The biology and treatment of plasmablastic lymphoma

Diffuse large B-cell lymphoma variants: an update.

Anaplastic large cell lymphoma (ALCL) was first described in 1985 as a large-cell neoplasm with anaplastic morphology immunostained by the Ki-1 antibody, which recognizes CD30. In 1994, the nucleophosmin (NPM)-anaplastic lymphoma kinase (ALK) fusion receptor tyrosine kinase was identified in a subset of patients, leading to subdivision of this disease into ALK-positive and -negative ALCL in the present World Health Organization classification. Due to variations in morphology and immunophenotype, which may sometimes be atypical for lymphoma, many differential diagnoses should be considered, including solid cancers, lymphomas, and reactive processes. CD30 and ALK are key molecules involved in the pathogenesis, diagnosis, and treatment of ALCL. In addition, signal transducer and activator of transcription 3 (STAT3)-mediated mechanisms are relevant in both types of ALCL, and fusion/mutated receptor tyrosine kinases other than ALK have been reported in ALK-negative ALCL. ALK-positive ALCL has a better prognosis than ALK-negative ALCL or other peripheral T-cell lymphomas. Patients with ALK-positive ALCL are usually treated with anthracycline-based regimens, such as combination cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) or CHOEP (CHOP plus etoposide), which provide a favorable prognosis, except in patients with multiple International Prognostic Index factors. For targeted therapies, an anti-CD30 monoclonal antibody linked to a synthetic antimitotic agent (brentuximab vedotin) and ALK inhibitors (crizotinib, alectinib, and ceritinib) are being used in clinical settings.

Anaplastic large cell lymphoma: pathology, genetics, and clinical aspects.

As readers have come to expect from Amirsys® reference tools, Diagnostic PathologyTM: Lymph Nodes and Spleen with Extranodal Lymphomas is filled with superior medical images, including gross and microscopic pathology, a wide range of pathology stains, ancillary tests and detailed medical illustrations. For each anatomical site, you’ll find specimen examination protocols plus detailed immunohistochemistry panels to accompany the images. This one-of-a-kind book covers a variety of benign and malignant disorders and lymphomas, such as infectious causes of lymphadenitis, reactive lymphadenopathies, immunodeficiency-associated lymphoproliferations, and granulocytic tumors of the lymph nodes, spleen and extranodal sites. Chapters include definitions, terminology, etiologies and pathogenesis, demographics, clinical presentations, therapy, prognoses, radiologic imaging, pathology, and differential diagnoses. The pathologic features are extensively detailed with descriptions of macroscopic features, microscopic findings, cytopathology, and ancillary studies. The latter include histochemistry, immunohistochemistry, cytogenetics, molecular diagnostics and ultrastructural findings.

/pdf/diagnostic-pathology-lymph-nodes-and-spleen-with-extranodal-3bussa7nil.pdf

Diagnostic pathology: lymph nodes and spleen with extranodal lymphomas

CD3-positive plasmablastic B-cell neoplasms: a diagnostic pitfall

Anaplastic lymphoma kinase-positive large B-cell lymphoma (ALK LBCL) is a rare, aggressive subtype of diffuse large B-cell lymphoma with characteristic ALK rearrangements. Diagnosis of ALK LBCL can be challenging because of its rarity, unique morphologic characteristics, and unusual immunophenotypic features, which significantly overlap with other hematologic and nonhematologic neoplasms. The purpose of this study is to further explore the clinicopathologic features of ALK LBCL to ensure the awareness and accurate diagnosis of this entity. We retrospectively reviewed the data from 26 cases in our institutions and additional 108 cases from the literature. ALK LBCL typically occurred in the lymph nodes of young and middle-aged, immunocompetent patients. The medium age was 35 years with a male to female ratio of 3.5:1. Vast majority of cases showed immunoblastic and/or plasmablastic morphology. All cases expressed ALK protein with a cytoplasmic granular pattern in most of them. Common B-cell markers (CD20, CD79a, and PAX5) were typically negative, but the tumor cells mostly expressed 2 B-cell transcriptional factors, BOB1 and OCT2. The 5-year overall survival (OS) was 34%, and the median survival was 1.83 years. In patients with stage III/IV disease, the 5-year OS was only 8%. Moreover, patients below 35 years of age had a significantly better OS than those aged 35 years or above.

ALK-positive large b-cell lymphoma

Fusion partners of KMT2A affect disease phenotype and influence the current World Health Organization classification of hematologic neoplasms. The t(11;16)(q23;p13)/KMT2A-CREBBP is considered presumptive evidence of a myelodysplastic syndrome (MDS) and a MDS-related cytogenetic abnormality in the classification of acute myeloid leukemia (AML). Here, we report 18 cases of hematologic neoplasms with t(11;16). There were 8 males and 10 females with a median age of 51.9 years at time of detection of t(11;16). Of 17 patients with enough clinical information and pathological materials for review, 16 had a history of cytotoxic therapies for various malignancies including 12/15 patients who received topoisomerase II inhibitors, and 15 were classified as having therapy-related neoplasms. The median interval from the diagnosis of primary malignancy to the detection of t(11;16) was 23.2 months. Dysplasia, usually mild, was observed in 7/17 patients. Blasts demonstrated monocytic differentiation in 8/8 patients who developed AML at the time or following detection of t(11;16). t(11;16) was observed as the sole chromosomal abnormality in 10/18 patients. KMT2A rearrangement was confirmed in 11/11 patients. The median survival from the detection of t(11;16) was 15.4 months. In summary, t(11;16)(q23;p13) is rare and overwhelmingly associated with prior exposure of cytotoxic therapy. Instead of being considered presumptive evidence of myelodysplasia, we suggest that the detection of t(11;16) should automatically prompt a search for a history of malignancy and cytotoxic therapy so that proper risk stratification and clinical management are made accordingly. The dismal outcome of patients with t(11;16) is in keeping with that of therapy-related neoplasms.

t(11;16)(q23;p13)/KMT2A-CREBBP in hematologic malignancies: presumptive evidence of myelodysplasia or therapy-related neoplasm?

