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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 91 No. 6 (March 15), 1998:
pp. 2076-2084
ALK-Positive Lymphoma: A Single Disease With a Broad
Spectrum of Morphology
By
Daniel Benharroch,
Zarouhie Meguerian-Bedoyan,
Laurence Lamant,
Chauki Amin,
Laurence Brugières,
Marie-Jose Terrier-Lacombe,
Eugenia Haralambieva,
Karen Pulford,
Stefano Pileri,
Stephan W. Morris,
David Y. Mason, and
Georges Delsol
From the Department of Pathology and CIGH/CNRS, CHU Purpan, Toulouse,
France; the Department of Pediatric Oncology, Institut Gustave Roussy,
Villejuif, France; the LRF Immunodiagnostics Unit, Department of
Cellular Science, John Radcliffe Hospital, Oxford, UK; the Service of
Pathologic Anatomy and Hematopathology Section, Bologna University,
Bologna, Italy; and the Department of Experimental Oncology, St Jude
Children's Research Hospital, Memphis, TN.
 |
ABSTRACT |
The t(2;5)(p23;q35) translocation, associated with anaplastic
large-cell lymphoma (ALCL), results in the expression of a chimeric NPM-ALK protein that can be detected by the ALK1 monoclonal antibody. This report describes the morphologic and phenotypic spectrum of 123 cases of lymphoma that all express ALK protein. The results provide
strong evidence that the morphologic patterns of ALCL described in
previous reports as representing possible subtypes of ALCL, eg, common
type, lymphohistiocytic, or small cell patterns, are morphologic
variants of the same disease entity. All of these morphologic patterns
could be found within this series, and in some patients different
subtypes coexisted in a single biopsy or were found in successive
biopsies from a single patient. The link between these morphologic
subtypes is further reinforced by the presence in all cases of a highly
characteristic large cell, with an eccentric nucleus and an
eosinophilic paranuclear region. We suggest that this cell can be
considered as a major distinguishing feature of ALK-positive lymphomas.
Another characteristic of these tumors was the perivascular pattern of
neoplastic cell infiltration seen in a significant number of cases. In
addition to ALK protein, all tumors expressed epithelial membrane
antigen and lacked CD15, features that may be of value in
differentiating ALCL from Hodgkin's disease. In the majority of cases
(84%), malignant cells showed both a cytoplasmic and nuclear staining
for ALK1 and thus presumably carried the 2;5 translocation, but
staining was restricted to the cytoplasm in a few cases, suggesting
that translocations other than t(2;5) may induce expression of ALK protein. We conclude from this study that ALK-positive neoplasms represent a distinct entity. Because their morphology is often neither
anaplastic nor large cell, we suggest that they should henceforward be
referred to as ALK lymphomas.
| |
INTRODUCTION |
ANAPLASTIC LARGE-CELL lymphoma (ALCL) was
first described in 19851 as a previously unrecognized
lymphoid tumor in which the neoplastic cells were labeled by the
monoclonal antibody Ki-1 (subsequently shown to recognize the CD30
receptor molecule). This entity was included in the revised Kiel
classification2 and in its successor, the REAL
scheme,3 and is now widely diagnosed.
Five years after the first description of ALCL, it was noted that
tumors carrying the (2;5)(p23;q35) chromosome translocation, a rare
cytogenetic abnormality thought initially to be characteristic of
malignant histiocytosis, were CD30 (Ki-1)-positive large-cell lymphomas.4-7 Then, in 1994, Morris et al8
showed that the (2;5) translocation fuses part of the nucleophosmin
(NPM) gene on chromosome 5q35 to a portion of the ALK
receptor tyrosine kinase gene on chromosome 2p23, resulting in
expression of a unique chimeric NPM-ALK protein. Antibodies specific
for the ALK kinase9,10 have been reported, and the absence
of this molecule from normal lymphoid cells means that a positive
immunocytochemical reaction for ALK protein is essentially specific for
the (2;5) translocation. The major exception is a rare large B-cell
lymphoma in which (by an unknown mechanism) full-length ALK protein is
expressed.11
Although ALCL is now widely recognized and its association with the
(2;5) translocation is beyond doubt, several areas of disagreement and
controversy remain. Firstly, estimates of the frequency of the (2;5)
translocation (and of the NPM-ALK fusion gene) in this neoplasm
vary from less than 15% to more than two thirds.12
Secondly, opinions differ as to whether the (2;5) translocation is
found in tumors other than ALCL. Some investigators report its presence
in a minority of large-cell B-cell lymphomas and pleomorphic T-cell
neoplasms,13-15 whereas others argue that it is specific
for ALCL.16-18
One reason for these disagreements may lie in the differing criteria
used for the diagnosis of ALCL. The range of morphologic features
recognized in this tumor is wider than was initially described.1 This is reflected in descriptions in the
literature of at least eight putative subtypes.19-24
Furthermore, it has been recognized for some years that its original
defining marker (the Ki-1/CD30 molecule) can be found on occasion in
neoplasms that are clearly not related to ALCL.25 In
addition, some investigators consider that occasional cases express
B-cell markers, whereas others argue that this phenotype is
incompatible with a diagnosis of ALCL.3,16
For these reasons, we have undertaken a review of a large series of
lymphomas in which the single criterion for selection was ALK
immunoreactivity (and, by implication, the presence of the
NPM-ALK fusion gene). It is probable that the NPM-ALK
gene is directly involved in the causation of human ALCL because its introduction into murine haemopoietic cells induces a transplantable large-cell lymphoma.26 By selecting a series of lymphomas
for review solely on the basis of this genetic anomaly, we aimed to identify a homogeneous entity. In essence, these "ALKomas" are more likely to represent a single clinicopathologic entity than are
neoplasms selected on the grounds of morphologic and phenotypic features that are not causally implicated in oncogenic transformation.
