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NEOPLASIA
From the Section of Pediatric Hematology/Oncology,
Departments of Pediatrics and Pathology, University of Colorado Health
Sciences Center; The Children's Hospital; and the University of
Colorado Cancer Center, Denver, CO.
This report describes an unusual extramedullary hematologic
malignancy in an 18-month-old child who presented with a capillary leak
syndrome that evolved into hyperleukocytosis with malignant cells. The
circulating tumor cells did not express an antigen profile typical of
any subtype of leukemia commonly observed in children. Tumor cells were
CD3 Anaplastic large cell lymphoma (ALCL) is a
heterogeneous subtype of non-Hodgkin lymphomas (NHLs) unified by a
characteristic pattern of lymph node invasion by malignant cells that
express epithelial membrane antigen (EMA) and CD30.1
Because EMA and CD30 can be expressed by a variety of neoplastic cells,
co-expression of anaplastic lymphoma kinase (ALK) aids in the diagnosis
of ALCL. Aberrant ALK function is thought to play a critical role in
the pathogenesis of ALCL, because most ALCLs contain chromosome
translocations that create ALK fusion proteins with constitutive kinase
activity.1,2 The prototypic ALK fusion protein is
nucleophosmin (NPM)-ALK, created by the t(2;5)(p23;q35).3
Four variant ALK chimeras have been identified recently in
ALCL.4-9 Tumors containing variant ALK chimeras are
characterized by cytoplasmic-restricted ALK
expression.1
The precise cellular origin of ALCL is unknown. The majority of ALCLs
express T-cell-associated antigens and have rearranged TCR
genes.2 The remaining cases express neither T- nor B-cell antigens and are termed null-ALCL. Most null-ALCLs are considered to be
of T lineage because they have either NK cells are thought to be derived from a bipotential common T cell/NK
cell progenitor and express some cell surface antigens associated with
T cells; they do not express T-cell-specific antigens, are by
definition surface CD3 In this report, we describe an 18-month-old boy with an unusual
malignancy characterized by a capillary leak and hemophagocytic syndrome, hyperleukocytosis, and circulating malignant cells with minimal bone marrow involvement and no identified nodal or extranodal tumor mass. The tumor cells were CD3 Case history
The patient was treated initially with high-dose intravenous
immunoglobulin and methylprednisolone. An extensive investigation for
viral infections, including Epstein-Barr virus and herpesviruses such
as human herpesvirus 8, was negative. Because of the patient's deteriorating clinical status, tentative diagnosis of
infectious-associated hemophagocytic syndrome, and symptoms suggestive
of "cytokine storm," Cyclosporin A (CsA) was added to the treatment
regimen. Within 24 hours of starting CsA and after 1 week of
methylprednisolone, the patient's WBC count abruptly increased from
5.5 ×109L (5500/µL) to 39.4 × 109L
(39 400/µL) over a 36-hour period, and malignant cells were noted in
the peripheral blood for the first time. The day before the development
of hyperleukocytosis, a bone marrow was obtained that showed no
malignant cells by microscopic examination, but retrospective
cytogenetic and fluorescence in situ hybridization (FISH) studies
revealed presence of the pseudodiploid clone with an ALK
translocation. The WBC count eventually peaked at
94 × 109L (94 000/µL) with 66% circulating malignant cells.
The neoplastic cells were homogeneous and monocytoid appearing. Some
cells contained numerous cytoplasmic vacuoles and exhibited cytoplasmic
buddings. Initial analysis indicated that the malignant cells expressed
no T, B, or histiocytic cell-associated antigens but strongly expressed
CD13 and CD30 and were negative for Tdt and cytochemical
myeloperoxidase (MPO) staining. Cytogenetic studies of peripheral blood
and bone marrow specimens detected abnormalities in the short arms of
chromosomes 2, 5, and 19. FISH studies showed rearrangement of
ALK with translocation to the der(19). Reverse transcriptase-polymerase chain reaction (RT-PCR) for
NPM-ALK fusion transcripts was negative. Because
of the unusual clinical presentation and evidence of a variant
ALK translocation in malignant cells that co-expressed CD30
and EMA, the patient was felt to have an atypical ALCL.
