Anaplastic large‐cell lymphomas of B‐cell phenotype are anaplastic lymphoma kinase (ALK) negative and belong to the spectrum of diffuse large B‐cell lymphomas
Eugenia HaralambievaKaren PulfordLaurence LamantStefano PileriGiovanna RoncadorKevin C. GatterGeorges DelsolDavid Y. Mason
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Abstract:
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.Keywords:
Anaplastic large-cell lymphoma
Large-cell lymphoma
Large cell
BCL10
T-Cell Lymphoma
Immunophenotyping
Null cell
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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Clinical and pathologic features of 24 patients with large cell lymphomas that expressed the activation antigen Ki-1 are described. Phenotypic and/or genotypic studies characterized these neoplasms as T-cell (16 cases), B-cell (six cases), or null cell (two cases) type. Males predominantly were affected. Age of patients ranged from 19 to 73 years, with a bimodal distribution, with peaks in the third and seventh decades. Lymphadenopathy was present in nearly all patients. Extranodal involvement, including skin, soft tissue, bone, central nervous system, lung, or small intestine was observed in a total of 54% of the patients, either at presentation or during the course of disease. "Prototypic" features of large cell anaplastic lymphomas were observed for eight T-cell lymphomas, with morphologic heterogeneity noted for the remainder. Eight patients, all with T-cell neoplasms (only one with prototypic morphology), have died of lymphoma (median survival, 5 months). An antecedent history of a lymphoproliferative disorder (mycosis fungoides, B-cell lymphoma, immunoblastic lymphadenopathy) was apparent in seven patients. An 8-year history of Crohn's disease occurred in one patient with a T-cell lymphoma involving small intestine. Phenotypically, loss of one or more markers was typically noted for T-cell neoplasms. Leukocyte common antigen was detected in all cases, although partial loss of immunoreactivity was noticed in some cases. Nearly all cases evaluated for Ia antigen or alpha-1-antichymotrysin were reactive. Eleven of 16 T-cell, two of six B-cell, and two null cell lymphomas expressed epithelial membrane antigen. Ki-1-positive large cell lymphomas are characterized by clinical, morphologic, and immunophenotypic heterogeneity.
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Anaplastic large-cell lymphoma or null-cell lymphoma is a clinical entity reported in people, classified according to the unique appearance of large pleomorphic cells that express CD30. Null-cell lymphoma has also been described in dogs when neither CD3 nor CD79α is expressed by the tumor. We describe a case of lymphoma in the dog in which neoplastic cells did not express routine B- or T-lymphocyte markers on flow cytometry or immunohistochemistry; however, cells immunohistochemically labeled for CD30. The dog in our case died 5 mo after initial presentation, confirming a poor prognosis. Identification of further similar cases in dogs would provide additional prognostic information for this subset of lymphomas. CD30 may also serve as a potential therapeutic target in anaplastic large-cell lymphomas.
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Abstract The anaplastic large cell lymphomas include anaplastic large cell lymphoma (CD30 +) of T and null cell types, primary cutaneous anaplastic large cell lymphoma, and anaplastic large cell lymphoma, Hodgkin’s-like. Anaplastic large cell lymphomas of B cell type are considered with the diffuse large B cell lymphomas in Chapter 18.
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We observed in the same patient the development of a tonsil mucosa-associated lymphoid tissue-type lymphoma in 1994, a mediastinal Hodgkin's disease in 1998, and a colonic CD30+ anaplastic diffuse large B-cell lymphoma in 2000. A same-sized FR3-JH fragment was demonstrated by polymerase chain reaction, both at the level of total DNA and of single micromanipulated cells, showing monocytoid, Reed-Sternberg, or anaplastic morphology. Moreover, an identical IgH nucleotide sequence was detected in mucosa-associated lymphoid tissue-type lymphoma and colonic CD30+ anaplastic diffuse large B-cell lymphoma, whereas mediastinal Hodgkin's disease IgH rearrangement involved different VH and JH genes. CD30+ Reed-Sternberg and diffuse large B-cell lymphoma cells contained Epstein-Barr virus EBER sequences that were not observed at the level of mucosa-associated lymphoid tissue-type lymphoma. Therefore, Epstein-Barr virus infection may have played a role in diffuse large B-cell lymphoma transformation of mucosa-associated lymphoid tissue-type lymphoma and in the lymphomagenesis of Hodgkin's disease. In addition to their different clonal origin, Reed-Sternberg cells of Hodgkin's disease expressed a CD15+, CD20+ (rare cells), CD30+, Oct-2−, EBNA2−, LMP1+ phenotype, whereas anaplastic and Reed-Sternberg-like cells of diffuse large B-cell lymphoma were CD15−, CD20+, CD30+, Oct-2+, EBNA2+, and LMP1+. Interestingly, we also detected scattered CD30+ Epstein-Barr virus− large cells with prominent nucleoli in the initial tonsil mucosa-associated lymphoid tissue-type lymphoma, suggesting that these cells could be prone to Epstein-Barr virus infection and/or large cell transformation.
