Anaplastic Large Cell Lymphoma Kinase Research Articles

Survival Benefits of Radiotherapy and Surgery in Lung Cancer Brain Metastases with Poor Prognosis Factors.

Radiotherapy and surgery are the standard local treatments for lung cancer brain metastases (BMs). However, limited studies focused on the effects of radiotherapy and surgery in lung cancer BMs with poor prognosis factors. We retrospectively analyzed 714 patients with lung cancer BMs. Analyses of overall survival (OS) and risk factors for OS were assessed by the log-rank test and Cox proportional hazard model. Age ≥ 65 years, a Karnofsky Performance Scale (KPS) score ≤ 70, anaplastic large-cell lymphoma kinase (ALK)/epidermal growth factor receptor (EGFR) wild type, and extracranial metastases were related to poor prognosis. Patients were stratified according to these poor prognosis factors. In patients with the ALK/EGFR wild type, whole brain radiotherapy (WBRT), stereotactic radiosurgery (SRS), and surgery improved the OS of patients. WBRT and SRS were the independent protective factors for OS. In patients with extracranial metastases, patients who received WBRT plus SRS or WBRT alone had longer OS than those who did not receive radiotherapy. WBRT plus SRS and WBRT were the independent protective factors for OS. Radiotherapy and surgery are associated with improved survival for lung cancer BMs with the ALK/EGFR wild type. Radiotherapy is associated with improved survival in lung cancer BMs with extracranial metastases.

NCOG-07. SURVIVAL BENEFIT OF RADIOTHERAPY AND SURGERY IN PATIENTS WITH LUNG CANCER BRAIN METASTASES WITH POOR PROGNOSIS FACTORS: A SINGLE-CENTER, RETROSPECTIVE, PROPENSITY SCORE MATCHING ANALYSIS

Abstract PURPOSE To investigate the effect of radiotherapy and surgery in patients with lung cancer brain metastases (BMs) with poor prognosis factors. METHODS We analyzed retrospectively 714 patients with lung cancer BMs. A 1:1 propensity score matching (PSM) was performed to balance potential confounders. Analyses of overall survival (OS) and risk factors for OS were assessed by log-rank test and Cox proportional hazard model. RESULTS Age ≥ 65 years, Karnofsky Performance Scale (KPS) score ≤ 70, anaplastic large-cell lymphoma kinase (ALK)/epidermal growth factor receptor (EGFR) wild type, extracranial metastases, non-surgery and non-radiotherapy led to poor prognosis. Patients were stratified according to these factors. Radiotherapy and surgery showed no survival benefit in patients with aged ≥ 65 years and pretreatment KPS score ≤ 70 before and after PSM. Before PSM,whole brain radiotherapy (WBRT) improved the OS and predicted good prognosis in patients with ALK/EGFR wild type or extracranial metastases. WBRT also predicted good prognosis in patients with non-surgery. Stereotactic radiosurgery (SRS) improved the OS and predicted good prognosis in patients with ALK/EGFR wild type or non-surgery. WBRT plus SRS improved the OS and predicted good prognosis in patients with extracranial metastases or non-surgery. WBRT plus SRS also predicted good prognosis in patients with ALK/EGFR wild type. Surgery improved the OS and predicted good prognosis in patients with non-radiotherapy. After PSM, SRS improved the OS and predicted good prognosis in non-surgery patients. WBRT plus SRS improved the OS and predicted good prognosis in patients with non-surgery or extracranial metastases. WBRT plus SRS predicted good prognosis in patients with ALK/EGFR wild type. Surgery improved the OS of patients with non-radiotherapy. CONCLUSIONS Radiotherapy has significant survival benefit in patients with lung cancer BMs with poor prognosis factors, including patients with ALK/EGFR wild type or extracranial metastases or non-surgery. Surgery only has significant survival benefit in patients with non-radiotherapy.