On the basis of this diagnosis, CsA was discontinued and plasmapheresis
and leukopheresis were performed daily for 5 days with significant
improvement in the patient's clinical condition. Induction
chemotherapy based on the Children's Cancer Group regimens used to
treat pediatric ALCL and other childhood NHLs was initiated. The
patient achieved a complete remission within 4 weeks and was treated
for a total of 8 months with a regimen that included Adriamycin, cyclophosphamide, cytosine arabinoside, daunorubicin, etoposide, high-dose methotrexate, vincristine, and intrathecal cytosine arabinoside but excluded steroids. The patient is currently in remission 14 months after completion of therapy.
Specimens
Cytogenetics and FISH Giemsa-banded cytogenetic studies were performed from unstimulated cultures of bone marrow and peripheral blood. Samples were prepared by using a direct technique and overnight culture methods as described previously.23,24 Cytogenetic results are described by using the International System for Cytogenetic Nomenclature.25FISH studies were performed by using a commercial ALK probe (Vysis, Downers Grove, IL) that was directly labeled with Spectrum Green and Spectrum Orange and hybridized to both interphase and metaphase targets following the manufacturer's protocol. In the use of this probe, cells with an intact ALK locus have a fused red/green signal on chromosome 2. If an ALK translocation has occurred, then the probe is split. The proximal Spectrum Green-labeled probe remains on the der(2) and the distal Spectrum Orange-labeled probe moves to the partner derivative chromosome. Additional FISH studies were performed with chromosome 2 and 19 whole chromosome paint probes and with probes for 5p-, 19p-, and 19q-specific subtelomeric sequences under conditions recommended by the manufacturer (Vysis). Fluorescence-activated cell sorter analysis Immunophenotyping of malignant cells was performed on the leukopheresis product by using directly conjugated fluorescent monoclonal or polyclonal antibodies to CD3, CD4, CD5, CD8, CD14, CD16/56 (combined), CD19, CD45, CD45RO, HLA-DR, TCR-  , and
TCR-  (Becton Dickinson, Mountain View, CA); CD10, CD20 (Coulter,
Miami, FL); CD13, CD61 (DAKO, Carpinteria, CA); CD2 (Immunotech, Miami,
FL); and CD7, CD25, CD30, CD33, CD34, CD95, CD95L, and CD122
(Pharmingen, San Diego, CA). Cells were also separately stained with
isotype controls for each antibody according to manufacturer's
protocol. Cells were analyzed by flow cytometry within 24 hours of
preparation at the University of Colorado Cancer Center Flow Cytometry
Core or at The Children's Hospital by using Coulter EpicsXL flow
cytometers and software.
Immunohistochemistry Immunohistochemical staining was performed by using the heat-induced antigen retrieval technique on paraffin-embedded cellblock sections made from peripheral blood leukocytes obtained from leukopheresis. The following monoclonal antibodies were used according to protocols recommended by the manufacturers: Granzyme B (Chemicon; CA); CD57 (Becton Dickinson); CD3, CD15, CD20, CD68, ALK-1, EMA, MPO, S-100 (DAKO, Carpinteria, CA); and CD30 (Immunotech). Standard cytochemical stains for MPO and nonspecific esterase (NSE) were performed on bone marrow aspirate smears.NK cell cytotoxicity assays A standard short-term (4-hour) 51Cr-release NK cell functional assay using NK-sensitive K562 and NK-insensitive Daudi tumor cells as targets was performed.26 Peripheral blood mononuclear cells (PBMCs) were isolated from a healthy volunteer (control) or from the patient's leukopheresis product by using Histo-paque 1077 (Sigma, St. Louis, MO) gradient separation. PBMCs served as effectors in the 51Cr-release assay. Targets were labeled with 100 µCi 51Cr as sodium chromate (ICN Pharmaceuticals, Irvine, CA) in standard media for 1 to 2 hours at 37°C. Radiolabeled target cells (5000) in 100 µL per well were plated in 96-well tissue culture plates. Patient or control PBMCs in a volume of 100 µL were added at ratios of 50:1; 25:1; 12:1; and 6:1 to the target cells. Plates were pelleted by centrifugation and incubated for 4 hours at 37°C. Following incubation, 100 µL cell-free supernatant was transferred to separate tubes and radioactivity was measured by using a gamma counter. Percentage of specific lysis was calculated by using the following formula: (e s/m s) × 100, where e, s, and m equal the amount of radioactivity
released from PBMCs incubated with effector cells (experimental lysis),
with 100 µL media instead of effector cells (spontaneous lysis), or
with 100 µL 1% Triton X-100 (maximum lysis), respectively.
