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REVIEW ARTICLE
From the Institute of Pathology and Consultation and
Reference Center for Lymph Node Pathology and Haematopathology,
University Hospital Benjamin Franklin, Free University, Berlin,
Germany; Laboratoire d' Anatomie et Cytologie Pathologiques,
Hôpital Purpan, Toulouse, France; Nuffield Department of Clinical
Laboratory Sciences, LRF Immunodiagnostics Unit, John Radcliffe
Hospital, University of Oxford, Oxford, England; Servizio di Anatomia
Patologica Anaplastic large cell lymphoma (ALCL) represents a generally
recognized group of large cell lymphomas. Defining features consist of
a proliferation of predominantly large lymphoid cells with strong
expression of the cytokine receptor CD30 and a characteristic growth
pattern. With the use of molecular and clinical criteria, 3 entities of
ALCL have been identified: primary systemic anaplastic lymphoma kinase
(ALK)+ ALCL, primary systemic ALK In 1985, a number of the authors1
described In 1982, Stein's group24,25 discovered a
new molecule that was initially termed Ki-1 and subsequently designated
CD30.26-28 CD30 is strongly expressed on Hodgkin and
Reed-Sternberg cells of classic Hodgkin disease, but is absent from the
cells of all normal tissues except for scattered activated large
lymphoid blasts preferentially located around B-cell follicles.
Biochemical studies29 and molecular cloning30
have revealed that CD30 is a 120-kd transmembrane cytokine receptor of
the tumor necrosis factor receptor family, for which the ligand (CD30L)
was identified.31 A soluble 85-kd form of
CD3032 was found to be released from the membrane-bound molecule by proteolytic cleavage33 and can be detected in
the sera of patients with CD30+ reactive and neoplastic
lesions. Immunohistochemical analysis of a large range of human tumors
has shown that CD30 is constantly expressed not only by Hodgkin and
Reed-Sternberg cells, but also by a subset of diffuse large cell
neoplasms, most of which had originally been diagnosed as malignant
histiocytosis, regressing atypical histiocytosis, anaplastic
(metastatic) carcinoma, malignant melanoma, seminoma, or even as
malignant fibrous histiocytoma.1,3,10,28,34 The frequent
presence of lymphoid markers and the consistent absence of molecules
associated with histiocytic or other cell lineages indicated a
lymphocytic origin for this new tumor category.1 The
lymphoid nature was further confirmed by the demonstration of clonal
rearrangements in antigen receptor genes.1,35,36 Because
of the constant Ki-1/CD30 expression and the frequent anaplastic
features, this tumor form was initially called anaplastic large cell
lymphoma (ALCL)1 and then, variably, lymphoma large cell
anaplastic CD30+ (Kiel classification37), Ki-1
lymphoma,2 or Ki-1+ large cell
lymphoma.3 However, the 2 latter terms are inadequate because CD30 is also expressed in some unrelated neoplasms, such as
Hodgkin disease1,25,28 or embryonal
carcinoma.38 The term anaplastic large cell is also not
adequate because the tumor cells in the small cell variant are not
large and the monomorphic or immunoblastic variants are not anaplastic.
Despite this and because of the absence of a better designation, the
term ALCL has now been adopted by the Revised European American
Lymphoma (REAL)13 and the new World Health
Organization (WHO) classifications.39
The histologic appearance of ALCL was originally described as a
preferential paracortical involvement of lymph nodes with intrasinusoidal dissemination (Figure
1C); although this growth pattern is
evident in partially involved lymph nodes, it remains otherwise
diffuse.1 Because of the wide histologic spectrum of the
tumor cell population and the admixture of reactive cells, several
groups proposed the subclassification of ALCL into the subforms listed
in Table 1.
The common type1,10,13,17 is characterized by sheets of
large lymphoid cells with chromatin-poor horseshoe-shaped nuclei containing multiple nucleoli (Figure 1A). Cells with these cytologic features have been called hallmark cells40 because they are encountered in all ALCL variants, including the small cell and lymphohistiocytic variants. Multinucleated cells with
Reed-Sternberg-like appearance may also occur. The tumor cells have an
abundant cytoplasm which, in imprint preparations, frequently shows
numerous vacuoles (Figure 1B). The monomorphic subform7
probably represents a variant of the common type. Because of the
cytologic resemblance of the latter to immunoblastic lymphoma, it can
easily be confused with nonanaplastic large cell lymphomas when
immunohistochemistry is not applied. In the giant cell-rich
type,3,10,13,17 a large number of the tumor cells contain
more than one nucleus. The small cell variant11 is
characterized by a mixture of small, medium-sized, and large lymphoid
cells (Figure 2). The nuclei of the small
and medium-sized cell population are often irregular. Large cells
surrounding small vessels are a frequent and characteristic finding.
