely paraffin-embedded tissues were
stained with hematoxylin-eosin, Giemsa, and Gordon-Sweet. Paraffin
sections from all cases had been stained by immunoperoxidase or
immuno-alkaline phosphatase (APAAP)42
techniques for the following antigens: CD45, CD45RO, CD20/L26, CD79a, and CD3 (purchased from Dako, Glostrup, Denmark); CD8
(a gift from Prof David Mason, Oxford, UK); CD30/Ber-H2 (kindly provided by Prof Harald Stein, Berlin, Germany); and
CD68.43 Additional phenotyping could be obtained on frozen
sections in 25 cases.
Only cases with unequivocal diagnosis of CD30+ anaplastic
large-cell lymphoma were included in the study. Diagnostic
immuno-morphological criteria were those defined in the REAL
classification,15 eg, the presence of large anaplastic
tumor cells with horseshoe-shaped or multiple nuclei containing
multiple or single prominent nucleoli and abundant, frequently
vacuolated cytoplasm that tended to grow in a cohesive pattern and
preferentially involved the lymph node sinuses. By definition, all
large tumor cells showed dot-like positivity in the Golgi area and/or
surface expression of the CD30 molecule.3,4 These criteria,
corresponding to the common or classic form of anaplastic large-cell
lymphoma, were integrated to include other morphological variants of
anaplastic large-cell lymphoma, eg, lymphohistiocytic, small-cell, and
giant cell.38-41 Based on these criteria, the cases could
be subdivided as follows: common type (n = 79), lymphohistiocytic
variant (n = 5), small-cell variant (n = 3), giant-cell rich (n = 8), and signet-ring (n = 1).
The following cases were excluded from the study: (1) primary cutaneous
T/null anaplastic large-cell lymphoma; (2) anaplastic large-cell
lymphoma with Hodgkin's like appearance15; (2) anaplastic large-cell lymphoma with B-cell phenotype; and (4) anaplastic large-cell lymphoma occurring in patients with previous diagnosis of
lymphoma or documentation of human immunodeficiency virus (HIV) infection. At the end, the analysis was restricted to T/null primary, systemic CD30+ anaplastic large-cell lymphoma with
morphology other than Hodgkin's like that occurred in the
immunocompetent host.
Immunohistological detection of the ALK protein.
Expression of the ALK protein was detected with the MoAb
ALKc29 that recognizes a fixative-resistant epitope on the
cytoplasmic portion of the ALK protein and is appliable to routinely
processed, paraffin-embedded samples. All cases were also stained in
parallel with the ALK1 MoAb (kindly provided by Prof David Y. Mason,
Oxford, UK) raised against a fragment (AA 419-520) of the cytoplasmic portion of ALK.28
Both the antibodies were applied for 30 minutes to dewaxed paraffin
sections (3- to 5-µm thick) after microwave antigen retrieval (3 times for 5 minutes at 700 W) in 1 mmol/L EDTA buffer, pH 8.0, as
previously described.44 Sections were then washed with
Tris-buffered saline, pH 7.6, and immunostained by the immuno-alkaline
phosphatase (APAAP) technique.42 The endogenous alkaline
phosphatase was blocked by adding levamisole to the substrate solution
at the final concentration of 1 mmol/L.45 Slides were then
counterstained for 5 minutes in Gill's hematoxylin and mounted in
Kaiser's gelatin.
Clinical data.
Detailed information on the clinical characteristics, treatment, and
outcome was available in 78 of 96 cases (53 ALK+ and 25 ALK). The clinical features evaluated for potential
prognostic importance were sex, age, Ann Arbor tumor stage, B symptoms,
performance status, type and number of extranodal sites (as assessed by
physical examination, computed tomography (CT) scan, and
bone marrow biopsy), maximum diameter of the largest tumor mass (bulky
>10 cm), and serum level of lactate dehydrogenase (LDH) level. B
symptoms were defined as recurrent fever (temperature >38.3°C),
night sweats, or the loss of greater than 10% of body weight within 6 months. The performance status was defined according to the World
Health Organization (WHO). The serum LDH level was
expressed as the ratio of the measured value to the upper limit of the
normal range reported in the laboratory of each participating institution.
The initial therapy and therapeutic response, details of remission,
progression or relapse, and subsequent therapies and follow-up were
recorded in each patient. The patients received different types of
therapy, depending on the Institution. Two cases in stage IA were
treated with radiotherapy only. Sixty-eight patients received various
combination-chemotherapy regimens containing doxorubicin. Eight
pediatric ALK+ lymphomas were treated with different
intensive chemotherapy regimens used for acute lymphoblastic leukemia.
Complete response (CR) was defined as the total disappearance of signs
and symptoms due to the disease as well as the normalization of all
previous abnormal findings. Partial response (PR) was defined as the
reduction of at least 50% of known disease with disappearance of the
systemic manifestations. No response (NR) was anything less than a PR.
Patients were stratified according to the International Prognostic
Index.36,37 Because all patients were less than 60 years of
age, a simplified age-adjusted International Prognostic Index was
applied that only considered three risk factors: tumor stage (I-II
v III-IV), performance status (0-1 v >1), and LDH
level (low v high). Based on these criteria, patients were
subdivided in two risk groups: (1) low/low-intermediate (simplified
International Prognostic Index, 0 to 1), as defined by the absence of
risk factors or the presence of one of them; and (2)
high/high-intermediate (simplified International Prognostic Index,
2), as defined by the presence of two or more risk factors.
Overall survival was measured from diagnosis to death from any cause,
with surviving patient follow-up censored at the last contact date.
Disease-free survival was defined as the time from therapy to the first
occurrence of relapse. Follow-up of patients not experiencing one of
these events was censored at their date of last contact. Estimates of
overall and disease-free survival distribution was calculated using the
method of Kaplan and Meier.46 Survival curves were compared
using the log-rank test.47 Multivariate survival analysis
was performed applying the Cox regression model.48
| |
RESULTS |
Pathological and immunohistological findings.
The results of ALK immunostaining in 96 anaplastic large-cell lymphomas
with T/null phenotype are summarized in
Table 1. Strong expression of the ALK
protein was observed in 58 of 96 (30 with T and 28 with null) cases
(60.4%). The ALKc and ALK1 MoAbs gave identical results, but ALKc
tended to react more strongly than ALK1 with the nuclei of tumor cells,
especially those of small size. In approximately 81% of
ALK+ cases the subcellular distribution pattern of the ALK
protein (nucleus and cytoplasm of large anaplastic elements and nucleus of small atypical cells) strongly suggested that tumor cells contained the NPM-ALK chimeric product.25,29 The remaining 19%
ALK+ lymphomas displayed a cytoplasm-restricted expression
of the ALK protein, suggesting that in these cases the ALK gene may
have fused with a genes(s) other than NPM.29,31,49
Expression of CD30 closely paralleled that of ALK in the large
anaplastic cells, whereas small tumor cells with nucleus-restricted
ALK-positivity were usually CD30.
