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Blood, Vol. 94 No. 10 (November 15), 1999:
pp. 3509-3515
By
From the Institutes of Hematology and Internal Medicine, University
of Perugia, Perugia, Italy; the LRF Immunodiagnostics Unit, John
Radcliffe Hospital, Oxford, UK; the Division of Pathology, Oncology
Reference Center, National Tumor Institute, Aviano, Italy; the
Institute of Pathology, University of Leuven, Leuven, Belgium; the
European Oncology Institute, Milan, Italy; the Institute of Pathology,
University of Bologna, Bologna, Italy; the Laboratory of Pathology,
Hospital Clinic, University of Barcelona, Barcelona, Spain; the
Department of Pathology, University of Würzburg, Würzburg,
Germany; the Laboratory of Anatomic Pathology, Hospital of Toulouse,
C.H.U. Purpan, Toulouse, France.
The tumor cells in ALK-positive lymphoma ("ALKoma") usually
express the product of the NPM-ALK chimeric gene, generated by the t(2;5) chromosomal translocation. However, 10% to 20% of
ALK-positive lymphomas express ALK fusion protein(s) other than
NPM-ALK, and in this report, we describe the immunohistologic and
clinicopathologic features of 15 such cases. The absence of the
NPM-ALK fusion gene was confirmed by reverse
transcriptase-polymerase chain reaction (RT-PCR) in 8 cases and by
fluorescence in situ hybridization (FISH) analysis in a
further 2 cases. In each case, ALK staining was restricted to the
cytoplasm and the N-terminus of NPM to the nucleus (contrasting with
lymphomas expressing NPM-ALK in which cytoplasmic as well as nuclear
labeling is seen). However, in the course of screening 53 ALK-positive
lymphomas, 2 biopsies were found that had a "cytoplasm-only" ALK
staining pattern but that nevertheless were shown to carry the (2;5)
(by NPM staining and RT-PCR). The 15 cases resembled typical
NPM-ALK-positive lymphomas in that all were of T or null phenotype,
usually occurred in young male patients, and frequently presented with
advanced disease associated with systemic symptoms and extranodal
involvement. Moreover, their prognosis was excellent and
indistinguishable from that of classical t(2;5)-positive tumors, but
was clearly different from that of ALK-negative anaplastic large-cell
lymphomas. These results suggest that lymphomas carrying variants of
the NPM-ALK fusion protein can be detected by immunostaining for ALK and NPM and also that they can be grouped with classical
t(2;5)-positive tumors as a single entity (ALK-positive lymphoma or
"ALKoma") that shows a better prognosis than ALK-negative
anaplastic large-cell lymphoma.
A DISTINCT CLINICOPATHOLOGIC entity
("ALK-positive lymphoma" or "ALKoma"),1,2
defined by expression of the anaplastic lymphoma kinase (ALK), has
emerged from the heterogeneous category of CD30+ anaplastic
large-cell lymphomas.3-9 ALK-positive lymphomas show a wide
morphologic spectrum1,2 ranging from the common type to the
small-cell or lymphohistiocytic variant,10-13 but share the
same phenotype (T or null),1,2,14 show a male predominance, and tend to occur in the first 3 decades of life.1,2,14-16 These lymphomas often present as rapidly growing and advanced tumors
that are frequently associated with systemic symptoms and extranodal
involvement, especially of skin and bone.16 However, their
prognosis is good compared with ALK-negative anaplastic large-cell
lymphomas.14-16
ALK expression in these cases is usually due to the presence of the
t(2;5)(p23;q35) chromosomal translocation,17 which causes fusion of ALK and NPM genes.18,19 The
resultant chimeric gene encodes an 80-kD fusion
protein18-20 containing the N-terminal portion of NPM
(amino acids 1-117)18,19 linked to the entire cytoplasmic
domain of the neural-associated receptor tyrosine kinase
ALK.21,22 The NPM-ALK hybrid protein is thought to play a
direct role in lymphomagenesis,23,24 probably by aberrant phosphorylation of intracytoplasmic substrates.18
The presence of NPM-ALK chimeric transcripts or proteins can be
detected in anaplastic large-cell lymphoma samples by the reverse
transcriptase-polymerase chain reaction (RT-PCR).25 In
addition, ALK protein is not expressed in lympho-hematopoietic tissues,
and immunostaining with antibodies specific for the cytoplasmic portion
of ALK2,26-28 has therefore been widely used to provide evidence for the t(2;5) translocation.