This review has enabled us to propose solutions to difficulties that
surround the diagnosis and categorization of ALCL. The number of cases
reviewed was considerably larger than has been reported previously and
included some cases from whom sequential biopsies were obtained. It was
culled in part from an extensive input of problem cases sent to one of
the investigators (G.D.) over 10 years. In consequence, we also gained
insight into morphologic variations that can cause difficulties in the
diagnosis of this disease.
| |
MATERIALS AND METHODS |
Biopsy Samples
A total of 123 cases of lymphoma expressing ALK protein were
identified. These were chosen from a large number of putative cases of
ALCL and other lymphomas that had been biopsied at the hospital of one
of the investigators (G.D.) or submitted to him for an opinion. They
were selected from a total of 145 cases with morphologic features of
ALCL that expressed both CD30 and epithelial membrane antigen (EMA) and
that did not express B-cell markers. The frequency of ALK-positivity
among the cases that satisfied our criteria for ALCL was therefore
85%. The male:female ratio among the 106 patients for which
information was available showed a slight excess (1.4:1) of male
subjects. Ages ranged from 3 months to 92 years, with a mean age of
21.3 years. In most instances (101 cases), the biopsy was of a lymph
node; in a further 18 cases, the sample came from an extranodal area,
including skin and bone. In 4 cases, the site of biopsy was unknown.
Special Investigations
Immunohistochemistry.
The anti-ALK monoclonal antibody ALK1 has been described
previously.10 Other antibodies were obtained from DAKO A/S
(Copenhagen, Denmark; CD3, CD45RO, CD20, anti-LMP1, and anti-EMA),
Immunotech (Marseille, France; CD30 and CD15), Biotest (Buc, France;
CD43 and MB2), Prof H. Stein (Freie Universität,
Berlin; CD30/Ber-H2), and the investigators' laboratories (CD45RA,
CD76, CD79a, CBF.78, and BNH.9).27,28
Immunostaining on paraffin sections was performed using the method
described by Shi et al,29 with some
modifications.16 Briefly, paraffin sections were mounted on
glass slides coated with silane (Sigma Chemical Co, St Quentin,
France). Sections were deparaffinized, placed in 10 mmol/L Na-citrate
buffer (pH 6), and heated in a microwave oven (Whirlpool
model; Philips, Eindhowen, Holland) at 900 W for cycles of 20 minutes
and 10 minutes. The slides were removed from the oven and allowed to
cool for 30 minutes at room temperature. After washing in water,
endogeneous peroxidase was blocked with 1% hydrogen peroxide in
methanol for 30 minutes. Slides were then rinsed in phosphate-buffered
saline before staining using a streptavidin-biotin three-stage
technique30 with the DAKO Strept ABC complex/HRP Duet kit
(DAKO; code no. K492). Labeling for ALK in 13 cases from which no
unstained material was available was performed on destained slides, as
previously described.31 Briefly, hematoxylin and
eosin-stained slides were immersed in toluene for 12 to 72 hours to
remove the coverslip and then placed in successive baths of absolute
alcohol, distilled water, and phosphate-buffered saline. This treatment
removes eosin staining of the cytoplasm but does not affect nuclear
staining. Immunohistochemical staining is then performed as for the
unstained sections.
In a few cases, double labeling was carried out by performing first the
immunoperoxidase technique for CD31 using nickel enhancement, followed
by the alkaline phosphatase-anti-alkaline phosphatase (APAAP) procedure for ALK.
Tissue Specimens
Reverse transcriptase-polymerase chain reaction analysis for NPM-ALK.
This procedure was performed in 20 cases, using the method of
Chomczynski and Sacchi as previously described,16 to
analyze RNA extracted from 5-µm frozen sections.
In situ hybridization for Epstein-Barr virus (EBV).
This procedure was performed in 12 cases using EBER oligonucleotides,
as described previously.32
Histopathologic Evaluation
Morphology.
Each case was reviewed by three pathologists and morphologic features
of the neoplastic cells were noted, including the presence of
Reed-Sternberg-like forms and giant cells. The degree of tissue involvement, the growth pattern (eg, cohesive, sinusoidal,
perivascular, etc), and the abundance of infiltrating cells, including
macrophages and plasma cells, was also noted.
The existence of possible morphologic subtypes of ALCL has been
proposed in the REAL scheme and elsewhere,3,19-24 and we therefore attempted to assign each case to one of these putative categories. This assessment was made independently by three observers (G.D., Z.M.-B., and D.B.) using conventional hematoxylin and
eosin-stained sections. In many instances, sections that had been
immunostained (for CD30 and EMA and with antibody BNH9)33
were also reviewed. Any controversial cases were reassessed by the
three pathologists to achieve a consensus.
Phenotype.
Tumors were considered to be of T-cell origin when the neoplastic cells
expressed CD3 or CD43 and/or CD45RO and/or CBF.78 and
lacked B-cell-associated markers (CD20, CD79a, and/or CD45RA, CD76, MB2).
| |
RESULTS |
Morphologic Features
It was evident from the morphologic review that the ALK-positive tumors
showed a broad spectrum of features, ranging from small-cell neoplasms
that many pathologists might have categorized as pleomorphic T-cell
lymphomas (Fig 1A) to cases at
the opposite extreme in which very large cells predominated (Fig 1B).
However, all cases shared one common feature, notably the presence of a population of large cells with a highly characteristic morphology (Fig
1A through E). The nucleus lay eccentrically within these cells and was
horseshoe or kidney shaped. In most cases, some crown-like nuclei could
also be seen (Fig 1D). Nucleoli were less prominent than in
Reed-Sternberg cells and often an eosinophilic region was seen near the
nucleus, probably representing a prominent Golgi apparatus (Fig 1A
through E).
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| Fig 1.
ALK-positive ALCLs show a wide morphologic spectrum. (A)
Small-cell pattern. A predominant population of small cells with irregular nuclei is associated with scattered large hallmark cells (arrow) showing eccentric lobated nuclei. (B) Giant-cell-rich pattern,
showing striking cellular pleomorphism. (C) Common-type ALCL showing
several hallmark cells (arrows). (D) Common-type ALCL showing several
hallmark cells (arrow) and also a cell with crown-like nuclei (long
arrow). (E) Lymphohistiocytic variant showing, in the hematoxylin and
eosin-stained section, a single hallmark cell (arrow). Note the
eosinophilic paranuclear area. Other cells are nonneoplastic, including
histiocytes and plasma cells. Immunostaining of this case for CD30
highlights the scattered malignant cell population.
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| Fig 2.