The 58 ALK+ lymphomas showed a morphological spectrum that
included variants of common type (82.7%), giant cell (3.5%),
lymphohistiocytic (8.6%), and small cell (5.2%)
(Fig 1A through D). In 5 of 58 ALK+ cases, more than one histological pattern was found
within a single biopsy at the time of initial diagnosis (3 with common plus small cell, 1 with common plus lymphohistiocytic, and 1 with lymphohistiocytic plus small cell). One ALK+ case showed a
common type morphology at diagnosis but was lymphohistiocytic at
relapse.
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| Fig 1.
ALK+ lymphoma, common type (lymph
node, paraffin section). (A) Scattered ALK+ anaplastic
tumor cells (labeled in red) are present in the paracortical area.
Residual lymphoid tissue is ALK. GC indicates a germinal
center (×150). (Inset) Higher magnification (×800) of the same case
showing cytoplasmic and nucleolar positivity of tumor cells for the ALK
protein (arrowhead). (B) ALK+ lymphoma, common type
(lymph node, paraffin section). Large anaplastic tumor cells show
cytoplasm-restricted positivity for the ALK protein (arrow; ×800).
(C) ALK+ lymphoma, common type (lymph node, paraffin
section). Tumor cells consists of a mixture of large anaplastic
elements expressing the ALK protein both in the nucleus and cytoplasm
(arrow) and small tumor cells showing nucleus-restricted ALK positivity
(arrowhead; ×800). (D) ALK+ lymphoma, small cell
variant (lymph node, paraffin section). The tumor cell population
mostly consists of small neoplastic elements showing nucleus-restricted
ALK-positivity. A small percentage of large neoplastic cells that
express the ALK protein both in the nucleus and cytoplasm (arrowheads)
is present around blood vessels (*; ×500). (E and F)
ALK+ lymphomas (paraffin sections). Rare small-size tumor
cells showing nuclear-restricted ALK-positivity are detectable in the
cortical area of the lymph node (E, arrow) and in the bone marrow (F,
arrow). The arrowhead in (F) indicates an ALK
megakaryocyte (both ×800). (A through F) Immunostaining with the ALKc
MoAb; APAAP technique.
|
|
No expression of the ALK protein was detected in 38 of 96 anaplastic
large-cell lymphomas. Most of these cases showed the histological
features of common type, but there was some tendency of
ALK anaplastic large-cell lymphomas to be more
pleomorphic than ALK+ cases, sometimes with giant cell
appearance. No lymphohistiocytic and small cell variants were observed
in the series of ALK anaplastic large-cell lymphomas.
Diagnostic impact.
Five of 58 ALK+ lymphomas were initially misdiagnosed as
metastatic carcinoma (n = 2, due to anaplasia and cohesive pattern of
growth of tumor cells), malignant histiocytosis and reactive lymphadenopathy (n = 2, because of the exuberant hyperplasia of reactive histiocytes), and peripheral T-cell lymphoma other than anaplastic large-cell lymphoma (n = 1, due to mixed proliferation of
small and large tumor cells). Immunohistochemistry for CD30 and ALK
antigens helped to reach a correct diagnosis in these cases.
Immunohistological labeling for the ALK protein was also particularly
valuable for detecting a low number of tumor cells, especially those of
small size (usually CD30), in the paracortex of
lymph nodes (Fig 1E), bone marrow (Fig 1F), spinal fluid and skin (not
shown). In 1 patient with the lymphohistiocytic variant of
ALK+ lymphoma, the administration of nonsteroid
anti-inflammatory drugs (to control high fever) caused a marked
regression of the lymphadenopathy at the time the lymph node biopsy was
scheduled. Because of the small amount of tissue available, the
diagnosis was only possible with the use of the anti-ALK antibody that
showed the presence of rare ALK+ tumor elements in the
context of an inflammatory background of neuthrophils, macrophages, and
plasma cells.
Clinical findings.
Clinical and laboratory findings were available in 78 of 96 cases (53 ALK+ and 25 ALK) and are summarized in
Table 2. ALK+ lymphoma
frequently occurred in the first three decades of life (Fig 2; mean age, 22.01 ± 10.87 years;
age range, 3 to 52 years). The present series included 12 pediatric
patients and 41 adult patients (>16 years of age). The male/female
(M/F) ratio was 3.0, with male predominance being particularly striking
in the second to third decades of life (M/F ratio, 6.5; Fig 2).
According to the Ann Arbor staging system, 28% of patients had stage
I-II and 72% had stage III-IV disease. Most cases (75%) presented
with systemic symptoms (high fever and/or weight loss in the absence of
pruritus). Lymphadenopathy was present in 92% of patients; 40% had
exclusively nodal disease. Extranodal involvement was frequent (60%),
with 41% of patients showing two or more extranodal sites. Skin
(usually nodules or ulcerated lesions; Fig
3A), bone (Fig 3B), and soft tissues (Fig 3C) were the most frequently
involved sites (skin, 21%; bone, 17%; soft tissues, 17%), followed
by bone marrow (11%), lung (11%), and liver (8%). Tumor cells
infiltrating the marrow ranged in size from small atypical cells to
large anaplastic elements, and in one case involvement was only evident
by ALK immmunostaining of the bone marrow biopsy (Fig 1F). Three of the 6 patients with bone marrow involvement had concomitant tumor cells
circulating in the peripheral blood. None of the 6 cases with affected
bone marrow showed concomitant skin lesions. The following extranodal
sites were rarely involved: pleura (n = 3), central nervous system
(CNS; n = 2), gut (n = 1), testis (n = 1), and parotid
(n = 1).
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| Fig 3.
Extranodal involvement in ALK+ lymphoma.
(A) Umbelicated skin lesion in a 38-year-old women. (B) Large ostelytic
lesions of the skull (arrows) in a 14-year-old boy. (C) Involvement of
the right psoas muscle (asterix) in a 25-year-old man.
|
|
As compared with ALK+ lymphoma, ALK
cases in this series were characterized by occurrence at older age
(mean age, 43.33 ± 16.15 years), lower M/F ratio (0.9), and lower
incidence of stage III-IV disease and extranodal involvement at
presentation (Table 2).
Response to treatment and survival.