This is particularly evident following immunostaining for CD30, which
highlights the large anaplastic cells. In contrast, heterogeneity is
seen in CD30 expression in the smaller cell population, with many small
cells being CD30
The sarcomatoid form of ALCL42 mimics soft-tissue tumors,
especially of malignant fibrous histiocyte type. The neoplastic cells
of this rare variant are large, bizarre, and often spindle-shaped, and
express CD30. Multinucleated forms are present in varying numbers. The
distinction from malignant fibrous histiocytoma is easily accomplished
by immunohistology because these and other soft-tissue tumors
consistently lack CD30 and other lymphoid markers. Other rare subforms
of ALCL are characterized by an abundant admixture of eosinophils or
neutrophils.13,43-45 Such cases may easily be mistaken as
Hodgkin disease, true histiocytic malignancies, or even as an acute
inflammatory process.44,45 This is especially valid for
the neutrophil-rich subform because it may mimic an acute inflammation
and, in the skin, a pustular lesion.44 An ALCL subform
with signet-ring appearance has also been described.15,46
Although there is accumulating evidence that ALCL and Hodgkin
disease are biologically distinct, the morphologic and immunophenotypic border between these disease categories is not sharp in all
instances.10,18,19,47 This applies especially
to Hodgkin disease cases rich in tumor cells, with lymphocyte
depletion, nodular sclerosis grade 2, or syncytial growth pattern. To
keep the entities of Hodgkin disease and ALCL distinct, investigators
in the late 1980s created a category (basket) under the term
ALCL-HD-related. The borderline cases, or gray-zone cases, could then
be collected in this basket for further
studies.3,10,48 Under the designation
Hodgkin-like ALCL, this type was adopted by the REAL classification as
a preliminary category.13 The tumors falling into this
category show features of both ALCL and Hodgkin disease. These
ambiguous cases contain relatively dense nodules or sheets of tumor
cells with features of classic Hodgkin and Reed-Sternberg cells (Figure
3). Tumor cells are usually present
within sinuses and, because of capsule thickening and nodular or
diffuse fibrosis, the sinusoidal dissemination is on occasion
recognizable only by immunolabeling for CD30. The proportion of admixed
reactive inflammatory cells is lower than that found in typical cases
of Hodgkin disease. The change from the term ALCL-HD-related to
ALCL-HD-like reflects the tendency in the early 1990s to believe that
most of these gray-zone lymphomas represent ALCL mimicking Hodgkin
disease. However, the frequent expression of the B-cell-specific
activation protein BSAP (PAX5) in the absence of the protein ALK
(discussed later) favors the opinion that most cases of ALCL-HD-like
represent a tumor cell-rich variant of classic Hodgkin disease and not
a true ALCL because the mentioned expression pattern is characteristic
for Hodgkin disease.49 Accordingly, the new WHO
classification has abandoned this subform and subsumes these cases
under classic Hodgkin disease.39,50,51
Immunohistochemical screening of a large number of
undifferentiated large cell malignancies has revealed that the tumor
cells of all ALCL cases show a strong expression of CD30 on the cell membrane and in the Golgi region (Figure 1D; diffuse cytoplasmic CD30
positivity is of dubious significance), so that the membrane-associated expression of CD30 was included in the definition of
ALCL.1,3,10,13,28 The analysis of conventional T- and
B-cell markers revealed 3 immunophenotypes (Table
2), with the T-cell type being the most frequent.1,6,52 The Large cell lymphomas with anaplastic morphology that express B-cell antigens are relatively rare1,6,58 (Table 2). They have been incorporated into the Kiel classification as a separate entity. However, according to the REAL and the new WHO classifications, they are not accepted as a distinct entity but are regarded as a morphologic and immunophenotypic variant of diffuse large B-cell lymphoma.13 Recent studies further support this view.59 Therefore, in the current article, these tumors are referred to as anaplastic large B-cell lymphomas. ALCLs that express both B-cell and T-cell antigens have been detected so far only by immunolabeling of frozen sections,1 possibly because of the higher sensitivity of this approach. The meaning of the double expression of T- and B-cell markers is obscure. Antigenic markers can be useful in the distinction of the different
clinical subforms of ALCL (further discussed later). Unlike the
systemic form, the primary cutaneous ALCL is usually negative for epithelial membrane antigen (EMA)4,12 and for the ALK protein60-63 (Table 3).
Moreover, nearly half of the cases arising in the skin are positive for
the cutaneous lymphocyte antigen recognized by monoclonal antibody HECA
452.12
Immunophenotypic differential diagnosis of ALCL versus Hodgkin disease As mentioned earlier, ALCL and Hodgkin disease share several morphologic and immunophenotypic features and, in some cases, assignment to one of these entities is not possible.3,10,13,64,65 This situation is particularly true for cases that lack expression of T-cell and B-cell antigens. The overlap between these conditions has vanished for the cases expressing ALK fusion proteins (chimeric ALK) because this protein is consistently absent from the tumor cells of all cases of Hodgkin disease.66-69 However, there is still an overlap (Figure 4) between ALK ALCL and
Hodgkin disease. In 1994, at the European Association of
Hematopathology Workshop in Toledo, Spain, it became evident that
markers such as CD15, BNH.9, and EMA despite initial optimismdo not
help in this distinction.19 This proved to be valid also for cytotoxic molecules because these may also be expressed by Reed-Sternberg cells of Hodgkin disease36,53,70 as well as by the tumor cells in ALCL. Recently, BSAP71 has
been found to be expressed by Reed-Sternberg cells but not by cells of
T-cell or null-cell-type ALCL.49,72 A preliminary study
has demonstrated the usefulness of this antigen in the differential
diagnosis of ALCL and Hodgkin disease.49
Initial studies73,74 on the configuration of the
antigen receptor genes in ALCL, which were performed using the Southern blot technique, demonstrated a surprising divergence between
immunophenotype and Ig and TCR gene rearrangements. More recent
investigations using the PCR in conjunction with
family-specific primers have, however, demonstrated an almost complete
concordance between the T-cell and B-cell antigen profile and the
presence of clonally rearranged TCR genes (Table 2).36 The
demonstration of clonally rearranged TCR
Normal lymphoid tissue contains a small population of large lymphoid blasts that express CD30.1,24,25 These nonneoplastic CD30+ blasts resemble the neoplastic cells of systemic ALCL1,25 in their cytologic features and tissue distribution (preferentially perifollicular and occasionally intrasinusoidal localization). It is therefore tempting to assume that they represent the normal precursor cells of systemic ALCL. The question to be answered now is whether these normal CD30+ blasts have the same cytotoxic T-cell phenotype and genotype as systemic ALCLs. Such studies are in progress in the authors' laboratory. So far, no likely candidate for the normal precursor cell for the
primary cutaneous ALCL can be identified. The anaplastic large B-cell
lymphoma might be derived from CD30+ germinal center B
cells (as are most diffuse large B-cell lymphomas) because they
carry
In the late 1980s, it was found that a proportion of ALCLs were
associated with a 2;5 chromosomal translocation.20-23 As
demonstrated by Morris et al76 in 1994, the 2;5
translocation causes the NPM gene located at 5q35 to fuse with a gene
at 2p23 encoding the receptor tyrosine kinase anaplastic lymphoma
kinase (ALK). The properties of wild-type NPM and ALK as well as their
chimerized genes and proteins are summarized in Table
4 and in Figure
5. Wild-type NPM (also known as B23)
was first identified in the late 1970s and early 1980s78,79
as a ubiquitous acidic 37-kd phosphoprotein associated with nucleoli.
