ALK-positive Diffuse Large B-cell Lymphoma Research Articles

Arsenic trioxide inhibits anaplastic lymphoma kinase (ALK)‐positive diffuse large B‐cell lymphoma through targeting ALK‐fusion oncoprotein

Arsenic trioxide inhibits anaplastic lymphoma kinase (ALK)‐positive diffuse large B‐cell lymphoma through targeting ALK‐fusion oncoprotein

ALK-positive diffuse large B-cell lymphoma is associated with Clathrin-ALK rearrangements: report of 6 cases

AbstractExpression of ALK protein by lymphoid cells and the description of variant anaplastic lymphoma kinase (ALK) translocations have typically been restricted to cases of T-cell and null anaplastic large-cell lymphoma (ALCL). All such cases result from a novel fusion created by the ALK gene on chromosome 2p23 and NPM on 5q35 or other variant translocation partners. A rare variant of diffuse large B-cell lymphoma (DLBCL), originally described in 1997, was thought to overexpress full-length ALK in contrast to a chimeric protein characteristic of ALCL. However, full-length ALK protein lacks tyrosine kinase activity and thus the mechanism of oncogenesis has remained elusive. We describe 6 cases of ALK+ DLBCL characterized by a simple or complex t(2;17)(p23;q23) involving the clathrin gene (CLTC) at chromosome band 17q23 and the ALK gene at chromosome band 2p23. All cases were studied using fluorescence in situ hybridization (FISH), complemented in one case with standard cytogenetic analysis, multicolor karyotyping (M-FISH), and reverse transcriptase-polymerase chain reaction. These results clearly demonstrate that most cases of ALK+ DLBCL share the same mechanism of deregulated ALK expression. Moreover, these results demonstrate the presence of CLTC-ALK fusions in these tumors and extend the list of diseases associated with this genetic abnormality to include classical T-cell or null ALCL, ALK+ DLBCL, and inflammatory myofibroblastic tumors. (Blood. 2003;102:2568-2573)

Adult ALK-positive diffuse large B-cell lymphoma: A limited institutional experience

Adult ALK-positive diffuse large B-cell lymphoma: A limited institutional experience

ALK-positive diffuse large B-cell lymphoma of the duodenum: A case report and review of the literature.

Anaplastic lymphoma kinase (ALK)-positive diffuse large B-cell lymphoma (ALK+ DLBCL) is characterized by the presence of immunoblastic or plasmablastic cells with a strong ALK protein expression that is frequently associated with t(2;17)(p23;q23). The present study reports a case of ALK+ DLBCL in a 26-year-old male with a duodenal mass. Histologically, the neoplastic cells demonstrated prominent plasmablastic differentiation with abundant amphophilic cytoplasma and central nucleoli. Paraffin immunohistochemistry revealed: an exclusively cytoplasmic granular expression of ALK; CD138, immunoglobulin A (IgA) and CD79α positivity; and focal expression of multiple myeloma oncogene 1 (Mum-1), CD30 and epithelial membrane antigen (EMA). However, the immunohistochemical staining was negative for CD3, CD38 and CD20. Fluorescence in situ hybridization (FISH) analysis using an ALK break-apart probe revealed the presence of ALK gene rearrangements in the patient. To the best of our knowledge, the current case represents the first example of primary extranodal ALK+ DLBCL presenting as a duodenal mass.

Acute Spontaneous Tumor Lysis Syndrome as the Initial Presentation of ALK-Positive Diffuse Large B-Cell Lymphoma

Anaplastic lymphoma kinase (ALK)-positive diffuse large B-cell lymphoma (DLBCL) is a recently described, uncommon form of DLBCL, which has been seen primarily in young men and which presents with advanced disease. The fact that ALK-positive DLBCL is an uncommon diagnosis is likely due to the combined effects of this being an uncommon disease coupled with the challenges in the pathologic identification of this neoplasm. Prompt and accurate identification of this tumor is becoming increasingly important, however, as we enter the era of therapeutic ALK inhibitors, which are currently undergoing study in several clinical trials. Here, we report a case of ALK-positive DLBCL in a 39-year-old male patient who presented with spontaneous tumor lysis syndrome. We review the clinical, morphologic, immunohistochemical, and molecular aspects of this case and of ALK-positive DLBCL in general, with the purpose of bringing to light the existence of this disease and its potential future therapy.

