Anaplastic large cell lymphoma: The evolution continues.

Aaplastic large cell lymphoma (ALCL) was first described in 1985 as Ki-1 lymphoma which was characterized by a neoplastic proliferation of lymphoid cells that were anaplastic in appearance, had a propensity to grow cohesively, invaded lymph node sinuses and consistently expressed the cytokine receptor CD30 molecule and epithelial membrane antigen (EMA).[1] As per its evolutionary history, ALCL was included in the revised Kiel classification as “large cell anaplastic lymphoma” and ultimately the term “anaplastic large cell lymphoma” was adopted as a preferred designation in the revised European-American lymphoma (REAL) classification.[23] It was considered as a high-grade non- Hodgkin's lymphoma (NHL), accounting for nearly 3% of adult and 10% of childhood NHL; the Kiel classification recognized anaplastic large cell lymphoma to be of B-, T- or null-cell origin that can have diverse clinical, histologic and cytologic presentations.[2] Subsequently it was discovered that the clinical behavior of B-cell ALCL was different and its prognosis was similar to that of diffuse large B-cell lymphoma; the CD30 staining pattern was also weaker. This group of B-cell ALCL was therefore removed from the diagnostic category of ALCL in the REAL classification and WHO classification of hematologic malignancies.[4]

Major breakthroughs came with the discovery that some ALCL tumors carried the t (2; 5) translocation which caused fusion of the nucleophosphin gene (NMP1) with a previously unrecognized gene, named anaplastic kinase (ALK).[5] ALK- 1 was considered as an important diagnostic and likely prognostic feature of ALCL with some investigators advocating recognition of “ALK-positive lymphoma” as a distinct clinicopathologic entity.[6] However the idea was rejected at that time by WHO classification on the ground that lymphomas with this typical morphology and immunophenotype that are ALK-1 negative do exist.[4] ALK1+ ALCL occurs in younger age group and carries better prognosis while ALK- ALCL (nearly 1/3rd of ALCL) cases exhibit immunophenotype heterogeneity and a more unfavorable clinical outcome.[2] Since then a large bulk of information has accumulated on the role of ALK in the molecular pathogenesis of ALCL. The new edition of the WHO classification (2008) recognizes, within the spectrum of mature T-cell neoplasms, two types of systemic ALCL according to ALK protein expression in tumour samples; (i) a distinct entity, named ALK+ ALCL which is characterised by ALK gene rearrangements and ALK protein expression; and (ii) and a provisional entity, the so-called ALK- ALCL which is a CD30+ T-cell lymphoma that cannot be distinguished morphologically from ALK+ ALCL but differs from this entity because of lack of ALK protein.[7]

It is very important to recognize ALCL because it is a highly treatable type of lymphoma with high 5-year overall survival rate. Majority ALCL cases have lymphadenopathy likely to be superficial.[8] However extranodal disease is an important component of ALCL and involves the Waldayer's ring, skin, lung, bone, soft-tissue, respiratory and gastrointestinal tract.[2] Separation of systemic ALCL into two entities (ALK+ and ALK-)[7] is clinically and prognostically relevant; ALK+ ALCL more frequently occur in the first three decades of life and in males while patients with ALK- ALCL are older and smears are usually composed of larger pleomorphic cells than the ALK positive cases.[68]

Fine needle aspiration (FNA) cytology has been utilized as an important diagnostic tool in the investigative armamentarium of ALCL.[38-10] Besides severe pleomorphism, various other FNA cytologic features of ALCL include “hallmark” cells with kidney-shaped or embryo-like nuclei, doughnut cells, multinucleated giant cells with wreath-like arrangement of nuclei, cells with multilobated nuclei, small to medium-sized plasmacytoid cells, nondescript small to medium-sized cells, tennis racket cells, Reed-Sternberg-like cells, prominent rod-shaped angulated basophilic nucleoli, cytoplasmic vacuoles, paranuclear cytoplasmic accentuation, mitotic activity and apoptotic bodies.[8-10] In addition to the common/classic or conventional type of ALCL, a number of variants have been reported such as lymphohistiocytic, neutrophil/eosinophil-rich, monomorphic and small cell.

Because of its anaplastic nature and the wide and unusual morphological spectrum, ALCL may pose diagnostic problem and is liable to be misdiagnosed as melanoma, metastatic carcinoma and sarcoma.[11] Although discovered in 1985, this NHL subtype existed since long, possibly in the guise of Hodgkin's lymphoma (HL) with which it shares not only morphological features but also CD30+ status. Review of archival HL cases aided by immunohistochemistry will support this statement. Among the lymphoma subtypes, ALCL, HL and T-cell-rich B-cell lymphoma (TCRBCL) have some overlapping cytomorphologic features and as a result one may be misdiagnosed as the other.[12] In such situations, immunocytochemical/immunohistochemical studies may be of help; the usual immunocytochemical profile of ALCL is as follows: CD30+, leukocyte common antigen (LCA)+, EMA+, ALK-1±, CD3±, CD15- and CD20-. Since its initial description, the change of nomenclature, the separation of B-cell ALCL as a diffuse large B-cell NHL and the provisional status of ALK- ALCL indicate that the evolution of ALCL still continues. Articles like “ALK-negative anaplastic large cell lymphoma mimicking a soft tissue sarcoma”[13] published in this issue of “Journal of Cytology” are likely to contribute to the status of “ALK-negative ALCL as a definitive clinicopathologic entity in WHO classification. All those who are interested on this subject and make a break-through research to solve the remaining mysteries behind this fascinating neoplasm can become a part of its evolutionary history.