P11.75.B Survival benefit of radiotherapy and surgery in patients with lung cancer brain metastases with poor prognosis factors

Abstract Background Radiotherapy and surgery are the standard treatments for lung cancer brain metastases (BMs). However, limitted studies focused on the treatments for patients with lung cancer BMs with poor prognosis factors. The purpose of this study was to investigate the effects of radiotherapy and surgery in patients with lung cancer BMs with poor prognosis factors, providing reference for clinical strategies. Material and Methods We analyzed retrospectively 714 patients with lung cancer BMs. A 1:1 propensity score matching (PSM) was performed to balance potential confounders. Analyses of overall survival (OS) and risk factors for OS were assessed by log-rank test and Cox proportional hazard model. Results Age ≥65 years, Karnofsky Performance Scale (KPS) score ≤70, anaplastic large-cell lymphoma kinase (ALK)/epidermal growth factor receptor (EGFR) wild type, extracranial metastases, non-surgery and non-radiotherapy led to poor prognosis. Patients were stratified according to these factors. Radiotherapy and surgery showed no survival benefit in patients with aged ≥65 years or pretreatment KPS score ≤70 before and after PSM. Before PSM, whole brain radiotherapy (WBRT) improved the OS and predicted good prognosis in patients with ALK/EGFR wild type or extracranial metastases. WBRT also predicted good prognosis in patients with non-surgery. Stereotactic radiosurgery (SRS) improved the OS and predicted good prognosis in patients with ALK/EGFR wild type or non-surgery. WBRT plus SRS improved the OS and predicted good prognosis in patients with extracranial metastases or non-surgery. WBRT plus SRS also predicted good prognosis in patients with ALK/EGFR wild type. Surgery improved the OS and predicted good prognosis in patients with non-radiotherapy. After PSM, SRS improved the OS and predicted good prognosis in patients with non-surgery. WBRT plus SRS improved the OS and predicted good prognosis in patients with non-surgery or extracranial metastases. WBRT plus SRS also predicted good prognosis in patients with ALK/EGFR wild type. Surgery improved the OS of patients with non-radiotherapy. We defined that the treatment would provide significant survival benefit if it both prolonged the OS and predicted good prognosis. Meanwhile, the results after PSM were more convincing than the results before PSM. Conclusion Radiotherapy has significant survival benefit in patients with lung cancer BMs with poor prognosis factors, including patients with ALK/EGFR wild type or extracranial metastases or non-surgery. Surgery only has significant survival benefit in patients with non-radiotherapy.

Genomic landscape and prognosis of patients with TP53-mutated non-small cell lung cancer.

BackgroundThe TP53 tumor suppressor gene plays an important role in preventing and inhibiting the growth of tumor by regulating cell cycle, apoptosis and DNA repair. Meanwhile, the TP53 gene is one of the most frequently altered gene in non-small cell lung cancer (NSCLC) patients. Mutant TP53 (TP53-MUT) may lose tumor suppressor activity and gain tumor promoting functions, which play an important role in cancer risk, therapy resistance and poor prognosis. The impact of TP53-MUT on the prognosis of NSCLC patients need to be further studied.MethodsWe obtained genomic and clinical data from The Cancer Genome Atlas (TCGA). Mutation profiles, the TMB, disease-free survival (DFS), and overall survival (OS) were compared between patients with different TP53-MUT statuses.ResultsTP53-MUTs were detected in 46.6% of patients with lung adenocarcinoma (LUAD) (264 of 566) and 82.3% of those with lung squamous cell carcinoma (LUSC) (401 of 487). The most frequently co-mutated genes in patients with LUAD carrying a TP53-MUT included classic driver genes such as epidermal growth factor receptor (EGFR) and anaplastic large-cell lymphoma kinase (ALK), while Kirsten rat sarcoma viral oncogene (KRAS) mutations and TP53-MUTs appear to be mutually exclusive. This mutual exclusivity was not observed in patients with LUSC, in whom titin (TTN) and CUB and Sushi multiple domains 3 (CSMD3) were the most frequently co-mutated genes. A higher TMB was significantly associated with TP53-MUTs in patients with LUAD but not in those with LUSC. In patients with stage I-III NSCLC who had undergone surgery, there was no significant difference in DFS between patients carrying TP53-wildtype (TP53-WT) and TP53-MUTs, irrespective of histology or mutation type. However, the presence of TP53-MUT was associated with shorter OS in patients with LUAD (49 vs. 54 months, respectively; P=0.13) and significantly longer OS in those with LUSC (62 vs. 29 months, respectively; P=0.015).ConclusionsIn contrast to most previous studies, we revealed TP53-MUT characteristic in NSCLC patients according to histology-specific differences and the association between TP53-MUT and the mutation landscape, the TMB, and the OS. These findings suggest a need for individualized management for patients with LUAD and LUSC who carry a TP53-MUT, and warrant further research.

