Bcl-2 Expression in Anaplastic Large Cell Lymphoma

To the Editor-in-Chief:

Anaplastic large cell lymphoma (ALCL) is a distinct clinicopathological entity that has been individualized in the Revised European American Lymphoma (REAL) classification. 1 This entity is defined as a T-cell or null-cell lymphoma expressing CD30 (Ki-1 antigen). Three different subtypes of ALCL have recently been identified: primary systemic anaplastic lymphoma kinase-positive (ALK+) ALCL, ALK− ALCL, and primary cutaneous ALCL. 2 ALK expression is the consequence of chromosomal translocations involving the ALK gene at 2p23 and the protein is detectable by immunohistochemistry. 2 The most frequent variant of the translocations implicating ALK is the t(2;5) translocation, which juxtaposes the ALK gene at 2p23 with the nucleophosmin (NPM) gene at 5q35. 2 Recently, it has been shown that the NPM/ALK chimeric protein activated the phosphatidylinositol 3-kinase/Akt (Pl-3K/Akt) anti-apoptotic pathway. 3 Therefore, in case of NPM/ALK expression, one would expect the Bcl-2 protein to be overexpressed in association with other anti-apoptotic factors. In a previous report published in the Journal, 4 we found in a short series of cases of NPM/ALK+ ALCL that the Bcl-2 protein was not expressed. The recent demonstration by Bai et al 3 prompted us to extend our previous series of cases and to look for a possible correlation between Bcl-2 and ALK expression.

To do so, we retrieved 75 cases of ALCL that had been diagnosed in the Hematopathology Department at Purpan Hospital during 1998 and 1999 (reviewed by G. D.). Seventy cases were lymph node biopsies (primary systemic ALK+ and ALK− ALCL) and five cases corresponded to primary cutaneous ALCL (ALK−). Tissue samples were processed routinely, ie, fixed in Duboscq-Brasil and/or formalin and embedded in paraffin. In all cases, a staining was performed with anti-Bcl-2 (clone 124; DAKO, Trappes, France) and anti-ALK (ALK1 kindly provided by Prof. D. Y. Mason, Oxford, UK) monoclonal antibodies on paraffin-embedded sections using microwave heating. 5 Among the 70 cases of primary systemic ALCL, 58 tumors expressed ALK and 12 tumors were ALK-negative. All but one case of ALK+ primary systemic ALCL were negative for Bcl-2 (57/58). In only one case, there was a faint staining in rare lymphoma cells compared to the strong staining observed in the surrounding small reactive lymphocytes. These results are in keeping with those published by Nakamura et al. 6 In their series, they failed to detect Bcl-2 in 31 cases of p80 (NPM/ALK)+ ALCL. 6 In the present study, 7 of 12 primary systemic ALK− ALCL and all cases (5/5) of primary cutaneous ALCL were Bcl-2-positive. Again, these results are confirmed in the study by Nakamura et al 6 and in a more recent publication by Paulli et al 7 dealing with cutaneous CD30+ lymphoproliferative disorders.

One can suspect that in NPM/ALK+ ALCL, the lack of Bcl-2 expression is caused by the overexpression of ALK, but this phenotype is difficult to reconcile with the activation of an anti-apoptotic pathway, as recently demonstrated. 3 Further studies are needed to understand the downstream pathway of PI-3K/Akt signaling. However, our study confirms the preliminary data indicating the lack of Bcl-2 expression in ALK+ ALCL. 4,6 These data strengthen the recent subdivision of ALCL into three distinct subgroups. Bcl-2 and ALK expression are mutually exclusive, and the lack of Bcl-2 expression may have diagnostic value, in some instances, in differentiating anaplastic cell lymphoma from Hodgkin’s disease. As ALCL are sensitive to chemotherapy, our findings are also consistent with the concept that Bcl-2 expression is associated with chemoresistance.