Large B-cell Research Articles

Neurolymphomatosis: A Case Series of Clinical Manifestations, Treatments, and Outcomes (P04.187)

Objective: Our goal was to ascertain common factors to render earlier diagnosis, and prognostic factors to predict response to therapy. Background Neurolymphomatosis involves infiltration of malignant lymphocytes into the peripheral nervous system, specifically cranial nerves, roots, plexuses, and/or peripheral nerves. It is distinct from more common neurological complications related to chemotherapy, irradiation, paraneoplastic disorders, and leptomeningeal carcinomatosis. Design/Methods: We review five patients who developed neurolymphomatosis at M.D. Anderson Cancer Center between 2010 and 2011. Clinical, radiologic, and laboratory data were extracted from their medical records. Results: The average age at onset was 48 (range 26 - 76) with primary diagnosis being non-Hodgkin9s lymphoma in three (Burkitt9s, large B-cell) and leukemia in two (AML, CML). Initial symptoms included weakness (5/5), pain (3/5), and sensory change (2/5) and localized to lower extremities (3/5), upper extremities (2/5), unilateral (4/5), bilateral (1/5), and cranial nerve (1/5). Physical exam findings included weakness (5/5), sensory disturbance (5/5), atrophy (4/5), hypotonia (2/5), and hyporeflexia (5/5). Three patients demonstrated MRI abnormalities with clinical correlation, affecting neural foramina (1/5), paraspinal (2/5), or subcutaneous (1/5) regions; no patients had imaging evidence of parenchymal, spinal cord, or leptomeningeal pathology. All patients had positive EMG/NCS and diagnoses included mononeuritis multiplex, multifocal plexopathy, demyelinating polyneuropathy, and chronic axonal polyradiculoneuropathy. One patient had positive CSF cytology; PET was performed and positive in four patients and no nerve biopsies or autopsies were performed. Therapies included systemic (5/5) and intrathecal chemotherapy (4/5), immunomodulators (2/5), and plasma exchange (1/5); no patients underwent radiotherapy. Mortality was 40% with average survival from neurologic presentation 6 months (range 1–12 months); the other patients progressed despite treatment. Neither age, gender, malignancy type, recurrence, positive CSF/imaging/EMG, nor intervention correlated with worse prognosis. Conclusions: Further studies are warranted to define risk for developing neurolymphomatosis and identify factors affecting outcome. Disclosure: Dr. Gildersleeve has nothing to disclose. Dr. Hormozdi has nothing to disclose. Dr. Kamiya Matsuoka has nothing to disclose. Dr. Woodman has nothing to disclose.

Molecular targeted therapy of diffuse large B cell lymphoma

The diffuse large B cell lymphoma (DLBCL) is the most common adult non-hodgkin lymphoma.At present,rituximab in combination with CHOP program has significantly improved the prognosis of DLBCL,and about 50％ of the DLBCL can be cured.However,due to the heterogeneity of the tumor,the refractory and relapsed DLBCL is still lack of effective treatment methods.With the application of gene expression profile (GEP) and the thorough research of the activation of lymphoma cells signal way,a lot of potential therapeutic targets have been found. Key words: Lymphoma, large B-cell, diffuse; Molecular targeted therapy

Genomic and Molecular Properties of Relapsed CNS Lymphoma Using Novel Primary Meningeal Lymphoma Cell Lines and Intracranial Xenografts,