Value of CT features for predicting EGFR mutations and ALK positivity in patients with lung adenocarcinoma

The aim of this study was to identify the relationships of epidermal growth factor receptor (EGFR) mutations and anaplastic large-cell lymphoma kinase (ALK) status with CT characteristics in adenocarcinoma using the largest patient cohort to date. In this study, preoperative chest CT findings prior to treatment were retrospectively evaluated in 827 surgically resected lung adenocarcinomas. All patients were tested for EGFR mutations and ALK status. EGFR mutations were found in 489 (59.1%) patients, and ALK positivity was found in 57 (7.0%). By logistic regression, the most significant independent prognostic factors of EGFR effective mutations were female sex, nonsmoker status, GGO air bronchograms and pleural retraction. For EGFR mutation prediction, receiver operating characteristic (ROC) curves yielded areas under the curve (AUCs) of 0.682 and 0.758 for clinical only or combined CT features, respectively, with a significant difference (p < 0.001). Furthermore, the exon 21 mutation rate in GGO was significantly higher than the exon 19 mutation rate(p = 0.029). The most significant independent prognostic factors of ALK positivity were age, solid-predominant-subtype tumours, mucinous lung adenocarcinoma, solid tumours and no air bronchograms on CT. ROC curve analysis showed that for predicting ALK positivity, the use of clinical variables combined with CT features (AUC = 0.739) was superior to the use of clinical variables alone (AUC = 0.657), with a significant difference (p = 0.0082). The use of CT features for patients may allow analyses of tumours and more accurately predict patient populations who will benefit from therapies targeting treatment.

Brentuximab vedotin in combination with chemotherapy for pediatric patients with ALK+ ALCL: results of COG trial ANHL12P1

AbstractApproximately 30% of pediatric patients with anaplastic large cell lymphoma (ALCL) relapse. Although brentuximab vedotin has demonstrated excellent activity in ALCL, it has not been used for newly diagnosed patients. Children's Oncology Group (COG) trial ANHL12P1 determined the toxicity and efficacy of brentuximab vedotin with chemotherapy in children with newly diagnosed nonlocalized anaplastic large cell lymphoma kinase (ALK)+/CD30+ ALCL. From 2013 to 2017, 68 children with ALK+ ALCL were enrolled and received brentuximab vedotin. All patients received 5-day prophase, followed by 6 cycles of chemotherapy. Brentuximab vedotin was given on day 1 of each of the 6 cycles. Of the 67 patients eligible for toxicity evaluation, 66 completed all 6 cycles of chemotherapy, resulting in 399 evaluable cycles. There were no toxic deaths, no case of progressive multifocal leukoencephalopathy syndrome, and no case of grade 3 or 4 neuropathy. The 2-year event-free survival (EFS) was 79.1% (95% confidence interval [CI], 67.2-87.1). The 2-year overall survival (OS) was 97.0% (95% CI, 88.1-99.2). Fourteen patients relapsed. Eleven of 14 (79%) relapses occurred within 10 months of diagnosis; only 1 patient (1.5%) relapsed during therapy. Quantitative reverse transcription polymerase chain reaction for NPM-ALK at baseline (minimal disseminated disease) demonstrated prognostic value for EFS (P = .0004). Overall, the addition of brentuximab vedotin to standard chemotherapy does not add significant toxicity or alter the desired interval between cycles. The addition of brentuximab vedotin prevented relapses during therapy, and the OS and EFS estimates compare favorably with results obtained using conventional chemotherapy. This trial was registered at www.clinicaltrials.gov as #NCT01979536.