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Posttransplantation lymphoproliferative disorders (PTLDs) eventually occur in approximately 5% of all organ transplant recipients. Most of cases are B-cell proliferations associated with the Epstein-Barr virus (EBV). T-cell PTLDs are relatively rare, although some estimate that up to 14% of posttransplantation malignant lymphomas are T-cell lymphomas even though only a few of these cases are described in the literature. A literature review found only 77 cases of T-cell PTLD, including 1 case following cardiac transplant, 15 cases associated with EBV, and only 1 case of anaplastic large cell lymphoma (ALCL). This single ALCL case followed a liver transplant, was of the T-cell phenotype, and was EBV negative. In this report, we describe a 14-year-old male who developed an EBV-positive, T-cell PTLD of the ALCL subtype after a period of 14 years following cardiac transplant. Immunohistochemical staining established the T-cell origin of the neoplasm with strong expression of CD45, CD3, CD43, and CD2 and also showed expression of CD30 consistent with the histologic features that suggested ALCL. EBER in situ hybridization detected the presence of the EBV. Polymerase chain reaction analysis for T-cell receptor-gamma gene rearrangements confirmed the T-cell lineage of this lymphoma. To our knowledge, this is the first reported case of an EBV-positive T cell lymphoma of the anaplastic large cell subtype following organ transplant.
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The immunologic phenotypes of 59 cases of diffuse, aggressive, non-Hodgkin's lymphomas were determined using a battery of immunologic and cytochemical techniques. Included were cases of diffuse, large cell "histiocytic," mixed cell, undifferentiated non-Burkitt's. Burkitt's lymphoma, lymphoblastic lymphoma, and mycosis fungoides/Sézary's syndrome were excluded from this study since these are distinct clinicopathologic entities with well-recognized immunologic phenotypes. The immunotype could be determined in 57/59 (97%) cases tested: 31 of 59 cases (53%) were B-cell type, 25 of 59 (42%) were peripheral T-cell type, and one was true histiocytic. Two cases had no detectable markers and were called "null cell." This relatively high frequency of peripheral T-cell lymphomas in an American series previously has not been observed and may be a result of progressive improvements in immunologic techniques. Monoclonal anti-T cell antibody staining was performed in 11 T-cell cases and corroborated the findings using spontaneous E-rosette formation. Eight of the T-cell lymphomas had a helper cell phenotype whereas one had a suppressor cell phenotype and two could not be subclassified. All B-cell lymphomas in this series possessed monoclonal surface immunoglobulin detected by direct immunofluorescence of viable cells. Enzyme cytochemistry profiles only partially correlated with immunotype and were not believed to be helpful in the determination of specific phenotypes. There were no significant differences between the B-cell and T-cell diffuse aggressive lymphomas with respect to sex, constitutional symptoms, stages, sites of extranodal involvement, complete remission rate, or survival when they were studied prior to the initiation of aggressive therapy. Although immunotyping can be successfully performed in essentially all cases of diffuse, aggressive non-Hodgkin's lymphomas, to date, the authors have been unable to demonstrate that immunotype alone has an independent prognostic effect.
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We would like to comment on a recent article by Shimada-Hiratsuka et al.,1 which described five cases of gastric T-cell lymphoma with and without human T-lymphotropic virus type 1. They referenced 33 previously reported cases of gastric T-cell lymphoma including those reported in the Japanese literature, and stated "the clinicopathologic features of T-cell lymphoma of the stomach have not yet been clarified." However, we call to your attention the fact that we previously have described the detailed clinicopathologic features of 14 patients with primary gastric T-cell lymphoma in Cancer in 1995.2 In our study,2 of the 233 cases of primary gastric lymphoma, 14 (6%) were found to be T-cell lymphomas (2 pleomorphic small, 10 pleomorphic medium-sized and large, and 2 large cell anaplastic); 2 patients were Stage IE, 3 were Stage II1E, 7 were Stage II2E, and the stage could not be determined in 2 patients. The MIB-1 (Ki-67) labeling indices of T-cell lymphoma (mean, 50.3%) were significantly higher than those of B-cell tumors (mean, 31.5%), and the survival probability for T-cell lymphoma was significantly lower than that for B-cell lymphoma. Multivariate analysis revealed the T-cell phenotype to be an independent predictor of poor prognosis in patients with primary gastric lymphoma.2 In addition, recently we found Helicobacter pylori in 11 of 15 patients with gastric T-cell lymphoma (73%),3 and also reported 1 additional patient with synchronous gastric T-cell lymphoma and adenocarcinoma who was coinfected with both H. pylori and the Epstein-Barr virus.4 We were surprised that Shimada-Hiratsuka et al. did not cite our work2 because their findings are partly consistent with our observations published 2 years before theirs, although they did perform a more detailed immunohistochemical and molecular analysis than we did. Shotaro Nakamura M.D.*, Masazumi Tsuneyoshi M.D.
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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.
Anaplastic large-cell lymphoma
Large-cell lymphoma
Large cell
BCL10
T-Cell Lymphoma
Immunophenotyping
Null cell
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