Safety and Clinical Activity Of Crizotinib In Patients With ALK-Rearranged Hematologic Malignancies

▪ IntroductionCrizotinib (Xalkori®) is an ALK inhibitor with proven efficacy in patients with ALK-rearranged advanced non-small cell lung cancer (NSCLC; Shaw AT et al, New Engl J Med 2013;368:2385–9). However, ALK rearrangement is implicated in other types of malignancy, including anaplastic large-cell lymphoma (ALCL) and diffuse large B-cell lymphoma (DLBCL). Here we assess the safety and anti-tumor activity of crizotinib in patients with advanced ALK-rearranged hematologic malignancies enrolled in an open-label phase 1b study (Pfizer; A8081013; NCT01121588). MethodsALK-positivity was confirmed by IHC for cases of ALCL; other malignancies required confirmation by FISH, PCR, or sequencing. Patients with brain metastases were eligible if neurologically stable for 2 weeks with no ongoing treatment requirement. Eligible patients received crizotinib 250 mg twice daily. Responses were assessed every 6 weeks using RECIST v1.1 or Revised Response Criteria for Malignant Lymphoma 2007 (Cheson criteria); best overall response was determined by RECIST or Cheson if only one assessment was available, and by Cheson criteria if both were available. Adverse events (AEs) were assessed using CTCAE v4.0. ResultsFifteen patients with advanced ALK-positive hematologic malignancies were enrolled; 14 with ALK-positive ALCL and one with ALK-positive DLBCL. At the data cutoff date of July 15, 2013, treatment was ongoing in 10 patients, and there were five discontinuations (1 due to early death, 1 due to global deterioration of health and 3 due to disease progression). Nine patients (60%) were male, and the median age was 25 years (range 15–37 years). Most patients were white (60%), with the remainder Asian. Two patients (13%) received prior radiation therapy. All patients received prior systemic therapy (median 2 lines [range 1–6]). ECOG performance status (ECOG PS) at baseline was 0 for 3 patients (20%), 1 for 7 patients (47%), 2 for 4 patients (27%), and 3 for 1 patient (7%). Median duration of treatment was 33 weeks (range 0.1–117 weeks). There were 9 confirmed responses (5 complete response [CR] and 4 partial response [PR]), for an objective response rate (ORR) of 60%. Additionally, 1 patient experienced stable disease (SD) of >12 months. Overall, the clinical benefit rate (CBR; CR + PR + SD) was 67%. AEs (all causality) were reported for all 15 patients and were predominantly of grade 1 or 2. The most common AEs were diarrhea (47% of patients), vomiting (47%, including 1 grade 3 event), visual impairment (40%), asthenia (27%), cough (27%), and neutropenia (27%, including 2 grade 3 events). Four patients experienced grade 4 events (abdominal pain, increased creatinine phosphokinase, lymphopenia, and multi-organ failure), and one of these patients also experienced a grade 5 event (central nervous system hemorrhage). ConclusionsCrizotinib showed anti-tumor activity in advanced ALK-rearranged hematologic tumors. The high ORR (60%) and CBR (67%) with crizotinib in this cohort is consistent with the high response rates seen with crizotinib in ALK-rearranged advanced NSCLC, and the safety profile of crizotinib was also similar to previous clinical experience with crizotinib. These data suggest that ALK inhibition can be effective in patients with ALK-positive hematologic malignancy and further investigation may be warranted in this setting. Disclosures:Gambacorti-Passerini:Pfizer: Research Funding. Off Label Use: Crizotinib is an ALK inhibitor which is indicated for use in ALK-positive advanced NSCLC. This study investigates the use of crizotinib in patients with ALK-positive malignancies other than NSCLC. Braiteh:Pfizer: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; Pfizer: Research Funding. Taylor:1. Bayer HealthCare Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees; 1. Bayer HealthCare Pharmaceuticals, Inc.: Honoraria. Brega:Pfizer: Equity Ownership; Pfizer: Employment. Paolini:Pfizer: Equity Ownership; Pfizer: Employment. Selaru:Pfizer: Equity Ownership; Pfizer: Employment.