Overall, 77.3% of ALK+ lymphoma obtained a CR and 15.0% a
PR, with a major response (CR + PR) rate of 92.3%. Four patients (7.7%) were resistant to chemotherapy. Of 25 ALK
anaplastic large-cell lymphomas, 56% obtained a CR and 28% a PR, with
a major response (CR + PR) rate of 84%. Four patients (16%) were
resistant to therapy. No patient died of therapy-related effects.
The median follow-up for all patients was 2.10 years (range, 0.07 to
13.17 years). Overall survival of ALK+ lymphoma was
significantly better than that of ALK lymphoma (71% ± 6% v 15% ± 11%, respectively; P < .0007;
Fig 4). Disease-free survival of
ALK+ lymphoma was significantly better than that of
ALK lymphoma, being at 10 years of follow-up 82% ± 6% and 28% ± 14%, respectively (P < .0001; not
shown).
The age-adjusted International Prognostic Index predicted survival
within the good prognosis group of ALK+ lymphomas
(Table 3). Overall 5-year survival was 94% ± 5% for the low/low intermediate risk group versus 41% ± 12% for the high/high intermediate group (P < .0001;
Fig 5).
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| Fig 5.
Overall survival of ALK+ lymphoma according
to age-adjusted International Prognostic Index (0 to 1, low/low
intermediate risk group; 2, high/high intermediate risk group).
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Thirteen of 53 ALK+ lymphomas died of disease (Table 3).
All 13 patients were initially treated with aggressive polychemotherapy (N = 6, 2° generation regimens; N = 6, 3° generation regimens; N = 1, regimen for acute lymphoblastic leukemia). Four of the 13 patients achieved a CR after combination therapy but relapsed immediately after (median time to relapse, 3 months). Relapse sites
included sites of previous disease in 2 cases and new sites in 2 cases.
Three of these cases were promptly treated with high-dose therapy
followed by peripheral stem cell support that only resulted in a
transient response (median survival time from relapse to death, 3 months). Five of the 13 patients responded partially to combination
chemotherapy. Two of them received only supportive therapy and died of
progressive disease. The remaining patients were treated with
radiotherapy only, additional chemotherapy, and high-dose chemotherapy
followed by peripheral stem cell rescue, respectively. All of them
showed transient response and died of disease. Four of the 13 patients
were resistant to chemotherapy and died of rapidly progressive disease
without receiving any further treatment.
Cox multivariate analysis related to all patients indicated ALK
expression and the International Prognostic Index as the only two
independent factors able to predict survival
(Table 4).
| |
DISCUSSION |
A distinct pathologic entity (ALK+ lymphoma) that is
characterized by expression of the anaplastic lymphoma kinase (ALK)
protein has recently emerged within the heterogeneous group of
anaplastic large-cell lymphomas.29,31,32 The clinical
significance of ALK protein expression among anaplastic large-cell
lymphomas is still limited,32,34 and no data are available
concerning the value of the International Prognostic
Index36,37 when applied to the homogeneous category of
ALK+ lymphoma.
In this retrospective study, we report on clinical findings, risk
factors, and treatment outcome of a large series (53 cases) of
ALK+ lymphomas, as defined by a highly specific MoAb (ALKc)
that is appliable to routine biopsies. The availability of MoAbs (ALK1 and ALKc)28,29 directed against the cytoplasmic portion of the ALK protein represents an obvious advantage over the anti-p80 (NPM/ALK) polyclonal antibodies32,34 that are prone to
problems of nonspecific reactivity and variations between different
samples and are available only in limited amounts. Our results clearly show that analysis of ALK expression by immunohistochemistry has important diagnostic and prognostic implications, and it should be
extensively applied to the study of CD30+ anaplastic
large-cell lymphoma.
This study confirms previous observations from our group29
and other groups31 that ALK+ lymphoma is a
single disease with a morphological spectrum, with the different
variants being defined by the ratio of small to large anaplastic tumor
cells and the presence of accompanying inflammatory cells (eg,
histiocytes in the lymphohistiocytic variant).29 Some
problem cases were encountered in this study and solved by immunocytochemical detection of the ALK protein. In particular, anti-ALK antibodies helped to recognize anaplastic large-cell lymphoma
of the lymphohistiocytic type (frequently misdiagnosed as reactive
condition or malignant histiocytosis), to distinguish between the small
cell variant of anaplastic large-cell lymphoma and peripheral T-cell
lymphoma of small size, and to define cutaneous infiltrates of
uncertain nature. Moreover, taking advantage of the fact that the ALK
protein is normally not expressed in human tissues (with the exception
of a few cells in the CNS),28,29 it was possible to
identify rare ALK+ tumor cells in needle aspirates of lymph
nodes (allowing early diagnosis of disease relapse in 1 patient) or in
bone marrow and spinal fluid at the time of initial diagnosis. These
results also point to the potential of anti-ALK antibodies for
monitoring minimal residual disease post-therapy.
Clinically, ALK+ lymphoma occurred in the first three
decades (in keeping with previous data)29,31,32,34 and
frequently presented with stage III-IV disease, usually associated with
fever that possibly reflects the release of cytokines by tumor cells. Administration of steroids to decrease fever (one of the most troublesome symptoms in these patients) should be avoided until a
pathological diagnosis is established, because ALK+
lymphoma is usually highly responsive to these agents. This policy should probably apply also to nonsteroid anti-inflammatory drus that,
in 1 patient with lymphohistiocytic variant of ALK+
lymphoma, caused a marked regression of the lymphadenopathy, probably
acting on the inflammatory component.
There was a higher frequency of extranodal involvement in
ALK+ than in ALK lymphoma. The most
commonly involved sites in ALK+ lymphoma were skin (21%),
bone (17%), and soft tissues (17%). High frequency of skin and bone
involvement was originally recognized as a characteristic of systemic
anaplastic large-cell lymphoma occurring in childhood,5 and
the presence of cutaneous lesions has been associated with an increased
risk of treatment failure at this age.10 Skin involvement
was not found to be a risk factor in our series of ALK+
lymphomas, but this issue needs to be further addressed in future prospective studies. The psoas muscle was a frequent site of
involvement among soft tissues, and this was often responsible for the
clinical picture at presentation (eg, low back pain), sometimes
misinterpreted as osteo-articular disease. We observed bone marrow
involvement by conventional histology in 11% of ALK+
lymphomas. This figure is higher than that reported in two previous large series of anaplastic large-cell lymphomas in childhood (no cases
with marrow infiltration)10 and in adults (1/31 with
involved marrow).6 In at least one study,50
immunostaining for CD30 was found to be more sensitive than
conventional morphology for detecting marrow infiltration by a low
percentage of anaplastic lymphoma cells. In this respect,
immunostaining for the ALK protein could result even more informative,
because small tumor cells are usually CD30.