Differentiating synchronous double primary lung adenocarcinomas from intrapulmonary metastasis by CT features, EGFR mutations and ALK rearrangement status.

BackgroundDifferentiating synchronous double primary lung adenocarcinoma (SDPLA) from interpulmonary metastasis (IPM) has significant therapeutic and prognostic implications. This retrospective study aimed to investigate the potential of computed tomography (CT) features and two known oncogenic driver mutations [epidermal growth factor receptor (EGFR) and anaplastic large-cell lymphoma kinase (ALK)] to discriminate synchronous double primary lung adenocarcinoma from one primary pulmonary adenocarcinoma with intrapulmonary metastasis.MethodsPatients with SDPLA were selected at our hospital, and those with IPM served as the control group. All 60 patients (40 with SDPLA and 20 with IPM) were tested for EGFR mutations and ALK status, and they underwent chest CT prior to any treatment. Independent-sample Student’s t-test was used for comparisons between two groups of normally distributed variables, and the Chi-square test was used to compare categorical variables.ResultsThe discordance rate of EGFR mutations was significantly higher in patients with SDPLA than in patients with IPM (40% vs. 5%, P<0.001). The incidence of ALK-positive status was 15%, and patients with IPM were more likely to be ALK-positive than patients with SDPLA (35% vs. 5%, P<0.001). Compared to IPM, SDPLA more frequently occurred in different lobes (P=0.024), presented with less lymphadenopathy (P=0.014), showed a smaller difference in diameter (Äd) between tumors (P=0.001) and more commonly presented as lobulated tumors (P<0.001), spiculated masses (P<0.001), ground-glass opacities (GGOs) (P=0.001) and air bronchograms (P=0.020).ConclusionPatients with SDPLA showed higher discordance with EGFR mutations and were less frequently ALK-positive than those with IPM. Thus, the CT characteristics are significantly different between SDPLA and IPM.

EP1.03-32 Prevalence of EGFR and ALK Mutations in Non Small Cell Lung Cancer in Viet Nam National Cancer Hospital

A significant percentage of non small cell lung cancer (NSCLC) have driver mutations. Epidermal growth factor receptor (EGFR) mutations and anaplastic large-cell lymphoma kinase (ALK) rearrangements are now routine biomarkers that have been incorporated into the practice of managing NSCLC. To date, there has been no assessment of the prevalence of these mutations in NSCLC in Viet Nam National Cancer Hospital. The prospective study of formalin fixed paraffin embedded (FFPE) tissues from patients diagnosed with NSCLC was performed to assess the prevalence of EGFR and ALK mutations in NSCLC in Viet Nam National Cancer Hospital. Patients with NSCLC in Viet Nam National Cancer Hospital were prospectively enrolled. FFPE tissue samples were tested for EGFR mutation by PCR and for EML4-ALK translocation by fluorescence in situ hybridization (FISH) A total of 103 patients were enrolled, 78 (76.7%) males and 25 females (23.3%), with a mean age of 57.7 years. Adenocarcinoma and Squamous cell carcinoma rate were 89.3% and 10.7%, respectively. EGFR testing of 103 patients (100%) demonstrated the wild type in 76 (73.8%) and mutated forms in 27 (26.2%). Some 74.0% of EGFR positive patients were non-smokers and 44.4% were females. Regarding the EML4-ALK translocation, testing in 103 cases (100%) gave positive results in only 11 (10.7%). Among 11 patients with EML4-ALK translocation, 6 patients (54.5 %) were females and 6 patients (54.5 %) were smokers. Moreover, only two squamous cell carcinoma patients had positive EGFR mutation and only one patient had concurrent EGFR mutation and ALK rearrangement In this sudy investigating the prevalence of EGFR and ALK mutations in non small cell lung cancer in Vietnam National Cancer Hospital, 26.2% had EGFR mutation and 10.7% had ALK translocation mutations, as compared to 35% and 6.1%, respectively, in Asian