Crizotinib in ALK-Positive Diffuse Large B-Cell Lymphoma: A Case Report

AbstractAbstract 4862 Background:Anaplastic lymphoma kinase (ALK)-positive diffuse large B-cell lymphoma (DLBCL) displays a rare and distinct variant of DLBCL characterized by very aggressive clinical course with an estimated median survival of only 11.0 months. Crizotinib, an ALK inhibitor, has demonstrated impressive clinical efficacy in patients with alk-rearranged tumors such as NSCLC. The potential role of Crizotinib in ALK-positive DLBCL has not been established yet. Case report:A 27-year-old female patient with initial advanced-stage IV ALK-positive DLBCL was primary refractory to 6 cycles of standard chemotherapy with CHOP. She was subsequently treated with different salvage combination chemotherapy regimens including high-dose chemotherapy with autologous stem-cell transplantation. However, disease followed a very aggressive course and relapse occurred fast after each regimen. 6 weeks after transplantation patient presented with right cervical lymphadenopathy and multiple cutaneous lesions. CT scan revealed additional bilateral cervical, axillary, mediastinal and abdominal lymphadenopathy and involvement of lung and liver. LDH levels were exorbitant elevated (233 mmol/l). On an individual base, our patient received the ALK inhibitor Crizotinib 250 mg per os twice daily. No glucocorticoids or other drugs with antineoplastic activity were co-administered. Within 72 hours LDH levels were halved (89 mmol/l). On day 8 cervical palpable lymphadenopathy disappeared. Initial erythematous papular cutaneous lesion decreased from 4.0 × 2.5 cm to a residual hyperpigmented macule of 1.5 × 2.5 cm. On day 16 LDH levels were almost within normal limits (6 mmol/l). However, remission was not sustained and patient developed resistance to Crizotinib. By day 21 after beginning the treatment with Crizotinib LDH levels increased again and patient presented with a swollen left arm due to lymphatic obstruction, detected by CT scan, which showed a general progressive disease, causing death one month later. Conclusion:To our knowledge, this is the first case which reports sensitivity in ALK-positive DLBCL to ALK inhibition with Crizotinib. Despite remission duration was short our results indicate a potential role of ALK in the pathogenesis of ALK-positive DLBCL and suggest ALK inhibition as a potentially promising treatment modality in the therapy of this rare and fatal disease. Disclosures:Off Label Use: Crizotinib is an ALK inhibitor, indicated for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) that is anaplastic lymphoma kinase (ALK)-positive. Recently impressive clinical efficacy of Crizotinib has been reported in two patients with ALK-positive anaplastic large cell lymphoma. Based on these data we initiated the treatment with Crizotinib in our patient, who showed very aggressive clinical behavior and fulminant early recurrence of a ALK-positive diffuse large B-cell lymphoma after salvage chemotherapy regimens on an individual base.