Anaplastic large-cell lymphoma often has an aggressive clinical course
for which combination therapy is warranted. An excellent outcome has
been reported for anaplastic large-cell lymphoma occurring in pediatric
and adult patients treated with polychemotherapy.2,10,12,13 Data on ALK expression were not available in those studies. More recently, Shiota et al34 reported on the prognostic
importance to distinguish between anaplastic large-cell lymphomas
expressing and not expressing the p80 (NPM-ALK) protein, with
p80+ cases usually showing a better survival. The results
presented in this report further confirm and extend these observations
on a larger series of patients. Moreover, we provide evidence that the
age-adjusted International Prognostic Index is able to predict outcome
within the homogeneous, prognostically favorable, group of
ALK+ lymphomas. This is in contrast with a recent report by
the non-Hodgkin's Lymphoma Classification Project12 in
which the International Prognostic Index was regarded as not important
for predicting survival of patients with T/null anaplastic large-cell
lymphoma that, even with a high prognostic index, showed a surprisingly good outcome. Lack of strict criteria (eg, ALK immunostaining) for
defining anaplastic large-cell lymphoma may have been responsible for
these differences.
Because of its similarities with Burkitt's lymphoma in terms of
clinical aggressiveness and comparable high growth
fraction,10 there has been the tendency to treat anaplastic
large-cell lymphoma occurring in childhood with the highly aggressive
polychemotherapy regimens used for lymphoblastic leukemia/lymphoma that
also involve prophylaxis for CNS involvement.7,10 In
contrast, less intensive regimens have been usually employed for the
treatment of anaplastic large-cell lymphoma occurring in young
adults.12,13 Clearly, the optimal strategy for the
treatment of anaplastic large-cell lymphoma is yet to be established.
The possibility to recognize by analysis of ALK expression anaplastic
large-cell lymphoma with good-prognosis (ALK+ lymphoma) and
to further dissect this homogeneous disease into low and high risk
cases according to the International Prognostic Index might be of great
relevance for the design of future prospective clinical trials. The
excellent outcome of low-risk ALK+ lymphoma (age-adjusted
International Prognostic Index, 0 to 1) warrants randomized comparison
of less versus more intensive conventional chemotherapy and certainly
does not support the use of high-dose therapy followed by autologous
bone marrow transplantation as a front-line treatment.51 In
contrast, patients with high-risk ALK+ lymphoma
(age-adjusted International Prognostic Index, 2) or ALK anaplastic large-cell lymphoma should be
probably enrolled in clinical studies aimed to compare the efficacy of
conventional polychemotherapy versus high-dose chemotherapy followed by
stem cell support.51,52 Other potentially interesting and
innovative therapeutic strategies in this category of patients include
(1) anti-CD30 immunotoxins53,54; (2) anti-CD30-targeted
tyrosine kinase inhibitors (to block anaplastic lymphoma
kinase)55,56; (3) induction of T-cell immune response
against the tumor-specific ALK protein; and (4) use of cis-retinoic
acid.57
Based on the above-noted findings, we suggest that, within the category
of CD30+ anaplastic large-cell lymphoma (T/null),
ALK+ lymphoma should be separated from the
ALK cases, because they represent a distinct disease
entity with favorable outcome. However, even for ALK+
lymphoma, prognostic factors, as defined by the age-adjusted International Prognostic Index, must be taken into consideration for
predicting patient survival.
| |
ACKNOWLEDGMENT |
The authors thank Claudia Tibidó for the excellent
secretarial assistance.
| |
FOOTNOTES |
Submitted October 23, 1998; accepted December 9, 1998.
Supported by AIRC (Associazione Italiana per la Ricerca sul Cancro) and
MURST. M.F. is supported by the Fondazione Antonio Castelnuovo.
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 Brunangelo Falini, MD, Istituto di
Ematologia, Policlinico, Monteluce, 06122 Perugia, Italy.
| |
REFERENCES |
1.
Murphy SB:
Pediatric lymphomas. Recent advances and commentary on Ki-1 positive anaplastic large cell lymphomas of childhood.
Ann Oncol
5:31, 1994
2.
Sandlund JT, Pui CP, Santana VM, Mahmoud H, Roberts M, Morris S, Raimondi S, Ribeiro R, Crist WM, Lin JS, Mao L, Berard CW, Hutchison RE:
Clinical features and treatment outcome for children with CD30+ large cell non-Hodgkin's lymphoma.
J Clin Oncol
12:895, 1994[Abstract/Free Full Text]
3.
Stein H, Mason DY, Gerdes J, O'Connor N, Wainscoat J, Pallesen G, Gatter K, Falini B, Delsol G, Lemke H, Schwarting R, Lennert K:
The expression of Hodgkin's disease associated Ki-1 in reactive and neoplastic lymphoid tissues: Evidence that Sternberg-Reed cells and histiocytic malignancies are derived from activated lymphoid cells.
Blood
66:848, 1985[Abstract/Free Full Text]
4.
Falini B, Pileri S, Pizzolo G, Durkop H, Flenghi L, Stirpe F, Martelli MF, Stein H:
CD30 (Ki-1) molecule: A new cytokine receptor of the tumor necrosis factor receptor superfamily as a tool for diagnosis and immunotherapy.
Blood
85:1, 1995[Free Full Text]
5.
Kadin ME, Sako D, Berliner N, Franklin W, Woda B, Borowitz M, Ireland K, Schweid A, Herzog P, Lange B, Dorfman R:
Chilhood Ki-1 lymphoma presenting with skin lesions and peripheral lymphadenopathy.
Blood
68:1042, 1986[Abstract/Free Full Text]
6.
Greer JP, Kinney MC, Collins RD, Salhany KE, Wolff SN, Hainsworth JD, Flexner JM, Stein RS:
Clinical features of 31 patients with Ki-1 anaplastic large cell lymphoma.
J Clin Oncol
9:539, 1991[Abstract]
7.
Vecchi V, Burnelli R, Pileri S, Rosito P, Sabattini E, Civino A, Pericoli R, Paolucci G:
Anaplastic large cell lymphoma (Ki-1/CD30+) in childhood.
Med Pediatr Oncol
21:402, 1993[Medline]
[Order article via Infotrieve]
8.
Kadin ME:
Primary Ki-1 positive anaplastic large cell lymphoma: A distinct clinicopathologic entity.
Ann Oncol
5:25, 1994[Free Full Text]
9.
Pileri S, Bocchia M, Baroni CD, Martelli M, Falini B, Sabattini E, Gherlinzoni F, Amadori S, Poggi S, Mazza P, Burgio V, Zinzani PL, Melilli G, Benni M, Saragoni L, Martelli MF, Stein H, Mandelli F, Tura S:
Anaplastic large cell lymphoma (CD30+/Ki-1+): results of a prospective clinico-pathological study of 69 cases.