Morphologic transformation in 2 relapsing cases. Giemsa
(A) and hematoxylin and eosin (B) staining is shown above and
immunostaining is shown below. (Case A) The morphologic appearance at
diagnosis was that of a lymphohistiocytic variant with scattered large
neoplastic cells. ALK staining confirmed the scarcity of malignant
cells (arrow). A few months later, this patient developed lung
involvement consisting exclusively of large cells. (Case B) In this
case, the morphologic appearance at diagnosis was that of a common-type ALCL with many large cells containing eccentric nuclei. Lymph node
biopsy at relapse showed the features of a small-cell variant. Scattered large cells were strongly positive for ALK1, whereas small
cells showed only moderate/weak staining.
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Once the characteristic features of these hallmark cells had been
recognized, it was easy to identify them in all cases in the series,
whatever the overall morphologic appearance (Fig 1A through E). In
cases showing lymphohistiocytic features, these cells were less easily
identified because of the large numbers of reactive histiocytes, but
were nevertheless present (Fig 1E). In small-cell variant cases, these
characteristic cells were mainly found around vessels in a perivascular
pattern best seen in immunostained sections (see below).
The presence of a neoplastic cell type common to all 123 ALK-positive
cases suggested that these cases represent variations on a theme. This
view was reinforced by the fact that, when we attempted to assign the
cases to one of the proposed subtypes of ALCL
(Table 1), almost 15% of cases could not
be classified because features of more than one subtype were found in a
single biopsy (Table 2).
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Table 2.
Morphologic Features of ALK-Positive ALCL in Which More
Than One Histologic Pattern Was Found Within a Single Biopsy
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Furthermore, in 4 of the 6 cases in which a repeat biopsy was performed
at the time of relapse, the morphologic features differed from those
seen initially, as shown in Table 3 and
Fig 2.
In 4 cases (1 of which showed lung involvement), we recognized features
of the putative but controversial Hodgkin's-like form of ALCL, namely
vaguely nodular fibrosis associated with capsular thickening and tumor
cells resembling Reed-Sternberg cells (Fig 3A). However, in all 4 cases, the malignant cells (unlike classical Reed-Sternberg cells) were CD15 and lacked evidence
of EBV (ie, EBER RNA). Furthermore, the Hodgkin's-like pattern was
seen only in some areas of the lymph node. Elsewhere, the neoplastic
infiltrate showed the typical features of ALCL (Fig 3B). We therefore
concluded that the resemblance of these cases to Hodgkin's disease was
purely superficial and that there was no evidence that they differed
from the other cases in this series.
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| Fig 3.
ALCL of common type in which, at low power magnification,
(A) sclerotic bands were evident, suggestive of nodular sclerosis Hodgkin's disease. (Inset) Malignant cells, showing
Reed-Sternberg-like appearance. These morphologic features are
consistent with Hodgkin's disease, but in other areas (B) the tumor
showed the typical appearance of common-type ALCL.
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Immunostaining
ALK protein.
By definition, all cases stained for ALK protein. Eighty-two percent
(101 of 123 cases) showed labeling to a similar degree of both the
cytoplasm and the nucleus (Fig 4A), but in
16% of cases (20 of 123), staining was limited to the cytoplasm (Fig 4B), and in 2 cases, only nuclei were labeled. The cellular
distribution of ALK1 immunostaining in cases showing the common,
lymphohistiocytic (Fig 4C), and giant cell patterns was comparable.
However, in cases of small-cell ALCL only the larger anaplastic cells,
often concentrated around vessels, were strongly positive (Fig 4D). In
contrast, ALK staining in the small-cell population was variable. In
most cases, only a proportion of these cells were positive, and
staining was weak and restricted to nuclei.
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| Fig 4.
Patterns of expression of ALK protein. (A) Both
cytoplasmic and nuclear expression of the protein was seen in most
tumors. (B) ALK staining was confined to the cytoplasm of neoplastic
cells in a few cases. This case was of common type, but showed
Hodgkin's-like areas. (C) Lymphohistiocytic variant showing scattered
positive cells, some of them with a fibroblast-like appearance. (D)
Small-cell variant, showing strong staining of large anaplastic cells,
associated with only moderate/weak nuclear staining in the small cells.
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Lineage markers.
Slightly more than half of the cases appeared to be of the T-cell
origin (54%; Table 4), although it was not
possible to give a precise figure for the frequency of this phenotype
because some cases had been studied in the past with only a limited
battery of antibodies. A T-cell phenotype was commoner among cases with lymphohistiocytic, small-cell, or mixed patterns (10 of 14, 7 of 7, and
12 of 17, respectively) than among cases with the common pattern (36 of
78 cases). In no cases was there any evidence for a B-cell derivation.
CD30 and EMA.
In every case, virtually all malignant cells were strongly reactive for
CD30, and the staining pattern was, as previously described, associated
mainly with the surface membrane and the Golgi area
(Fig 5A). All cases tested (120 of 120)
were also positive for EMA. The staining pattern was similar to
that of CD30, although, in some cases, only a proportion of malignant
cells was positive.
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| Fig 5.
Staining for CD30. (A) Characteristic pattern, as seen in
virtually all cases, comprising membrane staining associated with a
cytoplasmic dot in the Golgi area. (B) Spindle cells with a fibroblast-like appearance in a lymphohistiocytic case.
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Other markers.
In a previous study, H and Y blood group-related antigens, detected by
antibody BNH.9, were found in a significant proportion of
ALCL.28 In the present study, 86 of 108 cases (80%) were reactive with this antibody. However, the number of positive cells varied greatly from case to case. Another carbohydrate antigen, CD15,
was not expressed, except for 4 cases (3 showing the common pattern and
1 the features of giant-cell ALCL), in each of which a small proportion
of the neoplastic cells was stained.
EBV detection.
No evidence of EBV infection was found in the 64 cases investigated
using in situ hybridization and/or LMP-1 staining.
Special Morphologic Features
In addition to the features already described, which were seen in all
cases, a number of other histologic characteristics were observed in a
minority of biopsies. The two most common features related to the
pattern of tumor infiltration, and this was best appreciated in
sections immunostained for molecules expressed by the neoplastic cells
(ie, CD30, EMA, or ALK).