1098 - Crizotinib in ALK-Positive Diffuse Large B-Cell Lymphoma: A Case Report

ABSTRACT Background Anaplastic lymphoma kinase (ALK)-positive diffuse large B-cell lymphoma (DLBCL) is a distinct variant of DLBCL characterized by very aggressive clinical course with an estimated median survival of only 11.0 months. Crizotinib, an ALK inhibitor, has demonstrated impressive clinical efficacy in patients with alk-rearranged tumors. The potential role of Crizotinib in ALK-positive DLBCL has not been established yet. Case report A 27-year-old female patient with ALK-positive DLBCL was primary refractory to 6 cycles of standard chemotherapy with CHOP. She was subsequently treated with salvage combination chemotherapy regimens including high-dose chemotherapy with autologous stem-cell transplantation. However, disease followed a very aggressive course. 6 weeks after transplantation patient presented with right cervical lymphadenopathy and multiple cutaneous lesions. CT scan revealed additional bilateral cervical, axillary, mediastinal and abdominal lymphadenopathy and involvement of lung and liver. LDH levels were exorbitant elevated (233 mmol/l). On an individual base, our patient received the ALK inhibitor Crizotinib 250 mg per os twice daily. No glucocorticoids or other drugs with antineoplastic activity were co-administered. Within 72 hours LDH levels were halved (89 mmol/l). On day 8 cervical palpable lymphadenopathy disappeared. Initial erythematous papular cutaneous lesion decreased from 4.0 x 2.5 cm to a residual hyperpigmented macule of 1.5 x 2.5 cm. On day 16 LDH levels were almost within normal limits (6 mmol/l). However, remission was not sustained and patient developed resistance to Crizotinib. By day 21 after beginning the treatment with Crizotinib LDH levels increased again and patient presented with a swollen left arm due to lymphatic obstruction, detected by CT scan, which showed a general progressive disease, causing death one month later. Conclusion To our knowledge, this is the first case which reports sensitivity in ALK-positive DLBCL to ALK inhibition with Crizotinib. Despite remission duration was short our results indicate a potential role of ALK in the pathogenesis of ALK-positive DLBCL and suggest ALK inhibition as a potential treatment modality in the therapy of this fatal disease. Disclosure All authors have declared no conflicts of interest.

Anaplastic Lymphoma Kinase–Positive Diffuse Large B-Cell Lymphoma: A Rare Clinicopathologic Entity With Poor Prognosis

Anaplastic lymphoma kinase (ALK) -positive diffuse large B-cell lymphoma (DLBCL) is a rare variant of DLBCL that has been described only in small case reports. To shed more light on the clinical and pathologic features and outcome of these tumors, we reviewed data from 38 patients. We retrospectively analyzed 38 patients with ALK-positive DLBCL treated with cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) or CHOP-like regimens from different institutions to better define the presenting features, clinical course, and response to treatment. The histologic findings in all patients were similar. All patients expressed ALK fusion proteins, but virtually all were CD30 and CD20 negative. The median age was 43 years with a 5:1 ratio of males to females. Most patients (60%) followed an aggressive clinical course with advanced stage at diagnosis, frequent marrow infiltration, and poor outcome. Overall survival was 20.3 months (95% CI, 12.2 to 42.6 months). Of note, the median survival was only 12.2 months (95% CI, 9.1 to 32.5 months) in patients with advanced-stage disease. ALK-positive DLBCLs display clinicopathologic features that distinguish them from common DLBCL. Conventional therapy, as used for typical DLBCL, is of limited efficacy. Recognition of this new entity and the characteristic lack of CD20 expression are paramount. Novel front-line intensive chemotherapy regimens should be evaluated in this group of patients.

ALK-positive diffuse large B-cell lymphoma: report of four cases and review of the literature

BackgroundAnaplastic lymphoma kinase-positive diffuse large B-cell lymphoma (ALK-DLBCL) is a rare lymphoma with several clinicopathological differences from ALK-positive anaplastic large cell lymphoma (ALCL). The latest WHO classification of lymphomas recognizes ALK-DLBCL as a separate entity.MethodsA comprehensive comparison was made between the clinical and pathological features of the 4 cases reported and those found in an extensive literature search using MEDLINE through December 2008.ResultsIn our series, three cases were adults and one was pediatric. Two cases had primary extranodal disease (multifocal bone and right nasal fossa). Stages were I (n = 1), II (n = 1), III (n = 1) and IV (n = 1). Two cases had increased LDH levels and three reported B symptoms. IPI scores were 0 (n = 1), 2 (n = 2) and 3 (n = 1). All cases exhibited plasmablastic morphology. By immunohistochemistry, cases were positive for cytoplasmic ALK, MUM1, CD45, and EMA; they marked negative for CD3, CD30 and CD20. Studies for EBV and HHV-8 were negative. The survival for the patients with stage I, II, III and IV were 13, 62, 72 and 11 months, respectively.ConclusionALK-DLBCL is a distinct variant of DLBCL with plasmacytic differentiation, which is characterized by a bimodal age incidence curve, primarily nodal involvement, plasmablastic morphology, lack of expression of CD20, aggressive behavior and poor response to standard therapies, although some cases can have prolonged survival as the cases reported in this study. ALK-DLBCL does not seem associated to immunosuppression or the presence of EBV or HHV8. Further prospective studies are needed to optimize therapies for this entity.