Abstract 3477 Background:There is a paucity of molecular information regarding the phenotype of relapsed aggressive CNS lymphoma, a condition for which there are few effective treatment options and, as a consequence, patient survival is often short. To test our hypothesis that the molecular properties of CNS lymphoma at relapse are distinct from those at diagnosis we pursued two parallel lines of investigation: 1) the genomic analysis of relapsed aggressive CNS lymphomas in comparison to newly diagnosed specimens and 2) the generation of novel CNS lymphoma cell lines derived from recurrent meningeal lymphomas isolated from the cerebrospinal fluid. We hypothesize that this approach will facilitate the identification of the underlying molecular determinants of tumour progression, novel genome-based biomarkers and therapeutic targets. Methods:We compared genome copy number using high-resolution array comparative genomic hybridization (array-CGH) and used bioinformatics to study a carefully selected cohort of tumours comprised of 10 newly-diagnosed primary CNS lymphomas (large B-cell) and 7 relapsed/refractory CNS lymphomas (5 large B-cell, 2 of transformed histology). We evaluated copy number aberrations that occurred in the tumour cohort as a whole as well as those that occur predominantly in relapsed cases. In addition, we established five novel lymphoma cell lines from relapsed cases, three of which were derived from meningeal lymphomas isolated from the cerebrospinal fluid and expanded upon intracranial implantation in NSG mice as patient-derived xenografts. Results:There was a trend for an increase in the proportion of copy number losses involving the short arm of chromosome 6 as well as overall gains on chromosome 12 among the relapsed cases. Significant DNA copy number gains for STAT6 were noted in 4/7 relapsed cases. We observed a significant number of deletions present in between 50–90% of newly diagnosed tumors that were absent in CNS lymphomas at relapse, suggestive of complex genomic remodeling during tumour evolution. In addition, a region with potential prognostic implications was identified at chromosome 19p.13.3 that was deleted in 57% of relapsed tumors but not in newly diagnosed cases. Three of the five relapsed large cell cases exhibited significant deletions, including one focal homozygous deletion, at chromosome 4q23.3–4q23.5, a region not previously shown to be deleted in large cell lymphoma (Lenz et al., PNAS, 2008). Both chromosomes 14 and 22 have copy number aberrations that occur in > 80% of all tumours as well as high frequency focal aberrations that appear linked to either good or poor prognosis. Significantly, the MTAP and CDKN2A genes at 9q21 are homozygously co-deleted in 18% of poor prognosis or relapsed patients.Notably, each of the orthotopic xenografts exhibited an ABC immunophenotype and were diffusely infiltrative with meningeal tropism. In fact, CNS metastasis to the meninges was recapitulated when the lymphoma cells were implanted in flank and spontaneously metastasized to brain, within three months post injection. In vitro chemotaxis assays demonstrated responsiveness of human meningeal lymphoma cells to CXCL-13 and SDF-1, chemokines postulated to contribute to the CNS tropism of NHL. Importantly, genomic aberrations identified in the parent tumours were retained when the relapsed meningeal lymphomas were serially passaged by intracranial implantation as xenografts, as evidenced by array-CGH. Conclusions:We believe that this study represents the first analysis of the biologic and genetic properties of relapsed CNS lymphoma. This analysis provides the first direct evidence that chemokines previously shown to be expressed in the CNS lymphoma microenvironment direct chemotaxis of meningeal lymphoma cells isolated from patients. This result is suggestive of a molecular mechanism which may be essential to CNS tropism. In addition, we have established the first in vivo model system of CNS lymphoma which retains the genomic properties of relapsed, refractory disease and which has significant potential for preclinical testing of novel therapeutic strategies.Supported by Leukemia and Lymphoma Society and NIH Grant CA13908301. Disclosures:No relevant conflicts of interest to declare.

The utility of endobronchial ultrasound‐guided transbronchial needle aspiration biopsy in the diagnosis of mediastinal lymphoproliferative disorders

Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) biopsy is routinely used to stage lung cancer; however, its usefulness in diagnosing lymphoproliferative disorders has not been well established. In this retrospective study, we determined the utility of EBUS-TBNA in evaluating mediastinal lymphadenopathy in patients with suspected lymphoproliferative disorders. The authors searched the pathology database at their institution to identify all patients who had undergone EBUS-TBNA biopsy for possible lymphoproliferative disorders. The cytologic diagnoses were correlated with concurrent and subsequent biopsy findings and clinical follow-up data. Of 886 lymph nodes evaluated by EBUS-TBNA biopsy, 91 nodes from 33 patients (23 men and 10 women) were eligible. Fourteen patients had a history of lymphoma. Adequate material for diagnosis was obtained in 31 of 34 procedures (1 patient had 2 procedures). The cytologic diagnoses of the 31 adequate procedures included 19 with benign disease (8 reactive lymph nodes and 11 granulomatous inflammation), 8 with lymphoma (2 large B-cell, 2 small lymphocytic, 2 Hodgkin, 1 mantle cell, and 1 T-cell lymphoblastic), 2 with cells suspicious for Hodgkin lymphoma, and 2 cases with atypical cells. EBUS-TBNA proved to be useful for evaluating mediastinal lymphadenopathy in patients with suspected lymphoproliferative disorders. Its use may decrease the need for invasive diagnostic procedures. Immediate assessment is valuable in these cases because of the need to triage material for immunophenotyping or other studies to determine optimal and clinically meaningful diagnoses.