Experimental, spontaneous, and maximum lysis samples were plated in
triplicate. Percentage of specific lysis was calculated as previously
described. Fas/FasL killing assays were performed in an analogous
manner as previously described.27
Molecular analyses RNA extraction and RT-PCR analyses were performed as described previously.28 The sequences of PCR oligomers are provided in Table 1. Nucleotide sequencing of cloned PCR products and sequence analysis was performed as described previously.29
Morphologic and cytochemical features of the malignant cells The malignant cells present in Wright-stained peripheral blood were large and homogenous, and they contained large round to oval nuclei, slightly dense chromatin, inconspicuous nucleoli, and abundant blue cytoplasm. Large cytoplasmic blebs were also noted in some cells (Figure 1A). Many tumor cells contained multiple clear cytoplasmic vacuoles, but no cytoplasmic granules or Auer rods were seen. Malignant cells were negative for Sudan black B, NSE, and MPO cytochemical reactivity, although high expression of cytoplasmic MPO protein was detected by immunohistochemistry (Figure 1B).
Immunophenotypic properties of malignant cells A fluorescence-activated cell sorter (FACS) light-scatter profile of cells freshly obtained by leukopheresis showed 2 populations of cells expressing CD45 (Figure 2A). The malignant cells comprised the vast majority of CD45+ cells and showed a side-scatter profile characteristic of monocytes (region I). A much smaller population of cells with the side-scatter profile representing normal lymphocytes was also present (region II). FACS analysis gated on the malignant cells (region I) revealed an unusual immunophenotype. All the malignant cells strongly expressed CD13, CD25, CD30, CD45, CD45RO, HLA-DR, CD95 (Fas), and CD122. On dual-color FACS analysis, 68% of malignant cells expressed CD16/CD56 (combined antibody reagent) but lacked CD3 expression consistent with the antigen profile of NK cells (Figure 2B). With the use of single-color analysis, 56% of malignant cells expressed CD56. Approximately 20% of malignant cells expressed CD3dim, CD7dim, CD33bright, and CD14bright; however, it was not possible to determine whether the same population of cells simultaneously expressed a combination of these antigens or whether CD16/56+ cells also co-expressed these antigens because single-color rather than multicolor FACS was performed for these antigens. Less than 10% of the malignant cells expressed T-cell-associated antigens CD2, CD4, CD5, and CD8 or B-cell-associated antigens CD19 and CD20. Tumor cells also did not express CD10, CD34, CD61, Fas ligand, or surface TCR, , , or
chains.
On cellblock sections made from peripheral blood, malignant cells were
readily identified and appeared similar to neoplastic cells identified
in Wright-stained peripheral blood (Figure 1A). Immunohistochemical
staining demonstrated that the tumor cells did not express cytoplasmic
CD3, CD15, CD57 (mature NK antigen), CD68, or S100
(histiocyte-associated antigens). All the malignant cells stained
strongly with antibodies to CD30 (Figure 1C). The majority of
neoplastic cells stained positive with antibodies to EMA and ALK
(Figure 1D,E). ALK-1 staining was confined to the cytoplasm of the
malignant cells. Nearly all neoplastic cells were positive for the
cytotoxic protein granzyme B, although only a small percentage of cells
stained strongly positive (Figure 1F). TCR Malignant cells display cytotoxic properties of NK cells NK cells have the capacity to lyse tumor cells by 2 pathways. The predominant pathway involves release of cytotoxic granules containing perforin and granzyme B to target cells. A second pathway, primarily found in fully differentiated/activated NK cells, uses Fas ligand to kill Fas+ targets. In short-term (4-hour) 51Cr-release assays, unstimulated NK cells are defined by their ability to lyse NK-sensitive (K562) but not NK-insensitive (Daudi) target cells.Because the neoplastic cells expressed antigens associated with NK
cells, we performed 51Cr-release assays on freshly
isolated, unstimulated tumor cells to determine if they possessed NK
cytotoxic properties. PBMCs isolated from a normal control contained
12% NK cells as determined by FACS (data not shown). Isolated PBMCs
from the patient contained less than 1% normal lymphocytes, and no
cells expressing an NK cell phenotype
(CD56+CD3 Identification of a novel ALK translocation Cytogenetic studies of unstimulated peripheral blood and bone marrow specimens revealed structural abnormalities of chromosomes 2, 5, and 19 (Figure 3). FISH using a 2-color split signal ALK probe cocktail revealed a rearrangement in interphase nuclei. Metaphase FISH demonstrated that the proximal ALK sequences remained on the der(2), whereas distal ALK sequences were translocated to the der(19) (Figure 4A). This was not a cryptic t(2;5) because RT-PCR for NPM-ALK fusion transcripts was negative (data not shown). Additional FISH studies identified a reciprocal t(2;19) (Figure 4B,C) and showed that the der(5) results from an unbalanced translocation of 19q to distal 5p, leaving 5p subtelomeric sequences intact (Figure 4D). These detailed FISH studies established the karyotype of the main clone to be 46, XY, t(2;19)(p23;p13.1), der(5)t(5;19)(p15.3;q13.1).