In about three quarters of all cases (84 of 111), the tumor cells
showed a tendency to infiltrate lymphatic sinuses, as has been
described in earlier publications.19,33 However, an even more distinctive pattern, seen in almost half of the cases (51 of 111),
was a perivascular pattern of neoplastic cell infiltration (Fig 6). This appearance was more common
when the tumor showed lymphohistiocytic features (9 of 14 cases) than
when the common pattern was seen (31 of 70 cases). The perivascular
pattern was best seen after single or double immunostaining (Fig 6B
through E). Furthermore, all but 1 of the 6 cases with a small-cell
appearance showed perivascular distribution, and in these cases large
neoplastic cells were clearly associated with vessels (Fig 6E).
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| Fig 6.
Perivascular pattern of tumor cells infiltration. (A)
Several tumor cell foci are seen, all localized around vessels
(hematoxylin and eosin). (B through D) The perivascular pattern is
highlighted by staining for CD30 (B) or ALK (C) or by double labeling
for vessels, with anti-CD31 (brown) and for ALK protein (red). (E) In
the small-cell variant case, CD30 is strongly expressed by large cells
surrounding the vessel, whereas the small cell population is only
weakly positive.
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In one quarter of all cases, significant fibrosis with collageneous
bands was noted (excluding those with only a limited degree of
interstitial fibrosis). Spindle cells with a fibroblast-like appearance
were found in 20 cases (11%). These cells were evident only in
immunostained sections and were commonest (5 of 14 cases) in biopsies
showing the lymphohistiocytic pattern (Fig 5B). In 1 case, rare signet
ring tumor cells were seen in one area, as recently described in a case
of ALCL.24
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DISCUSSION |
The results of the present study of ALCL expressing ALK protein provide
strong evidence that the morphologic patterns described in previous
reports as representing possible subtypes of ALCL, eg, common type,
lymphohistiocytic, or small-cell patterns,19,20,22,33 are
morphologic variants of the same disease entity. All of these morphologic patterns could be found within this series, and in some
instances different subtypes coexisted in a single biopsy or were found
in successive biopsies from a single patient (Table 3). The link
between these morphologic subtypes of ALCL was further reinforced by
the presence in all cases of a highly characteristic large cell that
can be considered as a major distinguishing hallmark of the disease
(Fig 1). One of its distinguishing features is a perinuclear
eosinophilic region that we assume represents a prominent Golgi
apparatus. We have not shown this directly (by electron microscopy),
but it is noteworthy that CD30 staining frequently highlights the same
area (Fig 5A).
The proposed Hodgkin's-like form of ALCL is still the subject of
controversy.3,19 In 4 cases, typical features of ALCL were
associated with areas in which a Hodgkin's-like pattern was seen (Fig
5). However, these Reed-Sternberg-like malignant cells were
CD15 and lacked EBER RNA (found in 60 % of
Hodgkin's cases).34 These results suggest that occasional
cases of ALK-positive lymphomas show a superficial resemblance to
Hodgkin's disease but can be categorized correctly on careful
histologic examination and immunostaining. However, we also believe
that many tumors previously diagnosed as Hodgkin's-like ALCL are cases
of neoplastic cell-rich Hodgkin's disease (ie, they should be
designated ALCL-like Hodgkin's disease rather than Hodgkin's-like
ALCL).
In addition to NPM-ALK protein and EMA expression and lack of CD15, a
morphologic feature that may be of value in differentiating ALCL from
ALCL-like Hodgkin's disease is the perivascular pattern of neoplastic
cell infiltration (Fig 6). This has been reported as a frequent feature
in a series of cases of the small-cell variant of ALCLs,22
but we found it in almost half of our cases. It has not been noted in
Hodgkin's disease.35
It may be noted that some putative morphologic variants of ALCL
reported previously were not observed in this series of ALK-positive ALCL. Thus, in none of the cases was the number of fibroblast-like spindle cells high enough to give the tumor a sarcomatous appearance, as described by Chan et al,21 and no cases showed features
consistent with neutrophil-rich ALCL as described by Mann et
al,23 even though infiltrating granulocytes were present in
some cases. However, we would argue on the basis of our observation of
marked morphologic variability among ALK-positive lymphomas that these
are probably not distinct subtypes.
As noted in the description of ALCL in the REAL
classification,3 the majority of these ALK-positive ALCL
were of T phenotype, and in no case was there evidence for a B-cell
origin. T-cell antigen expression by ALCL cases showing the small-cell
pattern was of interest because the small-cell population showed
stronger staining for T-cell markers than did the larger anaplastic
cells. An opposite staining pattern was seen for CD30 and ALK antigens. However, despite the strikingly different morphology of these two cell
populations, the expression of NPM-ALK protein by the small cells
suggests that they also belong to the malignant cell population and
carry the t(2;5).
All tumors expressed EMA, confirming our previous reports on the
diagnostic value of this marker in ALCL.33,36 EMA is an epithelial sialomucin,37 encoded by the MUC1 gene
on chromosome 1q21-24,38 as is the CD30/Ki-1 molecule
(encoded at 1p36).25 This could suggest that the t(2;5)
promotes, by an unknown mechanism, the expression of these two antigens
by lymphoid cells.
Malignant cells carrying the 2;5 translocation show both cytoplasmic
and nuclear staining for NPM-ALK, and this appears to be due to
oligomer formation with wild-type NPM and subsequent transport
from the cytoplasm to the nucleus directed by nuclear localization
signals in the NPM molecule.39 However, in the present
study, only about 80% of cases showed both nuclear and cytoplasmic
staining pattern. In most of the remaining cases, staining was
restricted to the cytoplasm. Because all staining was performed on
routinely fixed paraffin-embedded tissue, these differences may be, at
least in part, artefactual. However, we have previously reported that,
in a case of ALCL carrying a variant t(1;2)(q25;p23) translocation, ALK
protein does not enter the nucleus,10,39 and our present
findings therefore suggest that, in a significant minority of ALCLs,
the ALK gene may fuse to a gene other than NPM.
Immunostaining for ALK protein, preferably in cryostat sections, should
allow such cases to be identified for more detailed molecular analysis.
In conclusion, our results argue that one can now define, through a
combination of morphologic review and immunostaining, a distinct
ALK-positive lymphoma entity that tends to occur in young patients. ALK
protein expression in these tumors is most commonly due to the creation
of the NPM-ALK fusion gene by the 2;5 translocation,
although there was at least one exception in this series, a (1;2)
translocation, and we suspect that other anomalies involving
breakpoints at 2p23 may well be found in this tumor in the future.