NPM shuttles continuously between the cytoplasm and the nucleolus and
thus functions as a carrier of newly synthesized proteins into the
nucleolus.80 The NPM molecule exercises this function
through an oligomerization motif81 at the N-terminal
region and 2 nuclear localizing signals at the C-terminal
domain82 (Figure 5). The wild-type ALK protein is a 200-kd
transmembrane receptor that is most closely related to leukocyte
tyrosine kinase (LTK)76,83-85 and whose postnatal expression is restricted physiologically to a few scattered cells in
the nervous system (some glial cells, a few endothelial cells, and some
pericytes).66 The intracellular tail of the ALK molecule carries the tyrosine kinase catalytic domain (Figure 5), which becomes
physiologically activated as a result of homodimerization following
ligand binding.86
The 2;5 translocation juxtaposes the portion of the NPM gene encoding
the N-terminal domain of NPM (amino acids 1-117) (Figure 5) to the part
of the ALK gene that codes for the entire cytoplasmic region of the ALK
protein.76,87 As a consequence, the ALK gene comes under
the control of the NPM promoter, which induces a permanent and
ubiqitous transcription of the NPM-ALK hybrid gene, resulting in the
production of an 80-kd chimeric protein termed NPM-ALK76 or
p80.88 This NPM-ALK protein contains the NPM
oligomerization domain and the intracytoplasmic region of ALK. The
C-terminal NPM domain carrying the nuclear localization signals and the
extracellular and transmembrane region of the ALK are
absent.76,87 The NPM-ALK protein can form homodimers (by
cross-linking with other NPM-ALK molecules) or heterodimers (by
cross-linking with wild-type NPM) (Figure
6). The formation of homodimers results
in the constitutive activation of the catalytic ALK domain contained in
the NPM-ALK fusion protein.86,87 The activated ALK domain
has been shown to bind GRB288,89 and the SH2 domains of
phospholipase C-
Methods for the demonstration of NPM-ALK and the subcellular distribution of this fusion protein The presence of the NPM-ALK translocation was initially demonstrated in tissue samples by Southern blot analysis,92 reverse transcriptase-polymerase chain reaction (RT-PCR),93-97 in situ hybridization,67 and, more recently, by 2-color fluorescence in situ hybridization (FISH).98 The application of these techniques has confirmed the association of ALCL with the 2;5 translocation. The Southern blot and RT-PCR techniques have, however, produced discrepant results over the frequency of the NPM-ALK fusion gene in ALCL and the occurrence of this anomaly in large B-cell lymphoma, Hodgkin disease, and even in normal cells.99-101 Because RT-PCR is prone to artifact102 and FISH is time-consuming and difficult to apply to paraffin sections, the production and use of polyclonal85,103,104 and monoclonal antibodies specific for fixative-resistant epitopes on the cytoplasmic tail of the ALK protein66,69 and also on the N-terminal domain of NPM105 represented a significant advance in the detection of the NPM-ALK anomaly. Because ALK protein is absent in all normal tissues, with the exception of scattered cells in the brain,66 a positive immunohistochemical staining in tissues (other than brain) indicates anomalous ALK expression, usually in the form of the t(2;5)-associated NPM-ALK fusion protein.66,69,103-105 Thanks to the generation of a monoclonal antibody against the N-terminus of NPM, the molecular association of the detected ALK with NPM can also be demonstrated immunohistologically because, in the presence of NPM-ALK, this antibody stains both the cytoplasm and the nucleus,105 whereas in tissues devoid of NPM-ALK, the labeling is restricted to the nucleus.105,106 The putative mechanism that might account for the different subcellular distribution of NPM-ALK is represented in Figure 6. The lack of nuclear localization signals in the chimeric NPM-ALK protein suggests that its transportation into the nuclei of tumor cells most likely occurs through the formation of heterodimers of NPM-ALK with wild-type NPM,107 which contains 2 nuclear localization signals.82 The availability of anti-ALK and anti-NPM antibodies applicable to archival paraffin-embedded tissues allowed the screening of large numbers of neoplasms, leading to a clear perception of the presence and frequency of the NPM-ALK fusion protein and the possibility of variant ALK proteins in lymphomas.66,69,106ALK proteins other than NPM-ALK In 3 large series of ALCL, 15% to 28% of chimeric ALK+ lymphomas were found to be negative for the t(2;5) translocation (as detected by immunohistochemistry), and it was suggested that they may represent cases in which the ALK gene fuses to a partner other than NPM to produce variant X-ALK protein(s).40,66,69,106 Such X-ALK+ lymphomas are characterized by a cytoplasm-restricted expression of the ALK protein (Figures 6 and 7) and a nucleus-restricted expression of wild-type NPM.106 Additional evidence to support the presence of chimeric ALK proteins other than NPM-ALK has been obtained from reports of genetic abnormalities affecting the ALK gene in ALK+ ALCL. These include the inversion (2)(p23;q35) and the translocations (1;2)(q21;p23) and (2;3)(p23;q21),108-110 suggesting the existence of genes other than NPM that can deregulate the ALK gene. The existence of variant ALK proteins has been confirmed by immunobiochemical studies using the monoclonal antibodies to ALK and NPM (N-terminal domain).111 Western blotting studies have demonstrated the presence of variant ALK proteins of 85, 97, 104, and 113 kd.111 These new ALK fusion partners have now been identified by 5' rapid amplification of cDNA ends (RACE) studies (Figure 7). Lamant et al112 described the 104-kd ALK protein as being TPM3 (nonmuscle tropomyosin)-ALK in a tumor exhibiting the (1;2)(q21;p23) translocation. The 85- and the 97-kd ALK proteins were found to be generated by a fusion of the ALK gene with the TFG (tropomyosin receptor kinase-fused gene).113 The larger TFG-ALK fusion protein (TFG-ALKlong) contains an additional 165-bp TFG sequence113 and is associated with the (2;3)(p23;q21) translocation.110 Both of the TPM3 and TFG genes have been found to be involved in the deregulation of the kinase domain of other oncogenic tyrosine kinases present in carcinomas.114,115 In common with NPM, both TFG and TPM3 proteins contain dimerization regions. The possibility therefore exists that the formation of homodimers of TPM3-ALK or TFG-ALK (to mimic ligand binding) results in the constitutive activation of the ALK kinase domain, conferring oncogenic activity on these variant ALK proteins. In support of this is the finding that both TFG-ALK and TPM3-ALK proteins are capable of auto-phosphorylation in vitro.112 The 2 other ALK fusion partners recently identified are ATIC (5-aminoimidazole-4-carboxamide-1-beta-D-ribonucleotide transformylase/inosine monophosphate cyclohydrolase),116-118 caused by the inversion (2)(p23;q35), and CLTCL (clathrin heavy polypeptide-like gene),119 which occurs as a result of the (2;22)(p23;q11) translocation (Figure 7). Recent studies have also been able to document the frequency with which the newly found ALK fusion variants occur (Figure 7).112,113,116-119 It is of pathogenic significance that all chimeric ALK variants contain the same functional kinase domain of ALK as that present in the NPM-ALK protein (Figure 7). The lack of nuclear localization signals in the variant fusion proteins (other than NPM-ALK) accounts for the absence of these fusion proteins from the nucleus and their distribution only in the cytoplasm (Figure 6).