TPM4 is a new ALK fusion partner On the basis of the FISH and RT-PCR results, we concluded that ALK was fused to a new 19p13.1 partner gene in this neoplasm. Because the rearrangements were complicated, we undertook studies to exclude the possibility of cryptic fusion of ALK to one of its other known partner genes and performed RT-PCR by using primers designed to amplify ATIC-ALK and TPM3-ALK fusion transcripts. Although the ATIC-ALK PCR was negative, we observed robust amplification of an approximate 300-base-pair (bp) product (and weaker amplification of larger products) with the TPM3-ALK primers from both peripheral blood and bone marrow specimens of the patient with the t(2;19) but not from samples lacking ALK translocations (Figure 5A). We cloned the PCR product and determined the nucleotide sequences of 2 independent clones with inserts of 308 and 426 bp (GenBank accession No. AF362886 and AF362887). The last 83 nucleotides of both clones were derived from ALK with the site of fusion identical to that seen in other ALK chimeric complementary DNAs (nucleotide 40843). The 5' portion of both clones shared homology with TPM3, but they were more homologous to alternatively spliced products of TPM4. The longer clone started with the outer TPM3 oligomer and the shorter clone started with the inner TPM3 oligomer. The clones also showed differential splicing within the region homologous to TPM4, but both showed fusion between TPM4 position 714 (numbering as per GenBank accession No. NM_00329030) and ALK 4084. TPM4 has been mapped to chromosome 19p13.1,31 indicating that the complex t(2;19) in this case fused ALK to a second member of the tropomyosin gene family. Amplification with primers designed to amplify TPM3-ALK transcripts occurred fortuitously because the TPM3 primers we used were homologous to both TPM3 and TPM4. To confirm the TPM4-ALK fusion, we designed a TPM4-specific oligomer that spanned the start codon. PCR using this and an oligomer located more 3' in ALK gave an approximate 950-bp product that was cloned and sequenced. This product contained TPM4 nucleotides 45-714 (100% match to NM_003290) fused to ALK starting at position 4084 (Figure 5B; GenBank accession No. AF310722).
We describe a leukemic presentation of an unusual extramedullary
hematologic malignancy in a young child with fulminant clinical symptoms. This case presented a diagnostic challenge because no solid
tumor mass could be identified, the circulating tumor cells did not
appear to arise from the bone marrow, and they did not express an
antigen profile typical of any subtype of leukemia commonly observed in
children. Because the clinical presentation of childhood ALCL is
diverse, is often associated with cytokine storm-like symptoms, and
can rarely be associated with circulating tumor
cells,32-37 the malignant cells were analyzed with this
diagnosis in mind. Consistent with a null-ALCL, tumor cells were
CD3 This case contained a t(2;19)(p23;p13.1), which we found created a new variant ALK fusion protein, TPM4-ALK. Chimeric ALK proteins are present in most childhood ALCLs, which are considered to comprise a distinct histopathologic entity unified by their expression of ALK fusion proteins.2 About 70% of these cases contain a t(2;5)(p23;q35) that produces NPM-ALK, a constitutively active tyrosine kinase that has oncogenic properties in a variety of experimental systems.3,38-41 The other 30% contain variant ALK fusion proteins created by translocations joining 2p23 to other regions of the genome. To date, 4 different ALK fusion variants have been identified in ALCL: t(1;2)(q25;p23) and TPM3-ALK, inv(2)(p23;q35) and ATIC-ALK, t(2;3)(p23;p21) and TFG-ALK, and t(2;22)(p23;q11.2) and CLTCL-ALK.4-9 At the time this patient presented, ALK translocations had only been described in ALCL. After we identified TPM4-ALK fusion in this case, Lawrence et al42 reported that TPM4-ALK and TPM3-ALK fusion genes also occur in a nonhematalogic malignancy termed inflammatory myofibroblastic tumor (IMT).42 Thus, ALK translocations can no longer be considered pathognomonic of ALCL. We identified 2 species of TPM4-ALK transcripts fortuitously when we cloned and sequenced RT-PCR products obtained with TPM3 and ALK primers. The 3' portions of the major 308-bp and minor 426-bp products we