In ALK-positive lymphomas, strong immunocytochemical labeling for ALK
protein is seen not only in the cytoplasm of neoplastic cells, but also
within their nuclei.2,16 This is due to dimerization of
NPM-ALK fusion protein with wild-type NPM, which carries nuclear localization motifs.29 However, not all ALK-positive
lymphomas of T-cell or null cell phenotype carry the NPM-ALK
fusion gene. The ALK gene can be involved in chromosomal anomalies
other than the t(2;5), such as t(1;2)(q25;p23)19 or
inv(2)(p23;q35),30 and in these ALK-positive lymphomas the
ALK protein tends to accumulate only in the cytoplasm.28,30
In 2 large studies,1,2 15% to 20% of ALK-positive
lymphomas of T-cell or null cell phenotype showed
cytoplasmic-restricted expression of ALK, suggesting that variants of
the NPM-ALK fusion gene are not uncommon.
In a recent study,31 we reported that antibodies specific
for the N-terminal region of the NPM molecule showed cytoplasmic labeling in 3 classical ALK-positive lymphomas. We speculated that this
could be used as a means of confirming whether a lymphoma in which ALK
is apparently restricted to the cytoplasm does indeed carry a variant
of the NPM-ALK fusion gene. In this report, we have studied a
series of such rare cases and report that in most but not all of them
the staining pattern of the N-terminus of NPM provided confirmation of
a variant translocation. This is the first series of such tumors
containing variant ALK fusion proteins to be identified, and we have
reviewed not only clinical and histologic features at presentation, but
also patient survival (after treatment by conventional chemotherapy) to
assess the prognostic significance of these genetic anomalies.
Patients and Tissue Samples
Anti-ALK and Anti-NPM Monoclonal Antibodies
Immunocytochemical Labeling Paraffin sections on silane-coated slides were dewaxed and then subjected to microwave heating (750 W for 3 cycles of 5 minutes each) in 1 mmol/L EDTA buffer, pH 8.0.2,32 Sections were allowed to cool at room temperature for approximately 20 minutes, were washed in Tris-buffered-saline, and were immunostained by an immuno-alkaline phosphatase (APAAP) technique,33 as previously described.2 Endogenous alkaline phosphatase was blocked with 1 mmol/L levamisole34 and antibodies were used as undiluted tissue culture supernatants. Slides were counterstained for 5 minutes in Gill's hematoxylin and mounted in Kaiser's glycerol gelatin (Merck, Darmstadt, Germany).RT-PCR Analysis RT-PCR studies were performed as previously described.35Clinical Data The clinical findings and outcome of the 84 T/null anaplastic large-cell lymphomas (59 ALK-positive and 25 ALK-negative) were reassessed, and the following parameters were reviewed: sex, date of birth, date and site of the diagnostic biopsy, sites of nodal and extranodal involvement (as assessed by physical examination, computerized tomography [CT] scan, and marrow biopsy), Ann Arbor Stage at the time of diagnosis, performance status, maximum diameter of the largest tumor mass, and serum lactate dehydrogenase (LDH). Patients were stratified according to a simplified age-adjusted International Prognostic Index.36 Overall survival was measured from diagnosis to death from any cause, with surviving patient follow-up recorded at the last contact date. Estimates of overall survival distribution were calculated using the method of Kaplan and Meier.37 Time-to-event distributions were compared using the log-rank test.38 The Cox regression model39 was used to correlate survival with prognostic factors and with the 3 different lymphoma categories defined by ALK and NPM immunostaining (NPM-ALK-positive, carrying a variant ALK fusion protein, and ALK-negative).
Identification of ALK-Positive Lymphomas Expressing Variants of NPM-ALK Immunostaining.