Chronic myeloid leukemia (CML) is a myeloproliferative disorder characterized by the BCR-ABL1 fusion gene resulting from t(9;22)(q34;q11.2), its variant translocations, or rarely, cytogenetically cryptic chromosomal rearrangements, and by a natural course of three distinct stages: chronic phase (CP), accelerated phase, and blast phase (BP) [1]. With tyrosine kinase inhibitors (TKIs) becoming standard front-line therapy, progression of CML from CP to BP has dramatically decreased, and the long-term cumulative probability of progression is only about 5% [2]. When BP does occur, in approximately 70% of patients the blasts are of myeloid lineage and in 20–30% of cases, lymphoid lineage [3]. While lymphoid BP is of B-cell lineage in almost all patients, rarely Tlymphoid BP can occur. To our knowledge, very few cases of CML with T-lymphoid or T/myeloid BP have been reported in the era of tyrosine kinase inhibitor therapy [4–9]. During a review of 2520 adult patients with CML diagnosed at The University of Texas MD Anderson Cancer Center since 1998, when TKI therapy was implemented in our hospital, to the year of 2016, we identified 449 patients with documented BP confirmed by histopathology. Of these 449 patients, 296 (65.9%) had myeloid BP, including 15 patients with extramedullary myeloid sarcoma as the sole presentation of blast transformation, 139 (31.0%) had lymphoid BP, and 14 (3.1%) had mixed phenotype BP. Of the 139 patients with lymphoid BP, 133 (95.7%) had B-lymphoid BP and six (4.3%) had T-lymphoid BP. Of the 14 patients with mixed phenotype BP, four (28.6%) had T/myeloid BP and 10 (71.4%) had B/myeloid BP. Of all cases of CMLBP, the incidence of T-lymphoid BP was 1.3% and the incidence of combined T-lymphoid and T/myeloid BP was 2.2%. The ratio of T-lymphoid vs. B-lymphoid BP was 1 : 22, and the ratio of combined T-lymphoid and T/myeloid vs. combined B-lymphoid and B/myeloid BP was 1 : 14. Four additional cases of CML-BP (three T-lymphoid and one T/myeloid) were collected from other institutions, forming a study group of 14 patients: nine with Tlymphoid and five with T/myeloid BP. The diagnosis of T/myeloid BP was made when both CD3 and myeloperoxidase were identified using cytochemistry, flow cytometry, and/or immunohistochemistry according to the WHO criteria for mixed phenotype acute leukemia. The clinicopathological data, including age, gender, medical history, imaging, molecular and cytogenetic studies, were reviewed and are shown in Table 1. To the best of our knowledge, this is the largest case series of T-lymphoid or T/myeloid BP of CML to date. There were eight men and six women. The median age at time of diagnosis of CML-BP was 53 years old. Four patients (#4, 8, 10, and 11) had an established history of CML-CP, and three of them had available date of diagnosis of CML-CP. The interval time from initial diagnosis of CML-CP to blastic transformation was 19.1, 73.2, and 8.3 months for patients #4, 10, and 11, respectively. Another four patients initially presented with BCR-ABL1positive T-lymphoblastic lymphoma, but had CML-CP in the concurrent bone marrow, and the remaining six patients had CML-BP in the bone marrow initially. By imaging, 10 patients had extramedullary involvement, including lymphadenopathy (8/10) and splenomegaly (2/ 10). By conventional karyotyping, additional cytogenetic abnormalities other than t(9;22)(q34;q11.2) were found in nine patients: including an extra copy of der(22) (n = 4), +8 (n = 2), +19 (n = 2), and others. Molecular data were available for 12 patients: six had the p210 and six had p190 subtype of BCR-ABL1 transcripts. Of four patients (#4, 8, 10, and 11) with a history of CML-CP, three of them had available treatment information. Patient #4 received interferon alpha and ara-C and subsequent allogeneic stem cell transplantation (alloSCT) due to inadequate response to interferon, and patients #10 and 11 received TKI therapy before blastic transformation. Overall, 13 patients had available treatment information for BP. Nine patients received TKIs, 11 received hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone) chemotherapy, and

T-lymphoid or T/myeloid blast phase of chronic myeloid leukemia in the era of tyrosine kinase inhibitor therapy: a report of 14 cases.

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ALK-positive large b-cell lymphoma

t(11;16)(q23;p13)/KMT2A-CREBBP in hematologic malignancies: presumptive evidence of myelodysplasia or therapy-related neoplasm?

T-lymphoid or T/myeloid blast phase of chronic myeloid leukemia in the era of tyrosine kinase inhibitor therapy: a report of 14 cases.