Advances in the treatment and prognosis of anaplastic lymphoma kinase negative anaplastic large cell lymphoma
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Abstract:
Anaplastic lymphoma kinase negative anaplastic large cell lymphoma (ALK- ALCL) is a definite entity in the WHO 2016 Classification that represents 2-3% of non-Hodgkin lymphoma (NHL) and 12% of T-cell NHL cases. ALK- ALCL lacks ALK protein expression, but expresses CD30 and has morphologic features similar to ALK positive anaplastic large cell lymphoma (ALK+ ALCL). Some studies indicate that ALK- ALCL and ALK+ ALCL possess different molecular and genetic characteristics. Besides, ALK- ALCL is worse than ALK+ ALCL in terms of treatment outcome, prognosis, and long-term survival. This review is aimed at summarizing information about ALK- ALCL, especially with respect to the treatment and prognosis.Keywords:
Anaplastic large-cell lymphoma
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Familial clustering of Hodgkin’s disease (HD) and increased risk of developing the disease among the siblings of affected patients suggest that both environmental and genetic factors may play an important role in its pathogenesis. An association between Epstein-Barr virus (EBV) and HD has been widely demonstrated. Recently, latent membrane protein of EBV has also been detected in CD30-positive anaplastic large cell lymphoma. Familial aggregation of HD and a three- to seven-fold-increased risk among the siblings of affected patients suggest increased genetically determined susceptibility. No data about genetic factors are available for anaplastic large-cell lymphoma. In this study, the authors report the case of a woman with anaplastic-lymphoma-kinase (ALK)-negative CD30-positive anaplastic large cell lymphoma, whose brother had developed HD 11 years previously. The clinical, histologic, and immunohistochemical features of the 2 lymphomas were studied. Both siblings showed bulky mediastinal involvement, effacement of normal lymph node architecture by large, atypical cells, resembling Reed-Sternberg cells, expression of EBV latent membrane protein-1 in the lymph node specimens, concordance of both HLA classes I and II. The clinical presentations and immunological studies disclose numerous similarities between the 2 cases and can suggest that their association is not fortuitous. At present, in problematic cases, a combination of morphologic, immunophenotypic and genetic studies may contribute to better define the tumour type.
Anaplastic large-cell lymphoma
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The Revised European American Lymphoma classification uses the term Hodgkin's-like anaplastic large cell lymphoma (HD-like ALCL) for borderline cases with features of both anaplastic large cell lymphoma (ALCL) and classical Hodgkin's lymphoma (HL). The aim of this study was to clarify the association between cytotoxic molecule (CM) expression and clinical outcome in HD-like ALCL.Subjects were 59 patients with HD-like ALCL, defined by nodal presentation without mediastinal bulky lesions, T- or null-cell phenotype, CD30+ anaplastic lymphoma kinase (ALK)- phenotype and by confluent sheets or nodules of large cells mimicking classic Hodgkin and Reed-Sternberg cells. We evaluated the presenting features and prognosis of subjects on categorization into two defined groups, namely CM (TIA1 and/or granzyme B)-positive (n = 21) and CM-negative (n = 38). The series consisted of 18 women and 41 men ranging from 16 to 88 years of age (median 59 years). The CM+ group had poorer disease-specific survival than the CM- group (P = 0.02) despite the absence of differences in other clinical characteristics. Multivariate analysis confirmed that CM expression was an independent prognostic factor, in contrast to phenotypic categorization (T-cell vs. null-cell group), which had no prognostic impact on disease-specific survival.CM expression is predictive of prognosis in HD-like ALCL.
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Reed–Sternberg cell
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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.
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Abstract Anaplastic large cell lymphoma is a unique diagnostic subcategory of the T-cell lymphomas in the current World Health Organization classification. Representing approximately 3% of adult and 10% to 30% of childhood non-Hodgkin lymphomas, anaplastic large cell lymphoma classically consists of CD30+ large lymphoid cells with abundant cytoplasm and pleomorphic, often horseshoe-shaped or kidney-shaped nuclei. Among the reported nodal and extranodal sites of occurrence, the gastrointestinal tract and central nervous system have rarely been noted. We report a case of primary anaplastic lymphoma kinase–negative anaplastic large cell lymphoma in the brain of a 46-year-old patient with acquired immunodeficiency syndrome. T-cell lineage was confirmed by T-cell receptor γ chain gene rearrangements using polymerase chain reaction, and extra copies of the anaplastic lymphoma kinase gene of chromosome 2 were demonstrated by fluorescence in situ hybridization analysis. To our knowledge, primary anaplastic large cell lymphoma of the brain has not previously been reported in acquired immunodeficiency syndrome.