Br J Haematol
86:513, 1994[Medline]
[Order article via Infotrieve]
10.
Reiter A, Schrappe M, Tiemann M, Parwaresch R, Zimmermann M, Yakisan E, Dopfer R, Bucsky P, Mann G, Gadner H, Riehm H:
Successful treatment strategy for Ki-1 anaplastic large cell lymphoma of childhood. A prospective analysis of 62 patients enrolled in three consecutive Berlin-Frankfurt-Munster group studies.
J Clin Oncol
12:899, 1994[Abstract/Free Full Text]
11.
Zinzani PL, Bendandi M, Martelli M, Falini B, Sabattini E, Amadori S, Gherlinzoni F, Martelli MF, Mandelli F, Tura S, Pileri S:
Anaplastic large cell lymphoma: Clinical and prognostic evaluation of 90 adult patients.
J Clin Oncol
14:955, 1996[Abstract/Free Full Text]
12.
The non-Hodgkin's Lymphoma Classification Project:
A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin's lymphoma.
Blood
89:3909, 1997[Abstract/Free Full Text]
13.
Tilly H, Gaulard P, Lepage E, Dumontet C, Diebold J, Plantier I, Berger F, Symann M, Petrella T, Lederlin P, Briere J, for the Groupe d'Etudes des Lymphomes de l' Adulte:
Primary anaplastic large-cell lymphoma in adults: Clinical presentation, immunophenotype, and outcome.
Blood
90:3727, 1997[Abstract/Free Full Text]
14.
Stansfeld A, Diebold J, Kapanci Y, Kelenyi G, Lennert K, Mioduszewska O, Noel H, Rilke F, Sundstrom C, Van Unnik J, Wright D:
Updated Kiel classification for lymphomas.
Lancet
1:292, 1988[Medline]
[Order article via Infotrieve]
15.
Harris NL, Jaffe ES, Stein H, Banks P, Chan JKC, Cleary ML, Delsol G, De Wolf-Peeters C, Falini B, Gatter KC, Grogan TM, Isaacson PG, Knowles DM, Mason DY, Muller-Hermelink HK, Pileri SA, Ralfkier E, Warnke RA:
A Revised European-American classification of lymphoid neoplasms: A proposal from the International Lymphoma Study Group.
Blood
84:1361, 1994[Free Full Text]
16.
Mason DY, Bastard C, Rimokh R, Dastugue N, Huret J-L, Kristoffersson U, Magaud J-P, Nezelof C, Tilly H, Vannier J-P, Hemet J, Warnke R:
CD30-positive large cell lymphomas (Ki-1 lymphoma) are associated with a chromosomal translocation involving 5q35.
Br J Haematol
74:161, 1990[Medline]
[Order article via Infotrieve]
17.
Morris SW, Kirstein MN, Valentine MB, Dittmer KG, Shapiro DN, Saltman DL, Look AT:
Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin's lymphoma.
Science
263:1281, 1994[Abstract/Free Full Text]
18.
Ladanyi M:
The NPM/ALK gene fusion in the pathogenesis of anaplastic large cell lymphoma.
Cancer Surv
30:59, 1997[Medline]
[Order article via Infotrieve]
19.
Shiota M, Fujimoto J, Semba T, Satoh H, Yamamoto T, Mori S:
Hyperphosphorylation of a novel 80 kDa protein-tyrosine kinase similar to Ltk in a human Ki-1 lymphoma cell line, AMS3.
Oncogene
9:1567, 1994[Medline]
[Order article via Infotrieve]
20.
Morris SW, Naeve C, Mathew P, Kirstein MN, Cui X, Witte DP:
ALK, the chromosome 2 gene locus altered by the t(2;5) in non-Hodgkin's lymphoma, encodes a novel neural-specific receptor tyrosine kinase that is highly related to leukocyte tyrosine kinase (LTK).
Oncogene
14:2175, 1997[Medline]
[Order article via Infotrieve]
21.
Iwahara T, Fujimoto J, Wen D, Cupples R, Bucay N, Arakawa T, Mori S, Ratzkin B, Yamamoto T:
Molecular characterization of ALK, a receptor tyrosine kinase expressed specifically in the nervous system.
Oncogene
14:439, 1997[Medline]
[Order article via Infotrieve]
22.
Fujimoto J, Shiota M, Iwahara T, Seki N, Satoh H, Mori S, Yamamoto T:
Characterization of the transforming activity of p80 a hyperphosphorylated protein in a Ki-1 lymphoma cell line with chromosomal translocation t(2;5).
Proc Natl Acad Sci USA
93:4181, 1996[Abstract/Free Full Text]
23.
Bischof D, Pulford K, Mason DY, Morris SW:
Role of nucleophosmin (NPM) portion of the non-Hodgkin's lymphoma-associated NPM-anaplastic kinase fusion protein in oncogenesis.
Mol Cell Biol
17:2312, 1997[Abstract]
24.
Kuefer MU, Look AT, Pulford K, Behm FG, Pattengale PK, Mason DY, Morris SW:
Retrovirus-mediated gene transfer of NPM-ALK causes lymphoid malignancy in mice.
Blood
90:2901, 1997[Abstract/Free Full Text]
25.
Mason DY, Pulford K, Bischof D, Kuefer MU, Butler LH, Lamant L, Delsol G, Morris S:
Nucleolar localization of the nucleophosmin-anaplastic lymphoma kinase tyrosine kinase is not required for malignant transformation.
Cancer Res
58:1057, 1998[Abstract/Free Full Text]
26.
Shiota M, Fujimoto J, Takenaga M, Satoh H, Ichinohasama R, Abe M, Nakano M, Yamamoto T, Mori S:
Diagnosis of t(2;5) (p23;q35)-associated Ki-1 lymphoma with immunohistochemistry.
Blood
84:3648, 1994[Abstract/Free Full Text]
27.
Hutchinson RE, Banki K, Shuster JJ, Barrett D, Dieck C, Berard CW, Murphy SB, Link MP, Pick Te, Laver J, Schwenn M, Mathew P, Morris SW:
Use of an anti-ALK antibody in the characterization of anaplastic large-cell lymphoma of childhood.
Ann Oncol
8:37, 1997[Abstract/Free Full Text]
28.
Pulford K, Lamant L, Morris S, Butler LH, Wood KM, Stroud D, Delsol G, Mason DY:
Detection of ALK and NPM-ALK protein in normal and neoplastic cells with the monoclonal antibody ALK1.
Blood
89:1394, 1997[Abstract/Free Full Text]
29.
