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Blood, Vol. 93 No. 8 (April 15), 1999:
pp. 2697-2706
ALK+ Lymphoma: Clinico-Pathological Findings and Outcome
Brunangelo Falini,
Stefano Pileri,
Pier Luigi Zinzani,
Antonino Carbone,
Vittorina Zagonel,
Chris Wolf-Peeters,
Gregor Verhoef,
Fabio Menestrina,
Giuseppe Todeschini,
Marco Paulli,
Mario Lazzarino,
Roberto Giardini,
Antonella Aiello,
Hans-Dieter Foss,
Iguacyra Araujo,
Marco Fizzotti,
Pier-Giuseppe Pelicci,
Leonardo Flenghi,
Massimo F. Martelli, and
Antonella Santucci
From the Institute of Hematology, University of Perugia, Perugia,
Italy; the Institutes of Pathology and Hematology, University of
Bologna, Bologna, Italy; the Institutes of Pathology and Clinical
Oncology, Centro di Riferimento Oncologico, Istituto Nazionale Tumori,
Aviano, Italy; the Institutes of Pathology and Hematology, University
of Leuven, Leuven, Belgium; the Institutes of Pathology and Hematology,
University of Verona, Verona, Italy; the Institutes of Pathology and
Hematology, University of Pavia, Pavia, Italy; the Institute of
Pathology, Istituto Nazionale Tumori of Milan, Milan, Italy; the
Institutes of Pathology and Hematology, Benjamin Franklin University,
Berlin, Germany; and the European Institute of Oncology, Milan, Italy.
A distinct pathologic entity (ALK+ lymphoma) that is
characterized by expression of the anaplastic lymphoma kinase (ALK)
protein has recently emerged within the heterogeneous group of
CD30+ anaplastic large-cell lymphomas. Information on
clinical findings and treatment outcome of ALK+ lymphoma
is still limited, and no data are available concerning the value of the
International Prognostic Index when applied to this homogeneous disease
entity. To clarify these issues, a recently developed monoclonal
antibody ALKc (directed against the cytoplasmic portion of ALK) was
used to detect expression of the ALK protein in paraffin-embedded
biopsies from 96 primary, systemic T/null anaplastic large-cell
lymphomas, and the ALK staining pattern was correlated with
morphological features, clinical findings, risk factors (as defined by
the International Prognostic Index), and outcome in 78 patients (53 ALK+ and 25 ALK ). Strong cytoplasmic
and/or nuclear ALK positivity was detected in 58 of 96 ALCL cases
(60.4%), and it was associated with a morphological spectrum (common
type, 82.7%; giant cell, 3.5%; lymphohistiocytic, 8.6%; and small
cell, 5.2%) that reflected the ratio of large anaplastic elements
(usually showing cytoplasmic and nuclear ALK positivity) to small
neoplastic cells (usually characterized by nucleus-restricted ALK
expression). Clinically, ALK+ lymphoma mostly occurred in
children and young adults (mean age, 22.01 ± 10.87 years) with a male
predominance (male/female [M/F] ratio, 3.0) that was particularly
striking in the second-third decades of life (M/F ratio, 6.5) and
usually presented as an aggressive, stage III-IV disease, frequently
associated with systemic symptoms (75%) and extranodal involvement
(60%), especially skin (21%), bone (17%), and soft tissues (17%).
As compared with ALK+ lymphoma, ALK cases
occurred in older individuals (mean age, 43.33 ± 16.15 years) and
showed a lower M/F ratio (0.9) as well as lower incidence of stage
III-IV disease and extranodal involvement at presentation. Overall
survival of ALK+ lymphoma was far better than that of
ALK anaplastic large-cell lymphoma (71% ± 6%
v 15% ± 11%, respectively). However, within the good
prognostic category of ALK+ lymphoma, survival was 94% ± 5% for the low/low intermediate risk group (age-adjusted
International Prognostic Index, 0 to 1) and 41% ± 12% for the
high/high intermediate risk group (age-adjusted International
Prognostic Index,  2). Multivariate analysis identified ALK
expression and the International Prognostic Index as independent variables that were able to predict survival among T/null primary, systemic anaplastic large-cell lymphoma. Thus, we suggest that such
parameters should be taken into consideration for the design of future
clinical trials.
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