Evidence has also been obtained for the presence of an exceedingly rare category of ALK+/IgA+ large B-cell lymphoma with immunoblastic (rather than anaplastic) morphology.120 Immunocytochemical labeling and Western blotting studies using polyclonal and monoclonal antibodies recognizing the N-terminal and the C-terminal of ALK, respectively, have demonstrated the presence of a 200-kd full-length ALK protein in the tumor cells.120 It appears likely that the ALK+ B-cell tumors recently described by Gascoyne et al101 may also represent cases of this rare category of B-cell lymphoma (R. Gascoyne, personal communication, August 1999). Unfortunately, this possibility could not be clarified because of the unavailability of tissue sections from these cases for re-evaluation by other laboratories. Occurrence of ALK expression outside lymphoid tumors ALK proteins may also be expressed in tumors other than lymphoid neoplasms. Falini et al69 reported the presence of full-length ALK protein in 1 of 35 cases of rhabdomyosarcoma. This is in keeping with the earlier observation by Morris et al76 that the rhabdomyosarcoma cell line RH30 expresses the 200-kd wild-type ALK protein. More recently, expression of ALK proteins has been observed in inflammatory myofibroblastic tumors121 and in neuroblastomas.122 In the former tumor lesion, the ALK expression appears to be due to a rearrangement of the 2p23 region where the ALK gene is located.Specificity of ALK gene expression and its correlation with immunophenotype and morphology in lymphoma Using the highly specific monoclonal anti-ALK antibodies ALK1 and ALKc, investigators found the expression of the chimeric ALK protein to be confined to ALCL of T/null type, with a frequency ranging from 53% to 89%.40,66,69 The only other lymphoid neoplasms to express ALK proteins are the rare large B-cell lymphomas reported by Delsol et al120 and by Gascoyne et al.101 The ALK molecule could not be detected in any other lymphoma types, including most cases of CD30+ primary cutaneous lymphoproliferative disorders (primary cutaneous ALCL and lymphomatoid papulosis), Hodgkin disease, and the majority of cases (more than 85%) of ALCL with Hodgkin-like appearance.40,66,69 ALK+ ALCLs usually encompass a wide morphologic spectrum ranging from the small cell to the giant cell-rich variant of ALCL,40,69,123 with most cases falling into the category of ALCL common type. There is a correlation between the size of the ALK+ tumor cells and the subcellular distribution of the ALK protein: The large anaplastic tumor cells are usually positive both in the cytoplasm and the nucleus (less commonly only in the cytoplasm), whereas the small tumor cells exhibit a nuclear-restricted ALK protein expression69 (Figures 1F-G; 2C,H; 3D; 6). The large ALK+ tumor cells make up the dominant population in the common and giant cell types. However, the latter types usually contain, in addition, a small proportion of small-sized elements (sometimes regarded as nonneoplastic on morphologic grounds alone) that express the ALK protein.69 In contrast, the ALK+ small cell elements represent the dominant population in the small cell and lymphohistiocytic variants,69 in which a small proportion of large ALK+ tumor cells is usually detectable, often located around vessels (Figure 2).The fact that the ALK protein is detectable in both the small and large tumor cells indicates that the genetic lesion leading to the anomalous ALK expression is present in both cell populations, and thus the large and the small cells belong to the same neoplastic clone. For this reason, we can dismiss the hypothesis that the large cells observed in the small cell variant of ALCL represent a subclone that has arisen in a (2;5) translocation-negative low-grade (small cell) lymphoma by acquiring the (2;5) translocation. According to a recent study,41 the transformation of the ALK+ small cell ALCL variant into the ALCL common type may be linked, at least in some cases, to the acquisition of additional chromosomal abnormalities (eg, those involving the sex chromosome and chromosomes 6, 7, 9, and 15). From the available data, it can be concluded that the wide morphologic spectrum observed in chimeric ALK+ lymphomas is due to the following: (1) the different ratio between the large and the small tumor elements (variable from case to case and also within a given case at presentation and relapse), which appears to be dependent on whether the NPM-ALK protein is dimerized with wild-type NPM (Figure 6); (2) the different tissue distribution of neoplastic cells (eg, perivascular pattern in the small cell and lymphohistiocytic variants); (3) the occasional occurrence of nodular sclerosis (producing a Hodgkin-like appearance); and (4) the presence of different reactive cells (eg, histiocytes in the lymphohistiocytic variant).69,123
Epstein-Barr virus (EBV) infection of the tumor cells in primary systemic and cutaneous ALCL of T/null-cell type is rare or absent.124-126 In contrast, EBV is frequently detectable in the anaplastic large B-cell lymphomas (Table 2),127,128 with the incidence of infection exceeding that of sporadic Burkitt lymphoma.127 In patients infected with human immunodeficiency virus (HIV), the infection rate of large B-cell lymphomas with anaplastic morphology is increased to more than 50% of the cases.129 In contrast to Burkitt lymphoma, EBV infection in anaplastic large B-cell lymphomas is usually associated with expression of the latent membrane protein-1.129
ALCL has been clinically subdivided into a primary form (de novo)
and a secondary form (anaplastic transformation from another lymphoma).