ALK-Positive Diffuse Large B-Cell Lymphoma: Report of Four Cases from Peru

BACKGROUND: Anaplastic lymphoma kinase-positive diffuse large B-cell lymphoma (ALK-DLBCL) is a rare lymphoma with several differences from ALK-positive anaplastic large cell lymphoma (ALCL). ALK-DLBCL appears as a defined disease entity characterized by the expression of the ALK protein, usually in a granular cytoplasmic fashion. These cells are usually CD20-negative but express plasma cells markers. The most common chromosomal abnormality is a fusion between the ALK and the clathrin gene. Clinically, ALK-DLBCL presents as lymph node-based disease affecting mostly middle-aged men, frequently showing aggressive behavior, a negative prognosis at advanced stage and a strikingly rare bone marrow involvement. Only 44 cases are currently reported in the English and non-English literature.METHODS: This is a retrospective study with data collected on four patients with ALK-DLBCL between 2002 and 2008 in a general hospital from Peru. Immunohistochemical studies were performed to detect expression of B-cell, T-cell, plasma cell markers and oncoviruses (i.e. EBV and HHV8). FISH cytogenetic studies were attempted but were unsuccessful. Clinical characteristics of the cases included age, sex, primary site of involvement, IPI score, Ann Arbor stage, therapy, survival in months and final outcome.RESULTS: The male:female ratio was 1:1; one 13-year-old girl and three adults of 27, 41, and 70 years of age were identified. Two patients had primary extranodal disease (multifocal bone lesions and right nasal fossa involvement) and the remaining two patients had exclusively nodal disease. Stages were I (n=1), II (n=1), III (n=1) and IV (n=1). Two patients had increased LDH levels and three patients reported B symptoms. IPI scores were 0 (n=1), 2 (n=1) and 3 (n=2). All cases exhibited immunoblastic/plasmablastic morphology. By immunohistochemistry the cases showed positive expression of cytoplasmic ALK-1, CD138, monoclonal cytoplasmic light chain, CD45 and EMA. All cases lacked expression of the CD3, CD20 and CD30 antigens. HHV8 and EBV were not expressed. The survival times ranged from 11 to 72 months; the latter was observed in a patient who presented with stage III disease and is still alive without evidence of lymphoma.CONCLUSIONS: ALK-DLBCL is a distinct subtype of B-cell lymphoma, which does not express CD20 and is characterized by marked plasmacytic differentiation. This lymphoma has clinically aggressive behavior and more effective therapies are warranted. However, some cases can have prolonged survival with intensive regimens.Table 1. Clinical characterisitics of the reported casesCaseAgeSexPrimary siteIPIStageTherapySurvival (months)Outcome141FNasal fossa0IARadiotherapy13Alive, free of disease213FCervical lymph node2IIBFrance NHL 96–2002*62Alive, free of disease370MCervical lymph node3IIIBCHOP72Alive, free of disease427MBone3IVBHyperCVAD11Alive, with disease*This regimen is based on induction with vincristine, prednisone, cyclophosphamide, daunorubicin, L-asparaginase and methotrexate, followed by consolidation based on cyclophosphamide, cytarabine, metrotexate, then intensification with vincristine and doxorubicin and manteinance based on metrotexate and mercaptopurine.