Micronodular T-cell/histocyte-rich B-cell lymphoma of the spleen: case report and review of the literature

A 37-year-old male presented with fever and massive hepatosple-nomegaly but no generalised lymphadenopathy. The full blood count prior to surgery revealed a pancytopenia. The bone marrow showed non-specific changes and normal haemopoietic cell lines, indicative of peripheral sequestration. A diagnostic and therapeutic splenectomy was performed. The macroscopic appearance of the spleen showed areas of congestion and infarction and enlarged hilar lymph nodes. Histological examination showed nodular aggregates of histiocytes and small T-cells, admixed with occasional large atypical B-cells. Similar micronodules were present within hilar lymph nodes. Immunohistochemistry showed the atypical cells were positive for CD20, C79a and negative for CD15, CD30 and EMA. CD23 was also negative within the nodules. The diagnosis of micronodular variant of T-cell/histo-cyte-rich B-cell lymphoma (TCRBCL) of the spleen was made. This entity was first defined in 2003 by Dogan, 1 who examined a case series of 17 cases. Only rare cases of splenic TCRBCL have been reported in the literature to date. This case report reviews the typical clinical presentation, diagnostic criteria and prognosis of this rare entity.

びまん性大細胞型B細胞リンパ腫Diffuse large B-cell lymphomaの新しいsubtype分類:胚中心B細胞型Germinal center B-cell-like (GCB) typeと活性型B細胞型Activated B-cell-like (ABC) type

びまん性大細胞型B細胞リンパ腫Diffuse large B-cell lymphomaの新しいsubtype分類:胚中心B細胞型Germinal center B-cell-like (GCB) typeと活性型B細胞型Activated B-cell-like (ABC) type

Histopathologic classification of 171 cases of canine and feline non-Hodgkin lymphoma according to the WHO

A retrospective collection of 171 lymphoid neoplasms (123 dogs and 48 cats) was classified according to the Revised European-American Lymphoma (REAL) classification, adopted in 2002 by the World Health Organization (WHO), to evaluate the WHO system for categorization of canine and feline neoplasms. Microscopic examination was performed after standard hematoxylin-eosin staining and immunohistochemical labelling for B (CD79a) or T (CD3) cell phenotypes. B-cell lymphomas were prevalent in dogs and T-cell lymphomas in cats. B-Large cell lymphoma (B-LCL) frequently showed plasmacytoid differentiation; notably, two canine plasma cell tumours (PCT) expressed both CD79 and CD3. There were difficulties in differentiating B-lymphoblastic lymphoma (B-LBL) from Burkitt-type lymphoma. Furthermore, intestinal T-cell lymphoma (ITCL) exhibited a huge morphologic variability. Finally, multicentric mature small and thymic T-cell lymphomas were diagnosed, although these categories are not codified by the WHO classification.

Prognosis of primary thyroid lymphoma: Demographic, clinical, and pathologic predictors of survival in 1,408 cases

There is a paucity of data regarding prognosis of primary thyroid lymphoma (PTL), with only case reports and institutional series reported. This is the first population-based study of PTL in the United States. PTL patients were identified in the SEER database. Bivariate (chi(2), Kaplan-Meier, and log rank) and multivariate (Cox proportional hazards) analyses were used to assess the associations between patient characteristics and survival. A total of 1,408 patients were identified over 32 years of follow-up (median, 3.75 years). Mean age was 66 years; 75% were female and 93% white. Overall, 98% had non-Hodgkin's lymphoma; 68% had diffuse large B-cell, 10% follicular, 10% marginal zone, and 3% small lymphocytic. A total of 88% had stage I-II disease. Median survival was 9.3 years. On bivariate analysis, older age, single marital status, stage II-IV disease, histology (large B-cell, follicular, or other non-Hodgkin's), earlier year of diagnosis, lack of prior malignancies, and no radiation/surgery predicted worse survival. Age >or=80 years, advanced stage, no radiation/surgery, and large B-cell or follicular histology predicted worse prognosis in multivariate analysis. Older age, advanced stage, histologic subtype, and lack of radiation/surgical treatment are associated with worse survival. Thyroid resection offers benefit only for patients with stage I disease. Management of PTL requires multidisciplinary collaboration.