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Abstract Anaplastic large cell lymphomas constitute a heterogeneous group of hematopoietic neoplasms that are characterized by immunopositivity for CD30 and the presence, in varying degrees, of large, pleomorphic “hallmark” cells. Primary systemic anaplastic lymphoma kinase-positive anaplastic large cell lymphomas are a subset of this group. Numerous heterogeneous histomorphologic patterns have been described in anaplastic lymphoma kinase-positive anaplastic large cell lymphomas, and all patterns tend to have a better prognosis than that found in anaplastic lymphoma kinase-negative cases. We provide a short review of the small cell variant of anaplastic large cell lymphoma to facilitate the diagnosis of this difficult-to-recognize entity, which may be confused with reactive processes, commonly presents with disseminated disease, and pursues an aggressive clinical course.
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T cell Non-Hodgkin lymphoma is a heterogeneous disease ranging from malignancies arising from thymic T cells halted in development, through to mature, circulating peripheral T cells. The latter cases are diagnostically problematic with many entering the category of peripheral T cell lymphoma, not otherwise specified (PTCL, NOS). Anaplastic Large Cell Lymphoma is one of the exceptions to this whereby aberrant expression of Anaplastic Lymphoma Kinase and distinctive presence of cell surface CD30 places this entity in its own class. Besides expression of a well-studied oncogenic translocation, ALCL, ALK+ may also have a unique pathogenesis with a thymic origin like T lymphoblastic lymphoma but a peripheral presentation akin to PTCL. This review discusses evidence towards the potential origin of ALCL, ALK+ and mechanisms that may give rise to its unique phenotype.
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Anaplastic large cell lymphomas constitute a heterogeneous group of hematopoietic neoplasms that are characterized by immunopositivity for CD30 and the presence, in varying degrees, of large, pleomorphic hallmark cells. Primary systemic anaplastic lymphoma kinase-positive anaplastic large cell lymphomas are a subset of this group. Numerous heterogeneous histomorphologic patterns have been described in anaplastic lymphoma kinase-positive anaplastic large cell lymphomas, and all patterns tend to have a better prognosis than that found in anaplastic lymphoma kinase-negative cases. We provide a short review of the small cell variant of anaplastic large cell lymphoma to facilitate the diagnosis of this difficult-to-recognize entity, which may be confused with reactive processes, commonly presents with disseminated disease, and pursues an aggressive clinical course.
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There is controversy in the literature as to whether anaplastic large‐cell lymphoma of B‐cell phenotype is related to the t(2;5)‐positive T‐ or ‘null’ cell lymphoma of the same morphology. We report a study of 24 lymphomas with morphological features of anaplastic large‐cell lymphoma which expressed one or more B‐cell markers and lacked T‐lineage markers. Clinical features were more in keeping with large B‐cell lymphoma than with classical t(2;5)‐positive anaplastic large‐cell lymphoma, and immunostaining for anaplastic lymphoma kinase (ALK) protein provided no evidence for the (2;5) translocation (or one of its variants). The staining patterns for CD20 and CD79 were typical of diffuse large B‐cell lymphoma, CD30 expression was variable, and most cases (15/22) lacked epithelial membrane antigen (EMA). These findings support the view that ‘B‐cell anaplastic large‐cell lymphoma’ is unrelated to t(2;5)‐positive (ALK‐positive) lymphoma, and that it represents a morphological pattern occasionally encountered among diffuse large B‐cell lymphomas. By the same reasoning, most tumours diagnosed as ‘ALK‐negative anaplastic large‐cell lymphoma of T‐cell or null phenotype’ probably belong to the spectrum of peripheral T‐cell lymphomas.
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