These tumors usually express CD30 and EMA and are of T or null
phenotype. Their morphology covers a wide morphologic spectrum, but
this heterogeneity does not appear to indicate the existence of
different disease entities. The hallmark cell we describe may be
present only in low numbers but is highly characteristic. It is not
seen in other lymphomas and, once recognized, is invaluable, in
combination with ALK staining, in defining this lymphoma entity.
Our results inevitably prompt a reevaluation of the term ALCL, which is
an inappropriate morphologic description for many of the tumors
described in this report (eg, those composed mainly of small cells).
There is subjective variation in the ability of hematopathologists to
define ALCL (and indeed we suspect that the term anaplastic means
different things to different pathologists). Furthermore, there is
disagreement as to whether ALCL of B-cell phenotype exists, because it
is recognized by the Kiel scheme but not included in the REAL
classification. Consequently the term ALCL will continue, in the
absence of agreed phenotypic or genotypic criteria, to be applied to a
poorly defined group of lymphomas. However, it now seems justifiable to
separate out the tumor type that we describe in this report and
henceforward to refer to it as ALK lymphoma or even, more colloquially,
as "ALKoma". It must be noted that a quite different, more
aggressive ALK-positive lymphoma has been described in adults
expressing full-length ALK protein rather than
NPM-ALK,11 but these cases are exceedingly rare and the advantages of using the word ALK to rename the tumors we
describe in this report should outweigh any potential risk of
ambiguity. The initial name for ALCL (Ki-1 lymphoma) was also based on
the expression of a marker molecule, but this title was abandoned when
it emerged that Ki-1 (CD30) expression was not restricted to one
lymphoma type. However, we are confident that ALK expression, given
that it appears to be directly implicated in the genesis of these
tumors,26 will prove a reliable defining criterion and can be incorporated into their name.
| |
FOOTNOTES |
Submitted September 8, 1997;
accepted November 3, 1997.
Supported by "Ligue Nationale Contre le Cancer," the
"Délégation à la Recherche Clinique," the
Leukemia Research Fund of Great Britain, National Cancer Institute
(NCI) Grants No. CA 01702 and CA 69129 (S.W.M.), the NCI Cancer Center
CORE Grant No. CA 21765, the American Lebanese Syrian Associated
Charities (ALSAC), St Jude Children's Research Hospital (Memphis, TN),
the Chief Scientist Office of the Israeli Ministry of Health (the
Yvonne Heymann Trust), and the Tabb Foundation.
Address reprint requests to Georges Delsol, MD, Laboratoire d'Anatomie
Pathologique, CHU Purpan, Place du Dr Baylac, 31059, Toulouse Cedex,
France.
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.
| |
ACKNOWLEDGMENT |
The authors thank the IGR and Drs Abd Alsamad, Archambeau, Bertrand,
Boccon-Gibod, Bouchind'homme, Bowman-Ferrand, Brousse, Demuet,
Deschalotte, Dijoud, Dumont, Fetissof, Galateau, Heymann, Hopfner,
Lagacé, Lefèvre-Wuithier, Levillain, Monégier du
Sorbier, Morel, Patelli, Patey, Perraudeau, Petrella, Rogez, Rousset,
Saint-André, Tapie, Trojani, Validire, and Vancina for their
contribution of cases. We also acknowledge the help of Bridget Watson
and Beata Ozieblowska in the preparation of, respectively, the text and illustration of this report.
| |
REFERENCES |
1.
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 the Hodgkin's disease associated antigen Ki-1 in reactive and neoplastic lymphoid tissue: Evidence that Reed-Sternberg cells and histiocytic malignancies are derived from activated lymphoid cells.
Blood
66:848,
1985[Abstract/Free Full Text]
2.
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]
3.
Harris NL,
Jaffe ES,
Stein H,
Banks PM,
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,
Piris MA,
Ralfkiaer 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]
4.
Rimokh R,
Magaud JP,
Berger F,
Samarnt J,
Coiffier B,
Germain D,
Mason DY:
A translocation involving a specific breakpoint (q35) on chromosome 5 is characteristic of anaplastic large cell lymphoma ("Ki-1 lymphoma3).
Br J Haematol
71:31,
1989[Medline]
[Order article via Infotrieve]
5.
Mason DY,
Bastard C,
Rimokh R,
Dastugue N,
Huret JL,
Kristoffersson U,
Magaud JP,
Nezelof C,
Tilly H,
Vannier JP,
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]
6.
Kaneko Y,
Frizzera G,
Edamura S,
Maseki N,
Sakurai M,
Komada Y,
Sakurai M,
Tanaka H,
Sasaki M,
Suchi T,
Kikuta A,
Wakasa H,
Hojo H,
Mizutani S:
A novel translocation t(2; 5) (p23; q35), in chilhood phagocytic large T-cell lymphoma mimicking malignant histiocytosis.
Blood
73:806,
1989[Abstract/Free Full Text]
7.
Bitter MA,
Franklin WA,
Larson RA,
McKeithan TW,
Rubin CM,
Le Beau MM,
Stephens JK,
Vardiman JW:
Morphology in Ki-1 (CD30) positive non-Hodgkin's lymphoma is correlated with clinical features and a unique chromosomal abnormality, t(2;5)(p23;q35).
Am J Surg Pathol
14:305,
1990[Medline]
[Order article via Infotrieve]
8.
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]
9.
Shiota M,
Nakamura S,
Ichinohasama R,
Abe M,
Akagi T,
Takashita M,
Mori N,
Fujimoto J,
Miyauchi J,
Mikata A,
Namba K,
Takami T,
Yamabe H,
Takano Y,
Izumo T,
Nagatani T,
Mohri N,
Nasu K,
Satoh H,
Katano H,
Fijimoto J,
Yamamoto T,
Mori S:
Anaplastic large cell lymphoma expressing the novel chimeric protein p80 NPM/ALK: A distinct clinicopathologic entity.
Blood
86:1954,
1995[Abstract/Free Full Text]
10.