A novel ALK rearrangement in an inflammatory myofibroblastic tumor in a neonate

Inflammatory myofibroblastic tumors (IMTs) are uncommon lesions primarily affecting children and young adults. They have rarely been described in infants, with a very small number described in neonates. Structural rearrangements in the anaplastic large-cell lymphoma kinase gene (ALK) has contributed to our categorizing this lesion as a neoplasm. In addition, rearrangements of the ALK gene have been implicated in the pathogenicity of many other hematolymphoid and non-hematolymphoid tumors, typically involving 2p23 with different partners or with pericentric inversion. We report a previously undescribed cryptic deletion and intrachromosomal-insertional translocation of the 3'-region of the ALK gene from 2p23 to the 2q33-q35 in an IMT of a newborn patient with an apparently normal G-band karyotype of the tumor.

Anaplastic Large Cell Lymphoma in Children and Adolescents

Anaplastic Large Cell Lymphoma (ALCL) is the most common mature T-cell neoplasm in children and adolescents. ALCLs comprise approximately 15% of all non-Hodgkin lymphomas (NHL) in children and adolescents and commonly present with advanced systemic disease. Dissimilar from ALCL in adults, ALCL in children is nearly universally anaplastic large cell lymphoma kinase (ALK) positive. Despite the relative rarity of the disease, a great deal of insight into the pathogenesis of ALCL has been learned by researching the essential oncogenic role of ALK. Many different treatment strategies have been utilized with similar event free survival (EFS) rates of 65–75%. This review will provide an overview of the pathology, clinical features, prognostics factors, and treatment for children and adolescents with ALK positive ALCL.

Frequent expression of follicular dendritic cell markers in Hodgkin lymphoma and anaplastic large cell lymphoma

AimsAlthough the tumour cells of Hodgkin lymphoma (HL) are derived from mature B-cells, the lineage infidelity of Hodgkin/Reed–Sternberg cells (HRSs) often causes diagnostic problems. Recently introduced HRS markers are also...

Targeted agents in non-small cell lung cancer therapy: What is there on the horizon?

Lung cancer is a heterogeneous group of diseases. There has been much research in lung cancer over the past decade which has advanced our ability to treat these patients with a more personalized approach. The scope of this paper is to review the literature and give a broad understanding of the current molecular targets for which we currently have therapies as well as other targets for which we may soon have therapies. Additionally, we will cover some of the issues of resistance with these targeted therapies. The molecular targets we intend to discuss are epidermal growth factor receptor (EGFR), Vascular endothelial growth factor (VEGF), anaplastic large-cell lymphoma kinase (ALK), KRAS, C-MET/RON, PIK3CA. ROS-1, RET Fibroblast growth factor receptor (FGFR). Ephrins and their receptors, BRAF, and immunotherapies/vaccines. This manuscript only summarizes the work which has been done to date and in no way is meant to be comprehensive.

Plasmablastic Lymphoma and Related Disorders

B-cell lymphomas with plasmablastic features are a heterogeneous group of lymphomas. While they may share overlapping morphologic or immunophenotypic features, distinct clinicopathologic or molecular genetic features exist for some that have allowed their recognition as distinct entities. Session 2 of the 2009 Society for Hematopathology/European Association for Haematopathology Workshop dealt with the theme of plasmablastic lymphomas (PBLs) and related disorders. Topics included human herpesvirus 8-associated Castleman disease and PBLs, PBLs occurring in the setting of HIV infection, anaplastic large cell lymphoma kinase+ diffuse large B-cell lymphoma, and other lymphomas with plasmablastic or plasmacytic features. In this report, we review PBLs and related disorders in the context of submitted cases and illustrate key diagnostic points, highlight controversial areas, and provide recommendations on features that should be assessed and terminology that might be used when dealing with these lymphomas.