Falini B, Bigerna B, Fizzotti M, Pulford K, Pileri S, Delsol G, Carbone A, Paulli M, Magrini U, Menestrina F, Giardini R, Pilotti S, Mezzelani A, Ugolini B, Billi M, Pucciarini A, Pacini R, Pelicci PG, Flenghi L:
ALK expression defines a distinct group of T/Null lymphomas ("ALK lymphomas") with a wide morphological spectrum.
Am J Pathol
153:875, 1998[Abstract/Free Full Text]
30.
Delsol G, Lamant L, Mariamé B, Pulford K, Dastugue N, Brousset P, Rigal-Huguet F, Al Saati T, Cerretti DP, Morris SW, Mason DY:
A new subtype of large B-cell lymphoma expressing the ALK kinase and lacking the 2;5 translocation.
Blood
89:1483, 1997[Abstract/Free Full Text]
31.
Benharroch D, Meguerian-Bedoyan Z, Lamant L, Amin C, Brugieres L, Terrier-Lacombe MJ, Haralambieva E, Pulford K, Pileri S, Morris S, Mason DY, Delsol G:
ALK-positive lymphoma: A single disease with a broad spectrum of morphology.
Blood
91:2076, 1998[Abstract/Free Full Text]
32.
Nakamura S, Shiota M, Nakagawa A, Yatabe Y, Kojima M, Motoori T, Suzuki R, Kagami Y, Ogura M, Morishima Y, Mizoguchi Y, Okamoto M, Seto M, Koshikawa T, Mori S, Suchi T:
Anaplastic large cell lymphoma: A distinct molecular pathologic entity: A reappraisal with special reference to p80(NPM/ALK) expression.
Am J Surg Pathol
21:1420, 1997[Medline]
[Order article via Infotrieve]
33.
Offit K, Lo Coco F, Louie DC, Parsa NZ, Leung D, Portlock C, Ye BH, Lista F, Filippa DA, Rosenbaum A, Ladanyi M, Jhanwar S, Dalla-Favera R, Chaganti RSK:
Rearrangement of the bcl-6 gene as a prognostic marker in diffuse large-cell lymphoma.
N Engl J Med
331:74, 1994[Abstract/Free Full Text]
34.
Shiota M, Nakamura S, Ichinohasama R, Abe M, Akagi T, Takeshita M, Mori N, Fujimoto J, Miyauchi J, Mikata A, Nanba K, Takami T, Yamabe H, Takano Y, Izumo T, Nagatani T, Mohri N, Nasu K, Satoh H, Katano H, Fujimoto J, Yamamoto T, Mori S:
Anaplastic large cell lymphomas expressing the novel chimeric protein p80NPM/ALK: A distinct clinicopathologic entity.
Blood
86:1954, 1995[Abstract/Free Full Text]
35.
Shiota M, Mori S:
The clinicopathological features of anaplastic large cell lymphomas expressing p80NPM/ALK.
Leuk Lymphoma
23:25, 1996[Medline]
[Order article via Infotrieve]
36.
The International Non-Hodgkin's Lymphoma Prognostic Factors Project:
A predictive model for aggressive non-Hodgkin's lymphoma.
N Engl J Med
329:987, 1993[Abstract/Free Full Text]
37.
Shipp M:
Prognostic factors in aggressive non-Hodgkin's lymphoma: Who has "high risk" disease?
Blood
83:1165, 1994[Abstract/Free Full Text]
38.
Pileri S, Falini B, Delsol G, Stein H, Baglioni P, Poggi S, Martelli MF, Rivano MT, Mason DY, Stansfeld AG:
Lymphohistiocytic T-cell lymphoma (anaplastic large cell lymphoma CD30+/Ki-1+) with a high content of reactive histiocytes.
Histopathology
16:383, 1990[Medline]
[Order article via Infotrieve]
39.
Kinney MC, Collins RD, Greer JP, Whitlock JA, Sioutos N, Kadin ME:
A small cell-predominant variant of primary Ki-1 (CD30)+ T-cell lymphoma.
Am J Surg Pathol
17:859, 1993[Medline]
[Order article via Infotrieve]
40.
Pileri SA, Mason DY, Mori S, Pulford K, Sabattini E, Roncador G, Piccaluga PP, Stein H, Falini B:
Frequent expression of the p80 NPM-ALK chimeric fusion protein in anaplastic large cell lymphoma, lympho-histiocytic type.
Am J Pathol
150:1207, 1997[Abstract]
41.
Kadin ME:
Anaplastic large cell lymphoma and its morphological variants.
Cancer Surv
30:77, 1997[Medline]
[Order article via Infotrieve]
42.
Cordell JL, Falini B, Erber WN, Ghosh AK, Abdulaziz Z, MacDonald S, Pulford KAF, Stein H, Mason DY:
Immunoenzymatic labelling of monoclonal antibodies using immune complexes of alkaline phosphatase and monoclonal anti-alkaline phosphatase (APAAP complexes).
J Histochem Cytochem
32:219, 1994[Abstract]
43.
Falini B, Flenghi L, Pileri S, Gambacorta M, Bigerna B, Durkop H, Eitelbach F, Thiele J, Pacini R, Cavaliere A, Martelli M, Cardarelli N, Sabattini E, Poggi S, Stein H:
PG-M1: A new monoclonal antibody directed against a fixative-resistant epitope on the macrophage-restricted form of the CD68 molecule.
Am J Pathol
142:1359, 1993[Abstract]
44.
Pileri S, Roncador G, Ceccarelli C, Piccioli M, Briskomatis A, Sabattini E, Ascani S, Santini D, Piccaluga PP, Leone O, Damiani S, Ercolessi C, Sandri F, Pieri F, Leoncini L, Falini B:
Antigen retrieval techniques in immunohistochemistry: Comparison of different methods.
J Pathol
183:116, 1997[Medline]
[Order article via Infotrieve]
45.
Ponder BA, Wilkinson WN:
Inhibition of endogenous tissue alkaline phosphatase with the use of alkaline phosphatase conjugates in immunohistochemistry.
J Histochem Cytochem
29:981, 1981[Abstract]
46.
Kaplan EL, Meier P:
Nonparametric estimation from incomplete observations.
J Am Stat Assoc
53:457, 1958
47.
Mantel N:
Evaluation of survival data and two new rank order statistics arising in its consideration.
Cancer Chemother Rep
50:163, 1966[Medline]
[Order article via Infotrieve]
48.
Cox DR:
Regression models and life-tables.
J R Stat Soc
34:187, 1972
49.
Wlodarska I, De Wolf-Peeters C, Falini B, Verhoef G, Morris SW, Hagemeijer A, Van den Berghe H:
The cryptic inv(2) (p23q35) defines a new molecular genetic subtype of ALK-positive ALCL.