Conventional Chemotherapy Followed by Consolidation with Autologous Hematopoietic TransplantationVs Chemotherapy Alone in HIV+ Patients with Large B Cell Lymphoma (LBCL) in First Complete Remission (CR). A Retrospective Analysis On Behalf of the EBMT Lymphoma Working Party and the GESIDA/PETHEMA Registry of HIV+ Patients with Non-Hodgkin's Lymphoma (NHL).

Abstract 4355Little is known about the additional benefit of Autologous Stem Cell Transplantation (ASCT) as consolidation treatment of NHL in 1st CR in HIV+ patients. We herein report a comparative analysis of HIV+ patients with a LBCL treated with chemotherapy (chemo) followed by ASCT and a matched cohort of HIV+ patients treated with chemo alone. MethodologyRetrospective, registry-based, matched cohort study. ASCT cohort: patients with diffuse large B-cell (DLBC) or plasmablastic NHL treated with ASCT in 1st CR after standard chemo and reported to the EBMT Registry. Chemo cohort: For each patient within the ASCT cohort we selected two controls from the HIV+ patients with NHL GESIDA/PETHEMA registry. Patients in both cohorts were in 1st CR following front-line or rescue (for partially responding patients) chemo and were matched according to histology, IPI and the use of Rituximab. We compared overall survival (OS), disease free survival (DFS) and cumulative incidence (CI) of relapse between both cohorts. These primary outcomes were defined according to the EBMT. OS was computed from diagnosis while DFS and CI of relapse were computed from 3 weeks after the last standard chemo cycle administered (end of chemo). ResultsThe ASCT cohort included 10 patients diagnosed between 1999 and 2005. The Chemo cohort included 20 patients, 16 diagnosed between 1999 and 2005. Both cohorts were comparable for the main clinical and patient features (Table 1). The median (range) follow-up (FU) time since the end of chemo for surviving patients was 56 months (mo) (24-106) in the ASCT cohort vs 37 mo (8-107.5) in the Chemo cohort; P=.28. Five years (yr) OS for the ASCT cohort and the Chemo cohort were 68.5% [CI95%: 39-98] and 46.5% [CI95%: 18-75], respectively; P=.6. Three yr DFS for the ASCT cohort and the Chemo cohort were 70% [CI95%: 41.5-98.5] and 59.5% [CI95%: 29-86]; respectively; P=.4. The CI of relapse in the ASCT cohort and the Chemo cohort were 21% [CI95%: 0-47] and 27% [CI95%: 2-51], respectively; P=.8 ConclusionsIn this retrospective registry-based, matched cohort study of HIV+ patients with large B-cell NHL we found a non-significant effect of ASCT as consolidation treatment in 1st CR patients, in terms of survival and relapse incidence. Nevertheless, due to the observed favorable tendency, future analysis including a higher number of patients and, eventually, randomized clinical studies, should be performed to further clarify these observations.Table 1:Patients and transplant featuresASCT cohortChemo cohortn=10%n=20%Prior AIDS defining disease43%30%p=NSAge at lymphoma diagnosis: median (range)40 (34-60.5)43.5 (30-56.5)p= NSMale sex7701470p= NSHistologyDiffuse large B cell / Plasmablastic8 / 280 / 2018 / 290 / 10p= NSIPI at diagnosis (>2)7701470p= NSAnn Arbor stage at diagnosis (>II)9901680p= NSTreatmentRituximab use5501050p= NSNumber of treatment lines: median (range)1 (1-2)1 (1-2)p= NSMonths from diagnosis to end of chemo: median (range)5.8 (3.5-11)4.3 (2.4-7.4)p=NS Disclosures:No relevant conflicts of interest to declare.

Primary Nasopharyngeal non-Hodgkin lymphomas: a retrospective review of 26 Moroccan patients

BackgroundNasopharyngeal non-Hodgkin lymphomas (NNHL) are extremely rare. In this study, we will report the progress achieved in the management of this disease in our institute.MethodsWe retrospectively reviewed the records of 26 patients having primary NNHL who were managed between January 1997 and December 2008, to evaluate and compare their clinical characteristics and treatment outcome. Clinical variables, including age, sex, stage, and treatment modality, were assessed. Disease free survival and overall survival were measured. Survival curves were constructed using the KaplanMeier method. The log-rank test was used to compare them.ResultsMedian age of our patients was 52.7 years. Nasal obstruction, nasal discharge and epistaxis were the frequent symptoms in NNHL patients. Histology of NNHL were mainly large B-cell and follicular lymphoma. Four patients (15.4%) were at stage I, 15 (57.6%) at stage II, and 7 (27%) were at stage III/IV. The patients were treated with chemotherapy alone (27%) or chemotherapy plus radiotherapy (73%). At early stage (stage I/II), the patients were managed with chemo-radiotherapy. When the whole treatment was completed, 18 patients (69.2%) achieved complete response and remained disease free. After 25.9 months median follow-up, overall survival at 1 year was 87% and disease free survival at 1 year was 71%. The difference in term of overall and disease free survival between stage I, II, III and IV was significant (Log rank test: p = 0.02 for overall survival and p = 0.01 for disease free survival).ConclusionFrom our study, we conclude that histological characteristics, principle of treatment and outcome of primary NNHL patients are particular and more studies have to be directed.