Pulford K,
Lamant L,
Morris SW,
Butler L,
Wood K,
Stroud D,
Delsol G,
Mason DY:
Detection of ALK and NPM-ALK proteins in normal and neoplastic cells with the monoclonal antibody ALK1.
Blood
89:1394,
1997[Abstract/Free Full Text]
11.
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]
12.
Chan WC:
The t(2;5) or NPM-ALK translocation in lymphomas: Diagnostic considerations.
Adv Anat Pathol
3:396,
1996
13.
Downing J,
Shurtleff S,
Zielenska M,
Curcio-Brint AM,
Behm FG,
Head DR,
Sandlund JT,
Weisenburger D,
Kossakowska AE,
Thorner P,
Lorenzana A,
Ladanyi M,
Morris S:
Molecular detection of the t(2;5) translocation of non-Hodgkin's lymphoma by reverse transcriptase-polymerase chain reaction.
Blood
85:3416,
1995[Abstract/Free Full Text]
14.
Arber D,
Sun L-H,
Weiss LM:
Detection of the t(2;5) (p23;q35) chromosomal translocation in large B-cell lymphomas other than anaplastic large cell lymphoma.
Hum Pathol
27:590,
1996[Medline]
[Order article via Infotrieve]
15.
Weisenburger DD,
Gordon BG,
Vose JM,
Bast MA,
Chan WC,
Greiner TC,
Anderson JR,
Sanger WG:
Occurrence of the t(2;5) (p23;q35) in non-Hodgkin's lymphoma.
Blood
87:3860,
1996[Abstract/Free Full Text]
16.
Lamant L,
Meggetto F,
Al Saati T,
Brugières L,
Bressac de Paillerets B,
Dastugue N,
Bernheim A,
Rubie H,
Terrier-Lacombe MJ,
Robert A,
Brousset P,
Rigal F,
Schlaifer D,
Shiota M,
Mori S,
Delsol G:
High incidence of the t(2;5) (p23;q35) translocation in anaplastic large cell lymphoma and its lack of detection in Hodgkin's disease. Comparison of cytogenetic analysis, reverse transcriptase-polymerase chain reaction, and P-80 immunostaining.
Blood
87:284,
1996[Abstract/Free Full Text]
17.
Herbst H,
Anagnostopoulos J,
Heinze B,
Durkop H,
Hummel M,
Stein H:
ALK gene products in anaplastic large cell lymphomas and Hodgkin's disease.
Blood
86:1694,
1995[Abstract/Free Full Text]
18.
Wellman A,
Otsuki T,
Vogelbrich M,
Clark HM,
Jaffe ES,
Raffeld M:
Analysis of the t (2;5) (p 23; q35) translocation by reverse transcription polymerase chain reaction in CD30+ anaplastic large cell lymphomas and in other non-Hodgkin's lymphomas of T-cell phenotype.
Blood
86:2321,
1995[Abstract/Free Full Text]
19. Stein H, Dallenbach F: Diffuse large cell lymphomas of B and T
cell type, in Knowles, DM (ed): Neoplastic Hematopathology. Baltimore,
MD, Williams and Wilkins, 1992, p 675
20.
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]
21.
Chan JKC,
Buchanan R,
Fletcher CDM:
Sarcomatoid variant of anaplastic large cell Ki-1 lymphoma.
Am J Surg Pathol
14:983,
1990[Medline]
[Order article via Infotrieve]
22.
Kinney MC,
Collins RD,
Greer JP,
Whitlock J,
Sioutos N,
Kadin M:
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]
23.
Mann KP,
Hall B,
Kamino H,
Borowitz MJ,
Ratech H:
Neutrophil-rich, Ki-1-positive anaplastic large cell malignant lymphoma.
Am J Surg Pathol
19:407,
1995[Medline]
[Order article via Infotrieve]
24.
Falini B,
Liso A,
Pasqualucci L,
Flenghi L,
Ascani S,
Pileri S,
Bucciarelli E:
CD30+ anaplastic large cell lymphoma, null type, with signet ring appearance.
Histopathol
30:90,
1997[Medline]
[Order article via Infotrieve]
25.
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]
26. (abstr, suppl 1)
Kuefer MU,
Look AT,
Tripp R,
Behm FG,
Pattengale PK,
Morris SW:
Retrovirus mediated gene transfer of NPM-ALK causes lymphoid malignancy in mice.
Blood
88:450a,
1996
27.
Al Saati T,
Tkaczuk J,
Krissansen G,
Print C,
Pileri S,
Ralfkiaer E,
Grogan TM,
Meggetto F,
Delsol G:
A novel antigen detected by the CBF.78 antibody further distinguishes anaplastic large cell lymphoma from Hodgkin's disease.
Blood
86:2741,
1995[Abstract/Free Full Text]
28.
Delsol G,
Blancher A,
Al Saati T,
Ralfkiaer E,
Lauritzen A,
Bruigeres L,
Brousset P,
Rigal-Huget F,
Mazerolles C,
Robert A,
Chittal SM:
Antibody BNH9 detects red blood cell-related antigens on anaplastic large cell (CD30+) lymphomas.
Br J Cancer
64:321,
1991[Medline]
[Order article via Infotrieve]
29.
Shi SR,
Key ME,
Kalra KL:
Antigen retrieval in formalin-fixed, paraffin-embedded tissues: An enhancement method for immunohistochemical staining based on microwave oven heating of tissue sections.
J Histochem Cytochem
39:741,
1991[Abstract]
30.
Al Saati T,
Clamens S,
Cohen-Knafo E,
Faye JC,
Prats H,
Coindre JM,
Wafflart J,
Caverivière P,
Bayard F,
Delsol G:
Production of monoclonal antibodies to human estrogen-receptor protein (ER) using recombinant ER (RER).
Int J Cancer
55:651,
1993[Medline]
[Order article via Infotrieve]
31.
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.
Am J Clin Pathol
103:82,
1995[Medline]
[Order article via Infotrieve]
32.
Brousset P,
Meggetto F,
Chittal S,
Bibeau F,
Arnaud J,
Rubin B,
Delsol G:
Assessment of the methods for the detection of the Epstein-Barr virus nucleic acids and related gene products in Hodgkin's disease.
Lab Invest
69:483,
1993[Medline]
[Order article via Infotrieve]
33.