Hyperactivated STAT3 in ALK–positive diffuse large B-cell lymphoma with clathrin-ALK fusion

Anaplastic lymphoma kinase (ALK)-positive large B-cell lymphoma is a rare subtype of diffuse large B-cell lymphoma (DLBCL). Although a few cases of ALK-positive large B-cell lymphoma harbor nucleophosmin-ALK chromosomal translocation similar to ALK-positive anaplastic large cell lymphoma, most reported cases are characterized by t(2;17)(p23;q23) involving the clathrin gene. Here, we report 2 cases of ALK-positive DLBCL. The 2 cases presented similar morphologic features and immunohistochemical characteristics, that is, positivity for ALK, IgA, CD138, and MUM1; weak positivity for CD30 and CD79a; and negativity for CD20. The clathrin-ALK transcript was identified by reverse transcription-polymerase chain reaction, and the sequence was determined by direct sequencing. Recently, the essential role of STAT3 activation as well as STAT 5 activation in nucleophosmin-ALK fusion protein-mediated lymphomagenesis was reported. However, differential effects of ALK-fusion variant proteins on proliferation, transformation, and invasion properties were reported. Thus, we evaluated the phosphorylation status of STAT 3 and STAT 5, and found highly hyperphosphorylated STAT 3 on tyrosine 705 but not STAT 5 in our 2 cases of ALK-positive DLBCL with clathrin-ALK fusion. Furthermore, STAT 5A expression was not detected in either of the ALK-positive DLBCL cases, although 11 of the 36 ALK-negative DLBCL cases revealed STAT 5A expression. Expression of the antiapoptotic proteins survivin and BCL-X(L), which were believed to be the targets of STAT 3, was investigated. However, there were no significant associations between expression of survivin or BCL-X(L) and ALK positivity among the diffuse large B-cell lymphomas. In summary, similar signaling transduction mechanism involving STAT proteins seems to underlie DLBCL harboring the clathrin-ALK or nucleophosmin-ALK fusion gene.

Cytomorphology and Molecular Characterization of CLTC-ALK Rearrangement in 2 Cases of ALK-Positive Diffuse Large B-cell Lymphoma with Extensive Bone Marrow Involvement

Aanaplastic lymphoma kinase (ALK)-positive diffuse large B-cell lymphoma (DLBCL) is an unusual disease entity first reported in 1997 as DLBCL with expression of full-length ALK protein. The World Health Organization classification enlists the disease as a rare variant of DLBCL. Herein we describe two cases of ALK-positive DLBCL with cytomorphologic and molecular characteristics for the first time in Korea. The patients were 35-yr-old and 24-yr-old male patients. Immunohistochemical studies on the lymph nodes revealed large sized neoplastic cells with plasmablastic differentiation, which were negative for CD30 and positive for ALK with the characteristic granular staining in the cytoplasmic region. Extensive involvement of bone marrow was observed in both cases showing large, extremely atypical cells. Fluorescence in situ hybridization and molecular studies on the bone marrow aspirate specimens led to the detection of a clathrin (CLTC)/ALK rearrangement. Despite aggressive chemotherapy, the patients died 15 and 17 months after the diagnosis, indicating poor prognosis of the disease entity. This is the first report demonstrating the cytomorphologic findings of ALK-positive DLBCL cells on bone marrow aspirates.

ALK‐positive diffuse large B‐cell lymphoma: report of three cases

Diffuse large B-cell lymphoma positive for anaplastic lymphoma kinase (ALK(+) DLBCL) is a rare variant of diffuse large B-cell lymphoma, with characteristic morphological, immunohistochemical and cytogenetic features. Only 34 cases of ALK-positive diffuse large B-cell lymphoma have so far been reported in the literature. We examined three new cases, which showed similar characteristics to previously reported cases, but with peculiar nuclear-membrane staining for ALK protein in one patient and a 5'-ALK gene deletion in another. All of them had stage IV disease at initial presentation, with poor outcomes. The tumour cells showed immunoblastic/plasmablastic histology and were positive for ALK and Oct2, but negative for CD3, CD20, CD79a, CD30 and PAX5. The staining pattern of ALK protein was cytoplasmic in two patients and associated with the nuclear membrane in one patient. Fluorescence in situ hybridization (FISH) analysis using the ALK break-apart probe revealed ALK gene rearrangements in all three patients, with a 5'-ALK gene deletion in one patient. These three cases suggest that different types of cytogenetic aberrations may involve the ALK gene in ALK-positive diffuse large B-cell lymphoma leading to peculiar immunohistochemical staining patterns.