Among the primary ALCLs, systemic and cutaneous categories have been
recognized both in immunocompetent patients and in HIV-positive patients (rarely) (Table 3 and Figure
8).
Primary systemic ALCL Primary systemic ALCL is the most frequent subform, accounting for 2% to 8% of non-Hodgkin lymphomas in adults10,13,130 and approximately 20%-30% of large cell lymphomas in children.2,131 Wright et al132 reported that the clinical features and the outcomes of systemic ALCL varied in different studies and argued that this is probably due to differences in the diagnostic criteria used, the varying age distribution of patients, and the inclusion, in clinical trials, of provisional categories such as ALCL-HD-like and ALCL of B phenotype, as well as of primary cutaneous forms of ALCL. An additional bias appears to be that in previous studies, ALK expression was not investigated, and therefore the 2 emerging entities of systemic ALCL (ALK+ and ALK) were not distinguishable. Because there is now
evidence that the clinical features and outcomes of systemic ALCL
differ significantly in cases harboring and cases lacking a
dysregulated ALK gene, we will discuss ALK+ and
ALK ALCL cases separately.
ALK+ ALCL.
ALK+ ALCL mostly occurs in the first 3 decades of life
(Figure 9),40,69,101,133,135
with male predominance being particularly striking in the
second and third decades of life (male/female ratio
6.5).133 This lymphoma frequently presents as an
aggressive stage III to IV disease, usually associated with systemic
symptoms (75%), especially high fever.133 Extranodal
involvement is frequent (60%), with approximately 40% of patients
showing 2 or more extranodal sites of the disease. In a large
study,133 the frequency of extranodal sites of lymphoma
involvement was as follows: skin 21%, bone (solitary or multiple
lesions) 17% (Figure 10), soft tissues
17% (Figure 10), lung 11%, and liver 8%, with involvement of the gut
and central nervous system (CNS) being a rare event. The incidence of
bone marrow involvement is approximately 11% when analyzed with
hematoxylin and eosin stains and approximately 30% when checked with
immunohistochemistry because scattered ALCL cells are detectable in
bone marrow trephines only when they are specifically
labeled.134
ALK+ ALCL appears to benefit from chemotherapy more than ALK forms of systemic ALCL. This prognostic difference
between ALK+ and ALK ALCL (as defined by
immunostaining with a polyclonal anti-p80 antibody) was first described
by Shiota et al,135 who reported that p80
(ALK+) ALCL cases showed a far better 5-year survival rate
(79.8%) than p80 (ALK) ones (32.9%). The authors
regarded it as unlikely that the younger age of the ALK+
patient group could have accounted for this difference in survival because similar findings were observed in patients of both groups (p80+ and p80) who were less than 30 years of
age.135 More recently, the different prognosis of
ALK+ ALCL and ALK ALCL was confirmed in 2 large series of ALCL patients (Figure 11)101,133 in which ALK
expression in tissue biopsy specimens was determined with anti-ALK
monoclonal antibodies. In these studies, the 5-year overall survival of
ALK+ versus ALK ALCL was 71% ± 6% versus
15% ± 11% in one study, respectively (Figure
11)133 and 79% versus 46% in the other.101
Other studies have also reported an excellent outcome for systemic ALCL
occurring in pediatric136-138 and young adult
patients.139,140 Although ALK expression was not
investigated in these studies, the young age suggests that these series
of patients contained a relatively large proportion of chimeric
ALK+ ALCL cases. In 2 patients, transformation of the
ALK+ small variant to common-type ALCL was found to be
predictive of a rapid clinical course,41 but this finding
must be confirmed by the study of a larger number of patients. ALCLs
expressing an ALK fusion protein other than NPM-ALK were found to
resemble typical NPM-ALK+ cases. They were of T or null
phenotype, usually occurred in young male patients, presented with
advanced disease associated with systemic symptoms and extranodal
involvement, and showed an excellent prognosis (14 of 15 patients alive
at a median follow-up of 2.26 years).106 These findings
suggest that lymphomas carrying variants of the NPM-ALK fusion protein
can be grouped with classic t(2;5)-positive tumors as a single entity
(ALK+ ALCL or "ALKoma") with a better prognosis than
ALK ALCL.106
It is noteworthy that, within the good prognostic group of chimeric ALK+ cases, Falini et al133 demonstrated that the 5-year survival was 94% ± 5% for the low/intermediate risk group (age-adjusted International Prognostic Index [IPI] 0-1) and 41% ± 12% for the high/intermediate risk group (age-adjusted IPI 2). Similar findings were observed by Gascoyne et al.101 These findings are in contrast to a recent report by the Non-Hodgkin's Lymphoma Classification Project, in which no significant difference was observed between ALCL patients with a low or a high IPI.130 However, this latter result was obtained in a less well-defined group of ALCL patients who were not characterized with anti-ALK antibodies. The opportunity to use immunohistochemical labeling techniques to identify cases of ALCL with good prognosis (ALK+ lymphomas) and to further classify this homogeneous disease into low- and high-risk cases according to the IPI might be of great relevance for the design of optimal therapeutic strategies. The excellent outcome of low-risk ALK+ lymphomas (age-adjusted IPI 0-1) warrants the randomized comparison of less versus more intensive conventional chemotherapy in this category of patients. This concept particularly applies to ALCL occurring in children, whose treatment, because of the large growth fraction and the clinical aggressiveness of the disease, has been mainly based on the highly aggressive regimens used for lymphoblastic leukemia and lymphoma. The low frequency (less than 5%) of CNS involvement by ALK+ lymphomas133 also questions the general policy of intrathecal therapy as prophylaxis for CNS involvement in children. Finally, these findings do not support the use of high-dose therapy followed by autologous bone marrow transplantation as a first-line treatment in ALK+ lymphomas with age-adjusted IPI of 0 to 1. This form of treatment has been proposed for "primary systemic CD30 (Ki-1)+ lymphomas"141 (for which data on ALK expression were not available at the time of the study), and that probably included heterogeneous entities (ALK+ and ALK ALCL as
well as cases on the borderline between ALCL and Hodgkin disease).