Delsol G,
Al Saati T,
Gatter KC,
Gerdes J,
Schwarting R,
Caverivière P,
Rigal-Huguet F,
Robert A,
Stein H,
Mason DY:
Coexpression of epithelial membrane antigen (EMA), Ki-1, and interleu-kin-2 receptor by anaplastic large cell lymphoma. Diagnostic value in so-called malignant histiocytosis.
Am J Pathol
130:59,
1988[Abstract]
34.
Brousset P,
Rochaix P,
Chittal S,
Rubie H,
Robert A,
Delsol G:
High incidence of Epstein-Barr virus detection in Hodgkin's disease and absence of detection in anaplastic large-cell lymphoma in children.
Histopathology
23:189,
1993[Medline]
[Order article via Infotrieve]
35.
Chittal SM,
Delsol G:
The interface of Hodgkin's disease and anaplastic large cell lymphoma.
Cancer Surv
30:87,
1997[Medline]
[Order article via Infotrieve]
36.
Delsol G,
Stein H,
Pulford KAF,
Gatter KC,
Erber WN,
Zinne K,
Mason DY:
Human lymphoid cells express epithelial membrane antigen.
Lancet
2:1124,
1984[Medline]
[Order article via Infotrieve]
37.
Hilkens J,
Ligtenberg MJL,
Vos HL,
Litvinov SV:
Cell membrane associated mucins and their adhesion-modulating properties.
Trends Biochem Sci
17:359,
1992[Medline]
[Order article via Infotrieve]
38.
Swallow DM,
Gendler S,
Griffiths B,
Kearney A,
Povey S,
Sheer D,
Palmer RW,
Taylor-Papamitriou J:
The hypervariable gene locus PUM, which codes for the tumour associated mucins, is located on chromosome 1, within the region 1q21-24.
Ann Hum Genet
51:289,
1987[Medline]
[Order article via Infotrieve]
39. Mason DY, Pulford KAF, Bischof D, Lamant L, Delsol G, Morris SW:
Nucleolar localisation of the NMP-ALK tyrosine kinase is not required
for malignant transformation. Cancer Res (in press)
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
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541 - 547.
[Abstract]
[Full Text]
[PDF]
|
|
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Anaplastic large cell lymphomas lack the expression of T-cell receptor molecules or molecules of proximal T-cell receptor signaling
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November 15, 2004;
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[Full Text]
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|
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Bcl-XL down-regulation suppresses the tumorigenic potential of NPM/ALK in vitro and in vivo
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April 1, 2004;
103(7):
2787 - 2794.
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[Full Text]
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|
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Prognostic Significance of MUC-1 Expression in Systemic Anaplastic Large Cell Lymphoma
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June 1, 2003;
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[Full Text]
[PDF]
|
|
|
|
|
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April 1, 2003;
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2789 - 2796.
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[Full Text]
[PDF]
|
|
|
|
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|
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Primary brain CD30+ ALK1+ anaplastic large cell lymphoma ('ALKoma'): the first case with a combination of 'not common' variants
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November 1, 2002;
13(11):
1827 - 1832.
[Abstract]
[Full Text]
[PDF]
|
|
|
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Anaplastic lymphoma kinase (ALK) protein expressing lymphoma after liver transplantation: case report and literature review
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55(11):
868 - 871.
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[Full Text]
[PDF]
|
|
|
|
|
|
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J. Clin. Oncol.,
September 1, 2002;
20(17):
3691 - 3702.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
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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]
|
|
|
|
|
|
|
L. Hernandez, S. Bea, B. Bellosillo, M. Pinyol, B. Falini, A. Carbone, G. Ott, A. Rosenwald, A. Fernandez, K. Pulford, et al.
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Am. J. Pathol.,
April 1, 2002;
160(4):
1487 - 1494.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
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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]
|
|
|
|
|
|
|
S A Pileri, S Ascani, L Leoncini, E Sabattini, P L Zinzani, P P Piccaluga, A Pileri Jr, M Giunti, B Falini, G B Bolis, et al.
Hodgkin's lymphoma: the pathologist's viewpoint
J. Clin. Pathol.,
March 1, 2002;
55(3):
162 - 176.
[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]
|
|
|
|
|
|
|
K. Seidemann, M. Tiemann, M. Schrappe, E. Yakisan, I. Simonitsch, G. Janka-Schaub, W. Dorffel, M. Zimmermann, G. Mann, H. Gadner, et al.
Short-pulse B-non-Hodgkin lymphoma-type chemotherapy is efficacious treatment for pediatric anaplastic large cell lymphoma: a report of the Berlin-Frankfurt-Munster Group Trial NHL-BFM 90
Blood,
June 15, 2001;
97(12):
3699 - 3706.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. Maes, V. Vanhentenrijk, I. Wlodarska, J. Cools, B. Peeters, P. Marynen, and C. De Wolf-Peeters
The NPM-ALK and the ATIC-ALK Fusion Genes Can Be Detected in Non-Neoplastic Cells
Am. J. Pathol.,
June 1, 2001;
158(6):
2185 - 2193.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Villalva, F. Bougrine, G. Delsol, and P. Brousset
Bcl-2 Expression in Anaplastic Large Cell Lymphoma
Am. J. Pathol.,
May 1, 2001;
158(5):
1889 - 1890.
[Full Text]
[PDF]
|
|
|
|
|
|
|
C Greenland, N Dastugue, C Touriol, L Lamant, G Delsol, and P Brousset
Anaplastic large cell lymphoma with the t(2;5)(p23;q35) NPM/ALK chromosomal translocation and duplication of the short arm of the non-translocated chromosome 2 involving the full length of the ALK gene
J. Clin. Pathol.,
February 1, 2001;
54(2):
152 - 154.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. L. Harris, H. Stein, S. E. Coupland, M. Hummel, R. D. Favera, L. Pasqualucci, and W. C. Chan
New Approaches to Lymphoma Diagnosis
Hematology,
January 1, 2001;
2001(1):
194 - 220.
[Abstract]
[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]
|
|
|
|
|
|
|
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]
|
|
|
|
|
|
|
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]
|
|
|
|
|
|
|
L. Lamant, K. Pulford, D. Bischof, S. W. Morris, D. Y. Mason, G. Delsol, and B. Mariame
Expression of the ALK Tyrosine Kinase Gene in Neuroblastoma
Am. J. Pathol.,
May 1, 2000;
156(5):
1711 - 1721.