Two patterns of immunostaining for ALK protein were observed in our
series of 59 ALK-positive lymphomas of T-cell or null cell phenotype
(Table 1). In 42 biopsies (36 common type
and 6 lymphohistiocytic/small cell type), ALK labeling was seen within the nuclei of large neoplastic cells (Fig
1, top left), and this was typically accompanied by diffuse cytoplasmic
reactivity (although in smaller ALK-positive neoplastic cells, labeling
was restricted to the nucleus). The other labeling pattern, seen in 17 of the 59 cases (Table 1), comprised ALK immunostaining restricted to the cell cytoplasm. We interpreted this distinctive staining pattern as
possibly indicating the presence of ALK fusion protein(s) that lacked
NPM and that was therefore not transported to the nucleus (through
heterodimerization with wild-type NPM).29
RT-PCR and fluorescence in situ hybridization (FISH)
analysis.
A total of 28 cases were investigated directly for the presence of the
NPM-ALK gene by RT-PCR or FISH analysis (Table 1). Each of the
16 cases with the classical immunostaining patterns for ALK and NPM
tested in this way were positive, as were the 2 cytoplasmic ALK only
cases in which NPM labeling had not provided evidence of a variant
ALK-protein. In contrast, 10 cases with nuclear-restricted labeling for
the N-terminal epitopes of NPM all lacked, as predicted, evidence of
the NPM-ALK gene: in 8 cases, the RT-PCR reaction was negative,
and in 3 of them, conventional cytogenetics showed variant
translocations, ie, t(1;2)(q21p23) in 2 cases and t(2;3)(p23;q35) in 1 case. In the remaining 2 cases, a cryptic inv(2)(p23;q35) had been
previously documented by FISH analysis.30
Clinical features of ALK-positive lymphomas carrying variants of
NPM-ALK.
The 15 ALK-positive lymphomas identified in this way as carrying
variants of the t(2;5) translocation showed clinical features similar
to those of classical ALK-positive cases.16 In particular, the patients tended to be young (mean age, 19 years; age range, 4 to
45), with male predominance (male/female ratio, 1.5), and they
frequently presented with advanced disease (9 of 15 cases in stage
III-IV) and systemic symptoms (11 of 15 patients). Similarly to
NPM-ALK-positive cases,16 these patients showed frequent involvement of extranodal sites (2 skin, 2 soft tissues, 3 lung, 2 central nervous system, 1 bone marrow, 1 pleura, and 1 gut). There was
no statistically significant difference between NPM-ALK-positive and
variant cases in terms of bulky disease, LDH levels, or performance status.
In this report, we describe the immunohistologic and clinicopathologic
features of 15 cases of ALK-positive lymphomas that appear to express
ALK fusion protein(s) other than NPM-ALK. Seventeen cases showed a
cytoplasmic-only pattern of labeling when paraffin sections were
immunostained for ALK protein, and this was associated with a negative
RT-PCR test result for NPM/ALK in 8 cases (some of them bearing variant
translocations at conventional cytogenetics or showing ALK proteins
lacking NPM at Western blotting)40 and the presence of
cryptic inv(2) (p23;q35) by FISH in an additional 2. Subsequently,
monoclonal antibodies directed against the N-terminal portion of
NPM31 were found to label only the nuclei of tumor cells
(reflecting reactivity with wild-type NPM) in 15 of these 17 atypical
cases, a staining pattern that differs from that of classical
NPM/ALK-positive lymphoma, ie, cytoplasmic and nuclear.
The authors thank Barbara Bigerna, Roberta Pacini, Barbara Ugolini,
Cristina Alunni, Laura Natali Tanci, and Gisberto Loreti for the
skillful technical assistance. We also thank Claudia Tibidò for
her excellent secretarial assistance.
Submitted December 29, 1998; accepted July 6, 1999.
Supported by A.I.R.C. (Associazione Italiana per la Ricerca sul Cancro)
and the Leukaemia Research Fund of Great Britain. M.F. is supported by
the Fondazione Antonio Castelnuovo, Italy.
The publication costs of this
article were defrayed in part by
page charge payment. This article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. section
1734 solely to indicate this fact.
Address reprint requests to Brunangelo Falini, MD, Istituto di
Ematologia, Policlinico, Monteluce, 06100 Perugia, Italy.
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ABSTRACT
INTRODUCTION