Blood
92:2688, 1998[Abstract/Free Full Text]
50.
Fraga M, Brousset P, Schlaifer D, Payen C, Robert A, Rubie H, Huguet-Rigal F, Delsol G:
Bone marrow involvement in anaplastic large cell lymphoma. Immunocytochemical detection of minimal disease and its prognostic significance.
Am J Clin Pathol
103:82, 1995[Medline]
[Order article via Infotrieve]
51.
Fanin R, Silvestri P, Geromin A, Cerno M, Infanti I, Zaja F, Barillari G, Savignano C, Rinaldi C, Damiani D, Buffoli A, Biffoni F, Baccarani M:
Primary systemic CD30(Ki-1)-positive anaplastic large cell lymphoma of the adult:sequential intensive treatment with F-MACHOP regimen (± radiotherapy) and autologous bone marrow transplantation.
Blood
87:1243, 1996[Abstract/Free Full Text]
52.
Chakravarti V, Kamani NR, Bayever E, Lange B, Herzog P, Sanders JE, August CS:
Bone marrow transplantation for chilhood Ki-1 lymphoma.
J Clin Oncol
8:657, 1990[Abstract]
53.
Falini B, Bolognesi A, Flenghi L, Tazzari PL, Broe MK, Stein H, Durkop H, Aversa F, Corneli P, Pizzolo G, Barbabietola G, Sabattini E, Pileri S, Martelli MF, Stirpe F:
Response of refractory Hodgkin's disease to monoclonal anti-CD30 immunotoxin.
Lancet
339:1195, 1992[Medline]
[Order article via Infotrieve]
54.
Pasqualucci L, Wasik M, Teicher BA, Flenghi L, Bolognesi A, Stirpe F, Polito L, Falini B, Kadin MA:
Antitumor activity of anti-CD30 immunotoxin (Ber-H2/saporin) in vitro and in severe combined immunodeficiency disease mice xenografted with human CD30+ anaplastic large cell lymphoma.
Blood
85:2139, 1995[Abstract/Free Full Text]
55.
Uckun FM, Evans WE, Forsyth CJ:
Biotherapy of B-cell precursor leukemia by targeting genistein to CD19 associated kinases.
Science
267:886, 1995[Abstract/Free Full Text]
56.
Bolen JB, Brugge JS:
Leukocyte protein tyrosine kinases: Potential targets for drug discovery.
Annu Rev Immunol
15:371, 1997[Medline]
[Order article via Infotrieve]
57.
Chou W-C, Su I-J, Tien H-F, Liang D-C, Wang C-H, Chang Y-C, Cheng A-L:
Clinicopathologic, cytogenetic, and molecular studies of 13 Chinese patients with Ki-1 anaplastic large cell lymphomas. Special emphasis on the tumor response to 13-cis retinoid acid.
Cancer
78:1805, 1996[Medline]
[Order article via Infotrieve]
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October 1, 2006;
108(7):
2407 - 2415.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. Jacobsen
Anaplastic Large-Cell Lymphoma, T-/Null-Cell Type
Oncologist,
July 1, 2006;
11(7):
831 - 840.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. A. Rizvi, A. M. Evens, M. S. Tallman, B. P. Nelson, and S. T. Rosen
T-cell non-Hodgkin lymphoma
Blood,
February 15, 2006;
107(4):
1255 - 1264.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. J. Murphy, P. O'Neill, F. O'Brien, H. Enright, M. Jeffers, J. A. Thornhill, and B. M. Loftus
Anaplastic Large Cell Lymphoma: A Unique Presentation with Urinary Bladder Involvement: A Case Report
International Journal of Surgical Pathology,
October 1, 2005;
13(4):
369 - 374.
[Abstract]
[PDF]
|
|
|
|
|
|
|
F. Jundt, N. Raetzel, C. Muller, C. F. Calkhoven, K. Kley, S. Mathas, A. Lietz, A. Leutz, and B. Dorken
A rapamycin derivative (everolimus) controls proliferation through down-regulation of truncated CCAAT enhancer binding protein {beta} and NF-{kappa}B activity in Hodgkin and anaplastic large cell lymphomas
Blood,
September 1, 2005;
106(5):
1801 - 1807.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
W.-Y. Au, S.-Y. Ma, C.-S. Chim, C. Choy, F. Loong, A. K. W. Lie, C. C. K. Lam, A. Y. H. Leung, E. Tse, C.-C. Yau, et al.
Clinicopathologic features and treatment outcome of mature T-cell and natural killer-cell lymphomas diagnosed according to the World Health Organization classification scheme: a single center experience of 10 years
Ann. Onc.,
February 1, 2005;
16(2):
206 - 214.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. Falini, C. Mecucci, E. Tiacci, M. Alcalay, R. Rosati, L. Pasqualucci, R. La Starza, D. Diverio, E. Colombo, A. Santucci, et al.
Cytoplasmic Nucleophosmin in Acute Myelogenous Leukemia with a Normal Karyotype
N. Engl. J. Med.,
January 20, 2005;
352(3):
254 - 266.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. E. Janik, J. C. Morris, S. Pittaluga, K. McDonald, M. Raffeld, E. S. Jaffe, N. Grant, M. Gutierrez, T. A. Waldmann, and W. H. Wilson
Elevated serum-soluble interleukin-2 receptor levels in patients with anaplastic large cell lymphoma
Blood,
November 15, 2004;
104(10):
3355 - 3357.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. O. Armitage, J. M. Vose, and D. D. Weisenburger
Towards understanding the peripheral T-cell lymphomas
Ann. Onc.,
October 1, 2004;
15(10):
1447 - 1449.
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. J. Schlette, L. J. Medeiros, A. Goy, R. Lai, and G. Z. Rassidakis
Survivin Expression Predicts Poorer Prognosis in Anaplastic Large-Cell Lymphoma
J. Clin. Oncol.,
May 1, 2004;
22(9):
1682 - 1688.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Rodriguez, M. D. Caballero, A. Gutierrez, J. Marin, J. J. Lahuerta, A. Sureda, E. Carreras, A. Leon, R. Arranz, A. Fernandez de Sevilla, et al.
High-dose chemotherapy and autologous stem cell transplantation in peripheral T-cell lymphoma: the GEL-TAMO experience
Ann. Onc.,
December 1, 2003;
14(12):
1768 - 1775.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. D. Khoury, L. J. Medeiros, G. Z. Rassidakis, M. A. Yared, P. Tsioli, V. Leventaki, A. Schmitt-Graeff, M. Herling, H. M. Amin, and R. Lai
Differential Expression and Clinical Significance of Tyrosine-phosphorylated STAT3 in ALK+ and ALK- Anaplastic Large Cell Lymphoma
Clin. Cancer Res.,
September 1, 2003;
9(10):
3692 - 3699.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J J Oudejans, R L ten Berge, and C J L M Meijer
Immune escape mechanisms in ALCL
J. Clin. Pathol.,
June 1, 2003;
56(6):
423 - 425.