Primary thyroid non-Hodgkin's lymphoma of Ann Arbor stages IE and IIE: prognostic factors

To investigate the prognostic factors of primary non-Hodgkin's thyroid lymphoma. From January 1981 to January 2008, 47 patients with stage IE and IIE pathologically confirmed as suffering from B cell non-Hodgkin's lymphoma and treated in hospital, were retrospectively analyzed. Pathology: diffuse large cell B-cell lymphoma (DLBCL) 28, mucosa-associated lymphoma (MALT) 19. The cancer specific survival (CSS) were calculated using the Kaplan-Meier method and compared by the Log-rank test. Age, sex, symptoms, extrathyroid extension, radiation doses, treatment modality and histological type characteristics were evaluated using the Cox regression analysis. The 5-year CSS rate was 61.8%. The 5-year CSS rate for the patients with primary tumor confined to thyroid and with extrathyroid extension were 86.7% and 50.0% (P=0.012). The 5-year CSS rate for the patients treated with radiation doses below 40 Gy and treated to 40 Gy or more were 30.8% and 79.0% (P=0.002). The 5-year CSS rate for the 18 patients with stage II received single modality therapy and the multimodality therapy were 33.3% and 61.1% (P=0.037). The 5-year CSS rate for patients with DLBCL lymphoma lesions and with MALT were 50.0% and 78.9% (P=0.038). Multivariate analysis by Cox regression showed that extrathyroid extension, radiation doses and histological type were independent prognostic factors. In primary non-Hodgkin's lymphoma of the thyroid, extrathyroid extension, radiation radiation doses and histological type are important prognostic factors. For patients with the stage II received multimodality therapy have a higher CSS than the ones received single-modality therapy.

皮膚生検より診断し得たintravascular Large B－cell Lymphomaの1例

59歳男性。発熱，呼吸苦を愁訴に他院を受診した。ARDSと診断され，ステロイドパルス療法等施行されるも，多臓器不全に陥った。集中治療が必要と判断され，当院救急部へ転院となった。重症感染症を疑い抗生剤投与，持続性血液濾過透析（CHDF）等行うも全身状態の改善はみられなかった。左大腿部に浮腫を伴う毛細血管拡張と，前胸部に点状紫斑を認めたことから，皮膚科にコンサルトされた。sIL－2R 19700と高値であり，Intravascular Large B－cell Lymphomaを疑い，同部位の皮膚生検を行った。真皮，脂肪織の血管内には，大型異型リンパ球様細胞が充満し，管腔を閉塞する像がみられた。免疫組織化学検査にて腫瘍細胞はCD3陰性，CD20陽性であり，以上の所見から本疾患と診断した。R－CHOP療法を開始し，臨床症状は改善した。

Late Relapse of Localized High-Grade Non-Hodgkin's Lymphoma: Clinical and Biological Features

