Prognostic Significance of Anaplastic Lymphoma Kinase (ALK) Protein Expression in Adults With Anaplastic Large Cell Lymphoma

Abstract

Anaplastic large cell lymphoma (ALCL) is an aggressive lymphoma that is frequently associated with the t(2;5)(p23;q35), resulting in expression of a fusion protein, nucleophosmin-anaplastic lymphoma kinase (NPM-ALK), which can be detected by either monoclonal or polyclonal antibodies to the ALK protein. The clinical features of adults with ALCL are incompletely described, and the prognostic factors that are useful for predicting survival remain unclear. This report describes the clinical and laboratory findings in 70 adults with systemic ALCL who were treated with curative intent. We attempted to identify the clinical and pathological factors of prognostic importance, including the International Prognostic Index (IPI), immunophenotype, and expression of the ALK protein. The median age of the patients was 49 years (range, 15 to 75). There were 26 women and 44 men with a median follow-up of 50 months for living patients. Advanced stage was present in 56% and B symptoms were noted in 70% of the patients. Immunostains showed that 46% of the cases had a T-cell phenotype, 36% a null phenotype, and 18% a B-cell phenotype. The expression of ALK protein was found in 51% of the cases. The IPI factors were evenly distributed between the ALK+ and ALK− groups, except that the ALK+ patients were younger (median age, 30 v 61 years; P < .002). The ALK+ cohort included cases with null (44%), T-cell (42%), and B-cell (14%) phenotypes. All 10 cases with cytogenetic or molecular evidence of a t(2;5) were ALK+. The 5-year overall survival (OS) of the entire cohort was 65%. The 5-year OS of the ALK+ and ALK− cases was 79% and 46%, respectively (P < .0003). Analysis of only the T-cell/null cases (n = 57) showed a 5-year OS of 93% for the ALK+ cases and only 37% for the ALK− cases (P < .00001). Univariate analysis of the clinical features showed that age ≤60 years (P < .007), a normal serum lactate dehydrogenase (LDH) (P < .00001), a good performance status (Eastern Cooperative Oncology Group [ECOG] <2) (P< .03), ≤1 extranodal site of disease (P < .012), and an IPI score ≤3 (P < .00001) were associated with improved OS. Although a younger age correlated with ALK positivity, multivariate analysis showed that only a normal serum LDH (P < .00001), an IPI score of ≤3 (P < .0005), and ALK protein expression (P < .005) predicted independently for an improved OS. We conclude that ALCL is a heterogeneous disorder. However, ALK protein expression is an independent predictor of survival and serves as a useful biologic marker of a specific disease entity within the spectrum of ALCL.

Comparative analysis of extra‐nodal NK/T‐cell lymphoma and peripheral T‐cell lymphoma: significant differences in clinical characteristics and prognosis

“…One of the limitations of our study relates to the fact that we did not separate the various subtypes of PTCL in our analysis. Increasingly, the various subtypes of PTCL are recognized as a biologically diverse group of conditions and 'lumping' them together may potentially obscure their distinct natural histories (5,21). Nonetheless, with the exception of ALK-1 positive anaplastic large-cell lymphoma, which has a favorable outcome, the prognosis of the other subtypes of PTCL is uniformly poor (20).…”

Aggressive B‐cell lymphomas: a review based on the workshop of the XI Meeting of the European Association for Haematopathology

“…However, since they are of B-cell lineage, do not in most cases express ALK and have nothing in common with the biological entity we recognize as anaplastic large cell lymphoma (ALCL), the use of the term 'pleomorphic' may be more appropriate than 'anaplastic' to avoid confusion with T-cell ⁄ null ALCL, which has a favourable clinical outcome in contrast to the inferior survival characteristics of DLBCL. 20,21 Recent studies of the molecular pathogenesis of DLBCL have suggested that aberrant activity of the somatic hypermutation mechanism may underlie many cases. 22 This may account for the lack of a dominant translocation mechanism in DLBCL and may explain the diversity of this group of lymphomas.…”

ALK‐negative anaplastic large‐cell lymphoma demonstrates similar poor prognosis to peripheral T‐cell lymphoma, unspecified

“…Subsequent expression of the anaplastic lymphoma kinase (ALK) protein is associated with an excellent prognosis. [15][16][17][18] In contrast, ALK-negative ALCL shows a variable prognosis 15 and a significantly lower expression of epithelial membrane antigen (EMA) and the cytotoxic phenotype proteins granzyme B and ⁄ or T-cell intracytoplasmic antigen (TIA)-1. [19][20][21][22][23] Thus, ALK-positive ALCL is a well-defined biological and clinical entity, but ALK-negative ALCL is more heterogeneous than hitherto assumed and needs further investigation.…”