In contrast, patients with high-risk ALCL, ie, ALK+
lymphomas with an age-adjusted IPI of  2 or lacking ALK,
should probably be enrolled in clinical studies aimed at comparing the
efficacy of conventional polychemotherapy versus high-dose chemotherapy followed by stem cell support.141,142 It will also be
important to investigate the efficiency of innovative forms of therapy
to improve the prognosis of ALK+ lymphomas with high IPI
and that of ALK ALCL. For example, the survival of mice
bearing xenografts of human CD30+ ALCL has been prolonged
when treated with anti-CD30 immunotoxin.143 In this
context, it is interesting that NPM-ALK also binds to the
intracellular domain of CD30.144 Thus, anti-CD30
monoclonal antibodies linked to toxins or radioisotopes may
provide new tools for the treatment of poor prognostic categories of
ALCL. Other novel approaches to the therapy of ALCL might be the use of
specific inhibitors for NPM-ALK145 or the induction of a
T-cell immune response to ALK protein.
ALK Hodgkin-like ALCL. This subform occurs in young patients (like ALK+ ALCL) but shows clinical features differing from those observed in ALK+ ALCL. For example, there is a high frequency of mediastinal involvement (bulky disease in approximately 60% of cases), frequent stage II presentation, and lack of skin and bone involvement.64 These clinical findings, together with the absence of ALK protein and expression of BSAP (PAX-5 gene product; see earlier) in most of the cases, further support the view that cases classified as Hodgkin-like ALCL are, in most instances, more related to Hodgkin disease than to ALCL. Primary cutaneous ALCL Primary cutaneous ALCL differs from the systemic form in its site of origin, its clinical features, and its almost invariable absence of the ALK protein.60-62,146 Primary cutaneous ALCL arises de novo in the skin and affects older patients with a median age of approximately 60 years. It accounts for approximately 9% of cutaneous lymphomas.147 The lesion usually presents as a solitary, asymptomatic, cutaneous or subcutaneous reddish-violet tumor, which can be superficially ulcerated148 (Figure 12). Less commonly, the disease is characterized by multiple tumor nodules aggregated in a circumscribed area or as multicentric tumors at multiple sites. Primary cutaneous ALCL has a more favorable prognosis than systemic ALCL (which may secondarily involve the skin). Approximately 25% of patients with primary cutaneous ALCL show partial or complete spontaneous regression, accounting for the previous designation of regressing atypical histiocytosis. Treatment of localized lesions usually includes excision with or without radiation and is associated with long-term survival.12,147,149 However, patients with disseminated skin disease seem to be at greater risk of developing extracutaneous involvement and may benefit from systemic polychemotherapy.148
Despite some differences, primary cutaneous ALCL and lymphomatoid
papulosis overlap in histologic, immunophenotypic, and clinical features (Table 5). The major clinical
difference is that lymphomatoid papulosis, despite relapses,
runs a benign clinical course, with spontaneous disappearance of
individual skin lesions in most instances.148 Given that a
histologic and immunohistochemical distinction between primary
cutaneous ALCL and lymphomatoid papulosis is often not possible because
of the overlapping features,147,148 clinical criteria
should be applied to determine whether the patient has a locally
progressive disease that requires treatment (ALCL) or a relapsing
condition that needs no treatment (lymphomatoid
papulosis).151
HIV-related ALCL True ALCL, especially the form bearing chimeric ALK proteins, is rare in HIV-infected patients (Falini et al, manuscript in preparation). Most ALCLs reported to occur in HIV-infected patients are different from true ALCL and appear to be related to the anaplastic variant of diffuse large cell B-cell lymphoma because they are of B-cell origin and are infected by EBV in most instances.152,153 Their prognosis usually relates to the immune status of the patient.Secondary ALCL These neoplasms may arise in the progression of other lymphomas, most commonly during the course of mycosis fungoides, peripheral T-cell lymphomas, Hodgkin disease, or lymphomatoid papulosis.10,154 Such tumors mainly occur in older adults,10 are usually ALK,63,66 and have a poor
prognosis,10,154 indicating that the appearance of CD30
expression in a previously CD30 lymphoma (most frequently
being primary cutaneous T-cell lymphomas) is an unfavorable
prognostic sign.
Increased levels of the soluble form of the CD30 molecule (higher than those in Hodgkin disease) have been detected in virtually all patients with ALCL at diagnosis.155 Interestingly, the soluble CD30 level returned to the normal range on achievement of a complete response, but increased again after relapse.156 Moreover, a correlation has been reported between a risk of lower survival and increased pretreatment levels of soluble CD30.156 Recently, a preliminary study has shown that NPM-ALK tyrosine kinase and possibly other ALK-variant fusion proteins consistently elicit an antibody response to the ALK protein in patients with ALK+ ALCL.157 Further studies are, however, necessary to ascertain whether the determination of soluble CD30 or levels of anti-ALK antibodies can serve as independent prognostic and disease monitoring indicators.