Anaplastic lymphoma kinase–positive diffuse large B-cell lymphoma with a complex karyotype and cryptic 3′ ALK gene insertion to chromosome 4 q22-24

Anaplastic lymphoma kinase (ALK)-positive diffuse large B-cell lymphoma (DLBCL) is a rare tumor that is frequently associated with t(2;17)(p23;q23), a translocation fusing the ALK gene at 2p23 to the clathrin heavy chain gene (CLTC) at 17q23. Here, we report a unique case of ALK-positive DLBCL with plasmablastic morphology and focal cytoplasmic granular ALK stain in an HIV-negative 33-year-old man. By conventional karyotyping, the lymphoma cells were near-tetraploid and included 4 structurally normal copies each of chromosomes 2 and 17. Fluorescence in situ hybridization revealed an apparently normal, intact ALK gene on each of the 4 chromosome 2 homologs plus a cytogenetically cryptic ALK gene insertion into 2 of the 4 chromosome 4 homologs at band 4q22-24. The lymphoma cells expressed CD138, lambda light chain, focal and weak CD30, and exhibited aberrant T-cell antigens, including perforin. This case indicates that ALK-positive DLBCL is more heterogeneous at the cytogenetic/molecular level than previously recognized.

ALK-positive diffuse large B-cell lymphoma: report of four cases and review of the literature

AbstractWe report detailed clinical and pathologic features of four cases of anaplastic lymphoma kinase-positive diffuse large B-cell lymphoma (ALK-DLBCL), a rare entity with only 29 currently reported cases. This study is the third largest of all reported series. Biopsies from four adult patients aged 41, 49, 53, and 71 years (three lymph nodes and one nasopharyngeal mass) exhibited immunoblastic/plasmablastic morphology. By immunohistochemistry and/or flow cytometry, they expressed cytoplasmic ALK-1, CD138, VS38 (3/3), monoclonal cytoplasmic light chain, CD45, EMA, CD4, and CD57 (2/3), and were negative for CD3, CD30, CD56, and TIA-1. Two showed variable CD79a expression, and one had rare CD20(+) cells. Two of three cases exhibited rare CD43(+) reactivity. One case showed scattered cytokeratin(+) cells, which could possibly lead to a misdiagnosis of carcinoma. After CHOP and radiotherapy, two stage I patients were free of disease at 58 and 36 months, whereas a stage IV patient was dead of disease at 22 months.

ALK-positive diffuse large B-cell lymphoma with ALK-Clathrin fusion belongs to the spectrum of pediatric lymphomas

ALK-positive diffuse large B-cell lymphoma with ALK-Clathrin fusion belongs to the spectrum of pediatric lymphomas

ALK-positive diffuse large B-cell lymphoma of the stomach associated with a clathrin-ALK rearrangement

ALK-positive diffuse large B-cell lymphoma is a rare, recently characterized lymphoma subtype that shows granular cytoplasmic ALK expression. This report describes a primary gastric ALK-positive B-lineage lymphoma in which a clathrin (CLTC)-ALK fusion was identified by RT-PCR and direct sequencing of the breakpoint. This confirmed the presence of t(2;17)(p23;q23) involving the CLTC gene and is only the 4th report of such a translocation in this lymphoma subtype and the first to describe this tumor within the stomach. As in previous reports, immunophenotyping showed the malignant cell to be a terminally differentiated B-lineage cell characterized by the absence of B-cell antigens and expression of antigens associated with plasma cell differentiation. This case confirms the existence of such a lymphoma subtype arising in extranodal locations and underscores the importance of detailed immunophenotyping and specialized molecular genetic investigations in confirming the diagnosis.