[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]
|
|
|
|
|
|
|
M. Trinei, L. Lanfrancone, E. Campo, K. Pulford, D. Y. Mason, P.-G. Pelicci, and B. Falini
A New Variant Anaplastic Lymphoma Kinase (ALK)-Fusion Protein (ATIC-ALK) in a Case of ALK-positive Anaplastic Large Cell Lymphoma
Cancer Res.,
February 1, 2000;
60(4):
793 - 798.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
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]
|
|
|
|
|
|
|
L. Hernandez, M. Pinyol, S. Hernandez, S. Bea, K. Pulford, A. Rosenwald, L. Lamant, B. Falini, G. Ott, D. Y. Mason, et al.
TRK-Fused Gene (TFG) Is a New Partner of ALK in Anaplastic Large Cell Lymphoma Producing Two Structurally Different TFG-ALK Translocations
Blood,
November 1, 1999;
94(9):
3265 - 3268.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Rosenwald, G. Ott, K. Pulford, T. Katzenberger, J. Kuhl, J. Kalla, M. M. Ott, D. Y. Mason, and H. K. Muller-Hermelink
t(1;2)(q21;p23) and t(2;3)(p23;q21): Two Novel Variant Translocations of the t(2;5)(p23;q35) in Anaplastic Large Cell Lymphoma
Blood,
July 1, 1999;
94(1):
362 - 364.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Pulford, B. Falini, J. Cordell, A. Rosenwald, G. Ott, H.-K. Muller-Hermelink, K. A. MacLennan, L. Lamant, A. Carbone, E. Campo, et al.
Biochemical Detection of Novel Anaplastic Lymphoma Kinase Proteins in Tissue Sections of Anaplastic Large Cell Lymphoma
Am. J. Pathol.,
June 1, 1999;
154(6):
1657 - 1663.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. D. Gascoyne, P. Aoun, D. Wu, M. Chhanabhai, B. F. Skinnider, T. C. Greiner, S. W. Morris, J. M. Connors, J. M. Vose, D. S. Viswanatha, et al.
Prognostic Significance of Anaplastic Lymphoma Kinase (ALK) Protein Expression in Adults With Anaplastic Large Cell Lymphoma
Blood,
June 1, 1999;
93(11):
3913 - 3921.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. Jones, C. D.M. Fletcher, K. Pulford, A. Shahsafaei, and D. M. Dorfman
The T-Cell Activation Markers CD30 and OX40/CD134 Are Expressed in Nonoverlapping Subsets of Peripheral T-Cell Lymphoma
Blood,
May 15, 1999;
93(10):
3487 - 3493.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. Lamant, N. Dastugue, K. Pulford, G. Delsol, and B. Mariame
A New Fusion Gene TPM3-ALK in Anaplastic Large Cell Lymphoma Created by a (1;2)(q25;p23) Translocation
Blood,
May 1, 1999;
93(9):
3088 - 3095.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. L. ten Berge, D. F. Dukers, J. J. Oudejans, K. Pulford, G. J. Ossenkoppele, D. de Jong, J. F.M.M. Misere, and C. J.L.M. Meijer
Adverse Effects of Activated Cytotoxic T Lymphocytes on the Clinical Outcome of Nodal Anaplastic Large Cell Lymphoma
Blood,
April 15, 1999;
93(8):
2688 - 2696.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. Falini, S. Pileri, P. L. Zinzani, A. Carbone, V. Zagonel, C. Wolf-Peeters, G. Verhoef, F. Menestrina, G. Todeschini, M. Paulli, et al.
ALK+ Lymphoma: Clinico-Pathological Findings and Outcome
Blood,
April 15, 1999;
93(8):
2697 - 2706.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. Facchetti, J. K. C. Chan, W. Zhang, A. Tironi, M. Chilosi, S. Parolini, L. D. Notarangelo, and L. E. Samelson
Linker for Activation of T Cells (LAT), a Novel Immunohistochemical Marker for T Cells, NK Cells, Mast Cells, and Megakaryocytes : Evaluation in Normal and Pathological Conditions
Am. J. Pathol.,
April 1, 1999;
154(4):
1037 - 1046.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. L. Cordell, K. A.F. Pulford, B. Bigerna, G. Roncador, A. Banham, E. Colombo, P.-G. Pelicci, D. Y. Mason, and B. Falini
Detection of Normal and Chimeric Nucleophosmin in Human Cells
Blood,
January 15, 1999;
93(2):
632 - 642.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. H. Kim, E. Y. Choi, Y. K. Shin, T. J. Kim, D. H. Chung, S. I. Chang, N. K. Kim, and S. H. Park
Generation of Cells With Hodgkin's and Reed-Sternberg Phenotype Through Downregulation of CD99 (Mic2)
Blood,
December 1, 1998;
92(11):
4287 - 4295.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. Brugieres, M.C. L. Deley, H. Pacquement, Z. Meguerian-Bedoyan, M.J. Terrier-Lacombe, A. Robert, C. Pondarre, G. Leverger, C. Devalck, C. Rodary, et al.
CD30+ Anaplastic Large-Cell Lymphoma in Children: Analysis of 82 Patients Enrolled in Two Consecutive Studies of the French Society of Pediatric Oncology
Blood,
November 15, 1998;
92(10):
3591 - 3598.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
I. Wlodarska, C. De Wolf-Peeters, B. Falini, G. Verhoef, S. W. Morris, A. Hagemeijer, and H. Van denBerghe
The Cryptic inv(2)(p23q35) Defines a New Molecular Genetic Subtype of ALK-Positive Anaplastic Large-Cell Lymphoma
Blood,
October 15, 1998;
92(8):
2688 - 2695.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. Falini, B. Bigerna, M. Fizzotti, K. Pulford, S. A. Pileri, G. Delsol, A. Carbone, M. Paulli, U. Magrini, F. Menestrina, et al.
ALK Expression Defines a Distinct Group of T/Null Lymphomas (""ALK Lymphomas"") with a Wide Morphological Spectrum
Am. J. Pathol.,
September 1, 1998;
153(3):
875 - 886.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
Abstract
Introduction
Abstract