The availability of monoclonal antibodies directed against the CD30 and ALK protein was an enormous achievement in the recognition and diagnosis of ALCL. The detection of CD30 (in conjunction with other lymphoid and nonlymphoid markers) is also important, not only in the differential diagnosis between ALCL and nonlymphoid anaplastic large cell tumors, but also in the distinction between ALCL and other types of lymphomas. It has recently been shown that the reproducibility of the diagnosis of ALCL on morphologic grounds is 46%, but it can be increased to 85% by immunostaining for CD30.130 Application of EMA might further improve the reproducibility because its expression is mainly restricted to ALK+ ALCL. The detection of ALK protein adds to our potential to distinguish ALCL of small cell and lymphohistiocytic types (whose small tumor cell components often lack CD30) from peripheral T-cell lymphomas and even reactive conditions,40,66,69 and will thus greatly increase the diagnostic reproducibility of the ALK+ ALCL to practically 100%. In addition, given the absence of ALK protein in all normal tissues but the brain, ALK antibodies can be used to detect single tumor cells at the time of initial staging procedures or after therapy (minimal residual disease, eg, in the bone marrow).66,133
ALCL represents a distinct category of large cell lymphomas defined by a strong expression of the cytokine receptor CD30 on all or most neoplastic cells and a so-called anaplastic cytology, usually associated with a characteristic growth pattern of the tumor cells, sinusoidal dissemination, and perifollicular or perivascular homing. On the basis of the morphologic, immunophenotypic, and clinical heterogeneity, several subtypes of ALCLs have been recognized, the most important ones being primary systemic ALCL (common type, lymphohistiocytic type, small cell variant, giant cell-rich type, and Hodgkin-like type); primary cutaneous ALCL, which belongs to the spectrum of so-called CD30+ cutaneous lymphoproliferative disorders; and secondary ALCL. Within the group of primary systemic ALCLs, a new distinct
clinicopathologic entity has emerged (Figure 8), accounting for 50% to
60% of the cases. It is defined by the expression of an ALK fusion
protein, which is NPM-ALK in approximately 72% to 85% of cases and
consists of a fusion protein containing ALK and other gene product(s)
in the remaining cases. The chimeric ALK+ ALCLs show a wide
morphologic spectrum, comprising varying proportions of the common type
(60% to 90%), giant cell-rich type (30% to 40%), and Hodgkin-like
type (less than 20%), and nearly all cases of the small cell and the
lymphohistiocytic type. Distinction of ALK+ ALCLs and
ALK In addition to the primary systemic group of ALCLs, a primary cutaneous form has been distinguished. It arises de novo in the skin and may rarely affect other organs secondarily. It shows a better prognosis than systemic ALCL and requires different therapy, at least in the early stages. It overlaps with lymphomatoid papulosis, with the result that on the basis of morphologic, immunophenotypic, and genetic findings, a distinction between primary cutaneous ALCL and lymphomatoid papulosis is frequently not possible (Table 5), and a definite diagnosis depends on knowledge of the clinical course. Anaplastic large B-cell lymphomas show overlapping features with
diffuse large B-cell lymphomas, classic Hodgkin disease (which has been
found to be B-cell derived in most instances), and Hodgkin-like ALCL
(for which the cell of origin is not yet clarified but which might be
B-cell derived in the majority of cases; Figure 4). It is clearly
different from ALCL of T/null-cell type, as supported by the consistent
absence of the ALK fusion protein in all but one study.
CD30+ large cell lymphomas expressing B-cell antigens must
not be confused with rare cases of CD30 Secondary ALCL may arise by transformation from another, usually
CD30 Although the findings reviewed in this article indicate enormous
progress in the characterization of ALCL and its subforms since the
first description of this lymphoma category 15 years ago, a number of
relevant questions remain to be answered. Is the ALK
After submission of manuscript, Elias Campo and colleagues identified a further variant ALK fusion protein, which consists of Moesin and ALK (MSN-ALK). The variant was reported at the meeting of the International Lymphoma Study Group in New York City, October 2-4, 2000. Unlike other ALK fusion proteins, the expression of MSN-ALK protein is restricted to the cell membrane.
We thank M. Schindler and H. Krosch for their help with the schematic representations and L. Udvarhelyi for his editorial assistance.
Submitted March 13, 2000; accepted July 13, 2000.
Supported by grants from the Deutsche Krebshilfe (70-2202-Mü3), the Deutsche Forschungsgemeinschaft DFG (Ste 318/5-2, SFB 366 B4), the Berliner Krebsgesellschaft, grant 9464 from the Leukemia Research Fund, A.I.R.C. (Associazione Italiana per la Ricerca sul Cancro), Projet Hospitalier de Recherche Clinique (PHRC 98), and Lique Nationale Contra le Cancer.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Harald Stein, Institute of Pathology, Benjamin Franklin University Hospital, Free University Berlin, Hindenburgdamm 30, 12200 Berlin, Germany.
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R Rust, G Harms, T Blokzijl, M Boot, A Diepstra, J Kluiver, L Visser, S-C Peh, M Lim, W A Kamps, et al. High expression of Mcl-1 in ALK positive and negative anaplastic large cell lymphoma J. Clin. Pathol., May 1, 2005; 58(5): 520 - 524. [Abstract] [Full Text] [PDF]
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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]
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 A. J. Lauder, H. E. Jolin, P. Smith, J. G. van den Berg, A. Jones, W. Wisden, K. G. C. Smith, A. Dasvarma, P. G. Fallon, and A. N. J. McKenzie Lymphomagenesis, Hydronephrosis, and Autoantibodies Result from Dysregulation of IL-9 and Are Differentially Dependent on Th2 Cytokines J. Immunol., July 1, 2004; 173(1): 113 - 122. [Abstract] [Full Text] [PDF]
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A. Zettl, T. Rudiger, M.-A. Konrad, A. Chott, I. Simonitsch-Klupp, R. Sonnen, H. K. Muller-Hermelink, and G. Ott Genomic Profiling of Peripheral T-Cell Lymphoma, Unspecified, and Anaplastic Large T-Cell Lymphoma Delineates Novel Recurrent Chromosomal Alterations Am. J. Pathol., May 1, 2004; 164(5): 1837 - 1848. [Abstract] [Full Text] [PDF]
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P. Borchmann, J. F. Treml, H. Hansen, C. Gottstein, R. Schnell, O. Staak, H.-f. Zhang, T. Davis, T. Keler, V. Diehl, et al. The human anti-CD30 antibody 5F11 shows in vitro and in vivo activity against malignant lymphoma Blood, November 15, 2003; 102(10): 3737 - 3742. [Abstract] [Full Text] [PDF]
