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We have read with interest the eletter by Dr Naresh dated 26 March1 in response to our earlier review.2 This letter dealt with the problem of the borders between classic Hodgkin’s lymphoma (cHL) and anaplastic large cell lymphoma (ALCL) and suggested that the proponents of the World Health Organisation (WHO) classification had a more flexible attitude towards cHL than ALCL.3 We believe that the WHO classification simply reflects the philosophy of the revised European–American (REAL) classification of lymphoid neoplasms, by drawing up a list of entities that can be readily recognised with the techniques available at the moment, which are defined by the amalgamation of cell morphology, phenotype, cytogenetics, molecular data, and clinical findings.4 This list can be easily updated, whenever new validated information becomes available in the literature.
We believe that the present scenario of cHL is much more homogeneous than the one depicted for ALCL. In fact, most if not all examples of cHL have a germinal centre cell derivation, as shown by molecular data and B cell specific activator protein (BSAP) expression,5 with cases of T cell origin being exceptional and still a matter of speculation.2 In addition, a reasonable explanation has been found for the lack of immunoglobulin (Ig) expression by Hodgkin and Reed-Sternberg cells (HRSC), being related to either crippling Ig gene mutations or deregulation of the transcription factors Oct-2, BOB.1, and PU.1.2,6 These mechanisms differ—for instance—from the ones at work in primary mediastinal large B cell lymphoma (PMBL), which also lacks Ig expression and can at times be confused with cHL in needle biopsies. In fact, PMBL shows functional IgVH gene mutations and intact expression of the above mentioned transcription factors, findings that—along with CD45 expression, regular B cell marker positivity, and the absence of CD15—allow the easy distinction between the two processes.7 Further information on the pathobiology of cHL (including the problem of the cytokinesis of HRSC)2 is expected from the studies using the recently developed gene expression profiling and tissue microarray techniques.8–11 The application of gene expression profiling may be more complex than in non-Hodgkin’s lymphomas because of the need to isolate single neoplastic elements from the reactive cellular background, but is certainly not impossible.8–10 Tissue microarray methods have already found a preliminary use, by showing in 330 examples of cHL that cyclin E plays a central role in the cell cycle deregulation of HRSC.12
On the other hand, the issue of anaplastic large cell lymphoma still sounds like the Pirandello’s drama “Six characters in search of their author”. The decision of considering anaplastic B cell tumours as a morphological variant of diffuse large B cell lymphoma (DLBCL)—adopted by the REAL classification4 and maintained in the WHO scheme3—is supported by the following arguments: (1) the consistent lack of ALK protein expression; (2) the evidence for possible transformation from a follicular lymphoma; (3) the occurrence of IgVH gene somatic mutations; and (4) the clinical behaviour, which is quite similar to that of the remaining forms of DLBCL.13,14 Focusing on what is currently diagnosed as ALCL of T/null cell derivation,13,14 a basic distinction should be made, based on ALK protein expression.13,14 ALK positive ALCL, which comprises about 60% of all ALCL cases, corresponds to a distinct clinicopathological entity, characterised by: (1) ALK protein expression as a result of the t(2;5)(p23;q35) or a variant translocation involving the ALK gene (at 2p23); (2) a wide morphological spectrum (ranging from the common type to the small cell variant); (3) male predominance; (4) prevalence in the first two decades of life; and (5) a very good response to conventional chemotherapy in most instances (about 80% of patients are cured).13,14 This form of ALCL has nothing to do with cHL, which always lacks t(2;5) or variant translocations.3 The combined application of antibodies against the ALK protein and BSAP has allowed the critical revision of the so called Hodgkin’s-like ALCL: at state of the art, there is evidence that most tumours diagnosed as such in the past are really histologically aggressive forms of cHL (ALK−, and BSAP+), whereas ALK+/BSAP− ALCLs provided with some nodularity and sclerosis (thus mimicking nodular sclerosing cHL) are exceedingly rare.13,14 ALK protein expression, which leads to homodimer formation and constitutional activation of the ALK catalytic domain, is probably involved in the process of lymphomagenesis and seems to act on signalling proteins, such as phospholipase Cγ and phosphoinositide 3-kinase, with a direct influence on the transduction of mitogenic signals and activation of the antiapoptotic Akt pathway, respectively.14 None of these events is known to occur in cHL. With regard to ALK negative ALCL, when excluding the primary cutaneous forms, which behave quite characteristically (with possible spontaneous regression in 25% of cases) and are related to lymphomatoid papulosis,14 the remaining tumours are controversial. In contrast to ALK+ tumours, they mostly occur in old patients and run a very aggressive clinical course, with a poor response to conventional regimens (only 30% of patients survive at five years). Thus, it is unclear whether ALK negative ALCL of the T/null cell type represents a separate entity or the end of the spectrum of peripheral T cell lymphomas. Within this context, a further intriguing problem is the recent observation that some cases phenotypically belonging to the null cell group express BSAP and carry IgVH gene clonal rearrangements, the genes encoding T cell receptor β and γ being in germ line configuration.15 This finding highlights the need for the systematic evaluation of ALK negative ALCLs using all of the tools available to collect histogenetically homogeneous tumours and to assess whether there is some common event among these that leads to neoplastic transformation.
Supported by AIRC grants to SAP and BF.