Treatment and prognosis of mature T-cell and NK-cell lymphoma: an analysis of patients with T-cell lymphoma treated in studies of the German High-Grade Non-Hodgkin Lymphoma Study Group

AbstractTo evaluate outcome and prognosis of patients with T-cell lymphoma we analyzed 343 patients treated within trials of the German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL). Two hundred eighty-nine patients belonged to 1 of the 4 major T-cell lymphoma subtypes: anaplastic large cell lymphoma (ALCL), anaplastic large cell lymphoma kinase (ALK)–positive (n = 78); ALCL, ALK-negative (n = 113); peripheral T-cell lymphoma, unspecified (PTCLU; n = 70); and angioimmunoblastic T-cell lymphoma (AITL; n = 28). Treatment consisted of 6-8 courses of CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone/prednisolone) or etoposide plus (CHOEP). Three-year event-free survival (EFS) and overall survival were 75.8% and 89.8% (ALK-positive ALCL), 50.0% and 67.5% (AITL), 45.7% and 62.1% (ALK-negative ALCL), and 41.1% and 53.9% (PTCLU), respectively. The International Prognostic Index (IPI) was effective in defining risk groups with significantly different outcomes. For patients, ≤ 60 years with lactate dehydrogenase ≤ upper normal value (UNV), etoposide improved improved 3-year EFS: 75.4% versus 51.0%, P = .003. In patients > 60 years 6 courses of CHOP administered every 3 weeks remains the standard therapy. Patients with ALK-negative ALCL, PTCLU, or AITL presenting with IPI > 1 have a poor prognosis and should be considered candidates for novel treatment strategies.

Cytomorphologic features of primary anaplastic large cell lymphoma of the psoas muscle: A case report and literature review

Ki-1 (CD30) positive anaplastic large cell lymphoma (ALCL) is an uncommon malignancy, which may present with nodal as well as extra-nodal disease. Primary skeletal muscle Ki-1 (CD30) positive ALCL is an even rarer event with few cases reported in the literature and only some with published cytomorphologic features. An 83-year-old woman underwent a fine needle aspiration (FNA) of a psoas muscle mass. Smears demonstrated a predominantly discohesive population of large pleomorphic cells. The nuclei were hypechromatic and lobulated, with often multinucleation. Nucleoli were prominent in a subset of cells. Cytoplasmic vacuolization was also present. No lymphoglandular bodies were identified. A cytodiagnosis of malignant cells favoring metastatic melanoma vs. poorly differentiated carcinoma was rendered. Morphologic and immunohistochemical features later revealed a primary psoas muscle Ki-1 (CD30) positive ALCL with negative staining for anaplastic large cell lymphoma kinase (ALK). Cytologic features of ALCL mimic epithelial neoplasms, sarcomas, melanoma and other lymphomas. Although rare, ALCL should be a diagnostic consideration when discohesive pleomorphic malignant cells are encountered on FNA of a muscle neoplasm.

ALK-negative anaplastic large cell lymphoma with extensive peripheral blood and bone marrow involvements manifested as “leukemic phase”

CD30-positive anaplastic large cell lymphoma (ALCL) is a distinctive malignant large cell lymphoma of T-cell lineage, often presenting in lymph node or extranodal sites. ALCL cases with extensive bone marrow and peripheral blood involvement manifested as “leukemic phase” are extremely rare and the most of those cases reported are anaplastic large cell lymphoma kinase (ALK) positive ALCL in childhood population. Here we report four adult cases of ALK-negative ALCL with extensive bone marrow and peripheral blood involvement manifested as “leukemic phase”. Circulating large lymphoma cells varied from 20 to 80% in peripheral blood and bone marrow biopsy showed various nodular or interstitial infiltrates. By reviewing the clinicopathologic data of previously reported ALCL cases with extensive bone marrow and peripheral blood involvement, there appears to be of large variations in regard to the patient's age, morphologic variants, immunophenotypic or genotypic characteristics of the disease. While most cases of ALCL with peripheral blood and bone marrow involvement were ALK-positive or carrying t(2;5) translocation, rare ALK-negative cases were also present. Leukemic ALCL patients usually have unfavourable prognosis, regardless of ALK expression.