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S. W. Morris ALK in NHL: To B (cell) or not to B (cell)? Characterization of the entity "ALK+ DLBCL" Blood, October 1, 2003; 102(7): 2316 - 2317. [Full Text] [PDF]
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R. D. Gascoyne, L. Lamant, J. I. Martin-Subero, V. S. Lestou, N. L. Harris, H.-K. Muller-Hermelink, J. F. Seymour, L. J. Campbell, D. E. Horsman, I. Auvigne, et al. ALK-positive diffuse large B-cell lymphoma is associated with Clathrin-ALK rearrangements: report of 6 cases Blood, October 1, 2003; 102(7): 2568 - 2573. [Abstract] [Full Text] [PDF]
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P. De Paepe, M. Baens, H. van Krieken, B. Verhasselt, M. Stul, A. Simons, B. Poppe, G. Laureys, P. Brons, P. Vandenberghe, et al. ALK activation by the CLTC-ALK fusion is a recurrent event in large B-cell lymphoma Blood, October 1, 2003; 102(7): 2638 - 2641. [Abstract] [Full Text] [PDF]
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M. Onciu, F. G. Behm, J. R. Downing, S. A. Shurtleff, S. C. Raimondi, Z. Ma, S. W. Morris, W. Kennedy, S. C. Jones, and J. T. Sandlund ALK-positive plasmablastic B-cell lymphoma with expression of the NPM-ALK fusion transcript: report of 2 cases Blood, October 1, 2003; 102(7): 2642 - 2644. [Abstract] [Full Text] [PDF]
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A. Younes and M. E. Kadin Emerging Applications of the Tumor Necrosis Factor Family of Ligands and Receptors in Cancer Therapy J. Clin. Oncol., September 15, 2003; 21(18): 3526 - 3534. [Abstract] [Full Text] [PDF]
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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]
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Pruritic Plaque in a 46-Year-Old Woman--Diagnosis Arch Dermatol, August 1, 2003; 139(8): 1075 - 1080. [Full Text] [PDF]
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M. Nishikori, Y. Maesako, C. Ueda, M. Kurata, T. Uchiyama, and H. Ohno High-level expression of BCL3 differentiates t(2;5)(p23;q35)-positive anaplastic large cell lymphoma from Hodgkin disease Blood, April 1, 2003; 101(7): 2789 - 2796. [Abstract] [Full Text] [PDF]
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R. Chiarle, J. Z. Gong, I. Guasparri, A. Pesci, J. Cai, J. Liu, W. J. Simmons, G. Dhall, J. Howes, R. Piva, et al. NPM-ALK transgenic mice spontaneously develop T-cell lymphomas and plasma cell tumors Blood, March 1, 2003; 101(5): 1919 - 1927. [Abstract] [Full Text] [PDF]
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F. Ravandi, M. Talpaz, and Z. Estrov Modulation of Cellular Signaling Pathways: Prospects for Targeted Therapy in Hematological Malignancies Clin. Cancer Res., February 1, 2003; 9(2): 535 - 550. [Abstract] [Full Text] [PDF]
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S A Pileri, E Sabattini, S Ascani, P L Zinzani, and B Falini How do we define Hodgkin's disease? The authors' reply J. Clin. Pathol., February 1, 2003; 56(2): 159 - 159. [Full Text] [PDF]
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A. Zettl, G. Ott, A. Makulik, T. Katzenberger, P. Starostik, T. Eichler, B. Puppe, M. Bentz, H. K. Muller-Hermelink, and A. Chott Chromosomal Gains at 9q Characterize Enteropathy-Type T-Cell Lymphoma Am. J. Pathol., November 1, 2002; 161(5): 1635 - 1645. [Abstract] [Full Text] [PDF]
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L. Hernandez, S. Bea, B. Bellosillo, M. Pinyol, B. Falini, A. Carbone, G. Ott, A. Rosenwald, A. Fernandez, K. Pulford, et al. Diversity of Genomic Breakpoints in TFG-ALK Translocations in Anaplastic Large Cell Lymphomas : Identification of a New TFG-ALKXL Chimeric Gene with Transforming Activity Am. J. Pathol., April 1, 2002; 160(4): 1487 - 1494. [Abstract] [Full Text] [PDF]
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P. Bonvini, T. Gastaldi, B. Falini, and A. Rosolen Nucleophosmin-Anaplastic Lymphoma Kinase (NPM-ALK), a Novel Hsp90-Client Tyrosine Kinase: Down-Regulation of NPM-ALK Expression and Tyrosine Phosphorylation in ALK+ CD30+ Lymphoma Cells by the Hsp90 Antagonist 17-Allylamino,17-demethoxygeldanamycin Cancer Res., March 1, 2002; 62(5): 1559 - 1566. [Abstract] [Full Text] [PDF]
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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]
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F. Turturro, M. D. Arnold, A. Y. Frist, and K. Pulford Model of Inhibition of the NPM-ALK Kinase Activity by Herbimycin A Clin. Cancer Res., January 1, 2002; 8(1): 240 - 245. [Abstract] [Full Text] [PDF]
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F. Vinante, A. Rigo, M. T. Scupoli, and G. Pizzolo CD30 triggering by agonistic antibodies regulates CXCR4 expression and CXCL12 chemotactic activity in the cell line L540 Blood, January 1, 2002; 99(1): 52 - 60. [Abstract] [Full Text] [PDF]
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S. J. Meech, L. McGavran, L. F. Odom, X. Liang, L. Meltesen, J. Gump, Q. Wei, S. Carlsen, and S. P. Hunger Unusual childhood extramedullary hematologic malignancy with natural killer cell properties that contains tropomyosin 4-anaplastic lymphoma kinase gene fusion Blood, August 15, 2001; 98(4): 1209 - 1216. [Abstract] [Full Text] [PDF]
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R. Suzuki, M. Seto, S. Nakamura, A. Nakagawa, K. Hara, and K. Takeuchi Sarcomatoid Variant of Anaplastic Large Cell Lymphoma with Cytoplasmic ALK and {{alpha}}-Smooth Muscle Actin Expression: A Mimic of Inflammatory Myofibroblastic Tumor Am. J. Pathol., July 1, 2001; 159(1): 383 - 384. [Full Text] [PDF]
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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]
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J. P. Greer, M. C. Kinney, and T. P. Loughran Jr. T Cell and NK Cell Lymphoproliferative Disorders Hematology, January 1, 2001; 2001(1): 259 - 281. [Abstract] [Full Text] [PDF]
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Top
Abstract
Introduction
-chain of the T-cell
receptor CD3 complex (TCR) is one of the most constantly
expressed T-cell antigens; a minority of cases express CD4 or CD8, with
a predominance of CD4.
and 
genes
and expressed the cytotoxic molecules perforin, granzyme B, and
T-cell-restricted intracellular antigen-1 (TIA-1) (Figures 
, includes all the morphologic variants
discussed in Table 
, in the Kiel classification,
included as a separate entity, and in the REAL classification, included
as a variant of diffuse large B-cell lymphoma.