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. Z. Rassidakis, A. Goy, L. J. Medeiros, Y. Jiang, A. Thomaides, Y. Remache, F. Cabanillas, A. H. Sarris, and F. Gilles
Prognostic Significance of MUC-1 Expression in Systemic Anaplastic Large Cell Lymphoma
Clin. Cancer Res.,
June 1, 2003;
9(6):
2213 - 2220.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. Z. Rassidakis, F.-X. Claret, R. Lai, Q. Zhang, A. H. Sarris, T. J. McDonnell, and L. J. Medeiros
Expression of p27Kip1 and c-Jun Activation Binding Protein 1 Are Inversely Correlated in Systemic Anaplastic Large Cell Lymphoma
Clin. Cancer Res.,
March 1, 2003;
9(3):
1121 - 1128.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
V Costes-Martineau, C Delfour, S Obled, L Lamant, G-P Pageaux, P Baldet, P Blanc, and G Delsol
Anaplastic lymphoma kinase (ALK) protein expressing lymphoma after liver transplantation: case report and literature review
J. Clin. Pathol.,
November 1, 2002;
55(11):
868 - 871.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. L. Kutok and J. C. Aster
Molecular Biology of Anaplastic Lymphoma Kinase-Positive Anaplastic Large-Cell Lymphoma
J. Clin. Oncol.,
September 1, 2002;
20(17):
3691 - 3702.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. A. Raetz, S. L. Perkins, M. A. Carlson, K. P. Schooler, W. L. Carroll, and D. M. Virshup
The Nucleophosmin-Anaplastic Lymphoma Kinase Fusion Protein Induces c-Myc Expression in Pediatric Anaplastic Large Cell Lymphomas
Am. J. Pathol.,
September 1, 2002;
161(3):
875 - 883.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. L. ten Berge, C. J. L. M. Meijer, D. F. Dukers, J. A. Kummer, B. A. Bladergroen, W. Vos, C. E. Hack, G. J. Ossenkoppele, and J. J. Oudejans
Expression levels of apoptosis-related proteins predict clinical outcome in anaplastic large cell lymphoma
Blood,
May 29, 2002;
99(12):
4540 - 4546.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
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;
99(6):
2100 - 2106.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. Falini and D. Y. Mason
Proteins encoded by genes involved in chromosomal alterations in lymphoma and leukemia: clinical value of their detection by immunocytochemistry
Blood,
January 15, 2002;
99(2):
409 - 426.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
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
J. Immunol.,
January 1, 2002;
168(1):
466 - 474.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
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
J. Clin. Pathol.,
December 1, 2001;
54(12):
933 - 939.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
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
Am. J. Pathol.,
August 1, 2001;
159(2):
527 - 535.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
R L Ten Berge, J J Oudejans, D F Dukers, and C J L M Meijer
Anaplastic large cell lymphoma: what's in a name?
J. Clin. Pathol.,
June 1, 2001;
54(6):
494 - 495.
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. P. Greer, M. C. Kinney, and T. P. Loughran Jr.
T Cell and NK Cell Lymphoproliferative Disorders
Hematology,
January 1, 2001;
2001(1):
259 - 281.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Stein, H.-D. Foss, H. Durkop, T. Marafioti, G. Delsol, K. Pulford, S. Pileri, and B. Falini
CD30+ anaplastic large cell lymphoma: a review of its histopathologic, genetic, and clinical features
Blood,
December 1, 2000;
96(12):
3681 - 3695.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
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,
November 1, 2000;
96(9):
2993 - 3000.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Pulford, B. Falini, A. H. Banham, D. Codrington, H. Roberton, C. Hatton, and D. Y. Mason
Immune response to the ALK oncogenic tyrosine kinase in patients with anaplastic large-cell lymphoma
Blood,
August 15, 2000;
96(4):
1605 - 1607.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Ladanyi
Aberrant ALK Tyrosine Kinase Signaling : Different Cellular Lineages, Common Oncogenic Mechanisms?
Am. J. Pathol.,
August 1, 2000;
157(2):
341 - 345.
[Full Text]
[PDF]
|
|
|
|
|
|
|
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
Am. J. Pathol.,
August 1, 2000;
157(2):
377 - 384.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Wellmann, C. Thieblemont, S. Pittaluga, A. Sakai, E. S. Jaffe, P. Siebert, and M. Raffeld
Detection of differentially expressed genes in lymphomas using cDNA arrays: identification of clusterin as a new diagnostic marker for anaplastic large-cell lymphomas
Blood,
July 15, 2000;
96(2):
398 - 404.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
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,
June 15, 2000;
95(12):
3653 - 3661.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. de Wolf-Peeters and R. Achten
Anaplastic large cell lymphoma: what's in a name?
J. Clin. Pathol.,
June 1, 2000;
53(6):
407 - 408.
[Full Text]
[PDF]
|
|
|
|
|
|
|
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
J. Clin. Pathol.,
June 1, 2000;
53(6):
445 - 450.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
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,
May 15, 2000;
95(10):
3204 - 3207.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. K. C. Chan
The Perivascular Cuff of Large Lymphoid Cells: A Clue to Diagnosis of Anaplastic Large Cell Lymphoma
International Journal of Surgical Pathology,
April 1, 2000;
8(2):
153 - 156.
[Abstract]
[PDF]
|
|
|
|
|
|
|
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;
95(6):
2144 - 2149.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
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;
156(3):
781 - 789.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. Falini, K. Pulford, A. Pucciarini, A. Carbone, C. De Wolf-Peeters, J. Cordell, M. Fizzotti, A. Santucci, P.-G. Pelicci, S. Pileri, et al.
Lymphomas Expressing ALK Fusion Protein(s) Other Than NPM-ALK
Blood,
November 15, 1999;
94(10):
3509 - 3515.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Siebert, S. Gesk, L. Harder, D. Steinemann, W. Grote, B. Schlegelberger, M. Tiemann, I. Wlodarska, and V. Schemmel
Complex Variant Translocation t(1;2) With TPM3-ALK Fusion Due to Cryptic ALK Gene Rearrangement in Anaplastic Large-Cell Lymphoma
Blood,
November 15, 1999;
94(10):
3614 - 3617.
[Full Text]
[PDF]
|
|
|
|
|
TOP
ABSTRACT
INTRODUCTION