Frequent Expression of CD99 in Anaplastic Large Cell Lymphoma

Originally described as a diagnostically useful marker for Ewing sarcoma, CD99 immunoreactivity has also been documented in a variety of other tumors, including hematopoietic neoplasms. By using conventional paraffin immunoperoxidase staining and tissue microarrays, we retrospectively investigated CD99 expression in a series of 160 anaplastic large cell lymphoma (ALCL) cases. Of the 160 cases, 103 (64.4%) were positive for CD99. The distribution of CD99 positivity was similar for nodal (66/103 [64.1%]), extranodal, (21/32 [66%]), and primary cutaneous lesions (16/25 [64%]). CD99 expression was present in 96 (64.4%) of 149 of the common type, 4 (80%) of 5 of the small cell variant, and 3 (50%) of 6 of the lymphohistiocytic variant cases. CD99 expression was slightly more frequent in anaplastic large cell lymphoma kinase (ALK)+ cases compared with ALK- cases (43/54 [80%] vs 44/81 [54%]). With 2 exceptions, ALK+ ALCL was seen only in patients younger than 41 years. We conclude that CD99 is frequently expressed in ALCL, with a slightly increased frequency in the younger age ALK+ cases. Nodal and extranodal ALCL should be considered in the differential diagnosis when a CD99+ neoplasm is encountered.

Activated c-Jun N-Terminal Kinase Is a Therapeutic Target in Advanced Stage ALK-Negative Anaplastic Large Cell Lymphoma.

Anaplastic large cell lymphoma kinase (ALK)-negative anaplastic large cell lymphoma (ALCL) is an aggressive T cell lymphoma. To find a novel therapeutic target for aggressive ALK-negative ALCL, we studied two ALK-negative CD30-positive ALCL cell lines, N1 and N2, which were previously reported. In vitro culture, N1 and N2 represent early and advanced stage lymphoma phenotype, respectively. Increased tumorigenicity of N2 was confirmed by its xenotransplantability in SCID mice, whereas N1 was not transplantable either in SCID or in NOD/SCID mice. Subcutaneous tumors formed in the flank of SCID mice inoculated with N2 consisted of large basophilic lymphoma cells with prominent nucleoli, strongly positive for CD2 and CD30. Subcutaneous tumor showed TCR γ rearrangement identical with those in N2, and expressed aberrant CD30 protein with molecular weight 100 Kd, which was expressed only in N2, but not in N1. Those suggested subcutaneous tumors had characteristics of advanced stage ALCL. We hypothesized that constitutively activated c-Jun N-terminal kinase (JNK) is a therapeutic target in advanced stage ALK-negative ALCL, because, (1) JNKs were highly phosphorylated in N2 compared to in N1 studied by immunoblotting using phospho-specific antibodies against JNKs (N1=1.2±0.1 and N2=2.9±0.3, p=0.01, signal intensity); (2)specific JNK inhibitor, SP600125(SP) significantly inhibited cell growth of N2 compared to those of N1in culture for three days(N1=95±1.8 and N2=58±1.6 at 5μM SP, p<0.05; N1=89±0.1 and N2=29±2.4 at 50μM SP, p<0.01, % of viable cell No. of control). Incubation with SP restored the expression of co-stimulatory molecule, CD86 protein, and putative tumor suppressor gene, JunB protein, both of which were strongly downregulated in N2 compared with in N1. Despite of significant growth inhibition, constitutive activation of AP-1 was still demonstrated in N2 incubated with 50μM SP, whereas it was completely inhibited in N1 in electro mobility shift assay using AP-1 DNA consensus sequence(N1=0.2±0.1 and N2=8.3±0.2, p<0.01, arbitrary density units). It suggested that SP exhibited its effect in pathway(s) other than transcriptional regulation through AP-1 complex in ALCL cell lines, N2. In vivo model, intraperitoneal injection of SP (30mg/weight) alternate days for 22days significantly suppressed the growth of subcutaneous tumors (DMSO=1.4±0.5 and SP=0.2±0.1, p<0.05, tumor weight[g] at day26). Tumors in SP-treated mice were exclusively localized in subcutaneous region, in contrast, tumors infiltrated and produced signs of hindlimb paralysis in two of three DMSO-treated mice. Histopathologically tumors in SP-treated showed increase of cells with nuclear condensation, suggesting apoptotic cell death. Furthermore, in addition to partial inhibition of phosphorylation of JNK, tumors in SP-treated mice showed significant decrease of levels of both mRNA (64±13%, p<0.05, real-time PCR) and protein (62±2%, p=0.02, signal intensity by immunoblotting) of BCL2, compared with those in DMSO-treated mice. Whereas no change was found in Bcl-XL expression. No change was found in CD30 protein expression. Taken together, the present study showed that aberrantly activated JNK(s) is a therapeutic target in some types of advanced stage ALK-negative ALCL, although details of signaling pathways triggered by JNK(s) in ALCL cells remained to be elucidated.