cloned match the type I and II TPM4-ALK transcripts identified in IMT, whereas the first 81 (major) and 103 (minor) bp are more divergent. GenBank searches performed recently (Hunger SP, unpublished data, 2001) show that these 5' portions are highly homologous to recently described alternatively spliced TPM4 isoforms. We later amplified and cloned fusion transcripts containing the complete portion of TPM4 fused to ALK (Figure 5B). These transcripts are identical to type II TPM4-ALK transcripts identified in IMT.42 The relevance of different species of TPM4-ALK fusion transcripts and proteins is unknown at this time and merits additional study. Even in the presence of an ALK translocation, the
clinical features present in this patient and the phenotype of the
malignant cells were very atypical for an ALCL and prompted us to
perform additional investigations. These studies demonstrated that the tumor cells also had features typically associated with both myeloid and NK malignancies. Although the profile of
CD3 The classification of NK cell malignancies is evolving and
becoming increasingly complex. Recently proposed classification schemes
differentiate immature (precursor) from mature NK cell malignancies and
from NK-like T-cell malignancies.16,17 Precursor NK
cell disorders resemble acute leukemia and include myeloid/NK cell
precursor leukemia, blastic NK cell leukemia/lymphoma, and possibly
myeloid/NK cell acute leukemia.16,45,46 Neoplasms derived
from mature NK cells include extranodal NK/T-cell lymphoma (nasal type)
and aggressive NK-cell leukemia/lymphoma.47 Table 2 compares the features of these closely
related entities with each other and with the malignancy that we
characterized.
The clinicopathologic features of the patient we describe do not
correspond with any previously described tumor of which we are aware.
Rather, this case has some features suggestive of an ALCL-like
malignancy (CD30+/EMA+/ALK+ with an
ALK translocation), some suggestive of a myeloid malignancy (CD13+/CD33+/HLA-DR+ and expressing
cytoplasmic MPO but lacking MPO activity) and some features (granzyme
B+/CD25+/CD122+ with the cytotoxic
activity of incompletely differentiated NK cells but
CD2
We thank Stephan Morris for generously sharing reagents, data on ATIC-ALK before publication, and thoughtful advice. We also thank Mitchell Bitter for his expert review of the pathology of this case and for review of this manuscript, Karen Helms and her colleagues in the flow cytometry core lab for expert assistance, Bette Jamieson for help with morphology studies, and Billie Carstens for expert figure layout and design. In particular, we thank reviewer B for a very detailed and useful critique of this manuscript.
Submitted December 15, 2000; accepted April 19, 2001.
Supported by grants from the Loewenstern Family Foundation (to S.P.H.), Cure For Lymphoma Research Foundation (to S.J.M.), Lymphoma Research Fund at The Children's Hospital Cancer Center and National Cancer Institute Cancer Center Core Grant CA 46934. S.P.H. is a Translational Research Grant Awardee of the Leukemia and Lymphoma Society of America.
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: Stephen P. Hunger, UCHSC Campus Box C229, 4200 East Ninth Ave, Denver, CO 80262; e-mail: stephen.hunger{at}uchsc.edu.
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Top
Abstract
Introduction
/CD56+; had germline TCR
genes; and strongly expressed CD30, epithelial membrane antigen, and
anaplastic lymphoma kinase (ALK) consistent with a null cell anaplastic
large cell lymphoma (ALCL). The malignant cells contained a
t(2;19)(p23;p13.1) that interrupted ALK and translocated it
to the der(19). Reverse transcriptase-polymerase chain reaction and
nucleotide sequence analysis revealed fusion of ALK to
tropomyosin 4, an ALK fusion partner not described previously in
hematologic malignancies. The clinical presentation and phenotypic features of this malignancy were not typical for ALCL because tumor
cells expressed both myeloid (CD13, CD33, HLA-DR) and natural killer
(NK) cell antigens. The neoplastic cells most resembled NK cells
because in addition to being CD3
) versus control
peripheral blood mononuclear cells (
) at various effector-to-target
ratios as determined by a standard 4-hour chromium release NK
cell assay.