Follicular dendritic cell tumor as an unknown primary tumor

A 70-year-old Japanese man presented to our hospital with a 1-month history of progressive general fatigue and anorexia. A physical examination revealed severe anemic condition, mild persistent splenomegaly, and no palpable surface lymph nodes. He had pleural effusion and ascites, though no malignant cells were detected in the effusion. He eventually died without any diagnosis of his disease. Immunohistochemical staining of his tumor after autopsy showed atypical cells that were negative for epithelial membrane antigen (EMA), keratin (AE1/3), keratin-20, vimentin, factor VIII, leukocyte common antigen (LCA/T200; CD45), myeloperoxidase (MPO), terminal deoxynucleotidyl transferase (TdT), lysozyme, CD1a, CD3, CD4, CD10, CD15, CD20 (L26), CD21, CD23, CD34, CD43, CD56, CD68, CD79a, CD138, and EBER-1 in situ. Only a few scattered cells expressed CD30, but they showed no staining for anaplastic large-cell lymphoma kinase (ALK). A few scattered cells expressed S-100 antigen and the majority of cells dominantly expressed dendritic cell-associated antigens (CD35, FDC, Ki-M1p). In conclusion, we found this unknown primary tumor to be consistent with a follicular dendritic cell tumor with anaplastic features.

Absence of human herpesvirus‐8 and Epstein–Barr virus in inflammatory myofibroblastic tumor with anaplastic large cell lymphoma kinase fusion gene

Inflammatory myofibroblastic tumor (IMT) is clinically and histologically characterized by inflammation. Some populations of IMT have anaplastic large cell lymphoma kinase (ALK) gene rearrangements. Infection with Epstein-Barr virus (EBV) and human herpesvirus-8 (HHV-8) in tumor cells of IMT has been reported; these reports, however, have been limited to ALK-negative IMT. The purpose of the present paper was to evaluate 21 cases of IMT for the presence of EBV and HHV-8. Immunohistochemically, 15 cases were ALK positive and six were negative. Of eight cases analyzed using reverse transcription-polymerase chain reaction, tropomyosin 3 (TPM3)-ALK, TPM4-ALK and clathrin heavy chain-ALK fusion genes were detected in one, two and two cases, respectively. All 21 IMT, irrespective of ALK expression, were negative for EBV by in situ hybridization for EBV-encoded RNA and immunohistochemical stain for latent membrane antigen-1. HHV-8 was also negative in all IMT by PCR for HHV-8 DNA sequence (KS330/233) and immunohistochemical stain for latent nuclear antigen. These results suggest that IMT may be a heterogeneous group in terms of pathogenesis, and EBV and HHV-8 do not play a major role in the pathogenesis of ALK-positive tumor.