Diffuse large cell lymphoma is the most common non-Hodgkin Lymphoma (NHL) that ranks among the most curable diffuse intermediate grade lymphomas. Most investigators have recognized that practically all patients with this cell type who are able to attain and maintain a complete response for 24 consecutive months are cured because late relapses seldom occur after this period of follow-up. However, relapses do occur late after the remission and the characteristics of patients who experience these relapses rarely have been studied especially for localized disease. From 1984 to 1996, three hundred and five patients aged more than 18 years were enrolled in a prospective multicenter study for primary treatment of localized stage I/II nodal and extra nodal high-grade NHL. The initial therapy consisted in three cycles of high dose CHOP regimen followed by involved field radiotherapy (40Gy). Of the 283 (93%) patients who obtained complete remission (CR), 36 (12.7%) patients relapsed more than 2 years after CR and 28 (9.8%) of them experienced relapse more than three years after CR. Clinical characteristics of patients at diagnosis are summarized in table 1. For the 28 patients who relapsed more than 3 years after diagnosis (group A), the median age was 55 years. There were 17 men and 11 women with predominant histology of diffuse large B cell lymphoma (n=15) and mixed small and large B-cell (n=6). Stage I disease was predominant (n=16) with normal LDH level (n=14). Extranodal disease was present in 11 patients. Most of the patients had no or one IPI risk factor at diagnosis (n=18). Relapses occurred after median CR duration of 84 (36–156) months. Seven patients (7/28; 25%) relapsed as a disseminated lymphoma and 17 of 21 patients who relapsed as a localized disease, relapsed at sites other than those of diagnosis. Only 4 patients relapsed at the same initial site of lymphoma. Nodal relapses remained the most frequent type of relapse (n=18; 64%). However, it is important to note that 10 patients experienced extranodal relapses especially in the central nervous system, the Waldeyer's ring and the gastrointestinal tract. Three patients had multiple extranodal localisations. All relapsed patients received chemotherapy alone (n=20) or followed by autologous stem cell transplantation (n=8). CR was obtained in 13 patients (13/23; 56%), and partial response in 1 patients. Chemotherapy failed in 5 patients and 4 patients deceased from toxicities. At the last follow-up, only 8 (8/24; 33%) patients are still alive and disease free (n=5) or in relapse (n=3). Sixteen patients deceased and lymphoma was the most frequent cause of death (13/24; 54%). In conclusion, late relapses in the setting of localized high grade NHL treated with short course of chemotherapy and involved field radiotherapy are frequent. Relapses occurred frequently at different sites from the initial presentation mostly nodal and extranodal localisations are frequent. The rate of cure for relapsed patients is low and death from lymphoma remains high. The role of novel therapeutic approaches with the addition of rituximab to chemotherapy with or without radiotherapy in preventing late relapses is awaited. More data will be presented at the meetingTable 1: clinical characteristics at diagnosis

Gem-(R)CHOP Versus (R)CHOP: A Randomized Phase II Study of Gemcitabine Combined with (R)CHOP in Untreated Aggressive Non- Hodgkin's Lymphoma - EORTC Lymphoma Group Protocol 20021

Despite recent advances many patients with aggressive NHL succumb to their disease and improvements in front-line chemotherapy are still needed. Gemcitabine is active in lymphoma. We embarked on a randomized phase II trial to determine the efficacy, feasibility and toxicity of the addition of gemcitabine to standard front-line chemotherapy. The trial consisted of two parts. The first part was designed to determine the maximal tolerated dose of gemcitabine and the second to determine the response rate, feasibility and toxicity of the treatment. Patients, 18–70 years old, with stage II–IV previously untreated B-large cell, follicular grade 3, anaplastic large cell or peripheral T cell lymphoma were eligible. They were randomized to receive either 8 cycles of standard CHOP given every 3 weeks or the same treatment combined with gemcitabine (Gem-CHOP). In the second part of the trial patients with B-NHL also received 8 cycles of rituximab (R). The starting dose of gemcitabine was 800 mg/m2 on days 1 and 8. Dose escalation to 1000 and 1250 mg/m2 and reduction to 800 mg/m2 on day 1 only were foreseen. Twenty-five patients, 7 with T and 18 with B-NHL, were enrolled in the trial; 15 in the dose-finding part and 10 in the second part before early closure due to low accrual. Twelve received Gem-(R) CHOP and 13 (R)CHOP. Maximal tolerated dose of gemcitabine was 800 mg/m2 given on days 1 and 8; dose limiting toxicity was hematologic. Five patients (42%) treated with Gem-(R)CHOP achieved CR in comparison to 10 (77%) treated with (R)CHOP. Three out of 4 patients with T-NHL responded to Gem-CHOP and 2 out of 3 to CHOP. Median time to treatment failure was 1.49 years for the Gem-(R)CHOP arm and 3.13 years for the (R)CHOP arm. Four patients receiving Gem-(R)CHOP had serious pulmonary toxicity, as compared to none receiving (R)CHOP. One patient died of severe pneumonitis. The apparently immunologically mediated pulmonary toxicity prompted us to add in the second part of the trial a three-day course of prednisone starting on day 8, together with the second gemcitabine dose. After this change, no additional cases of pulmonary toxicity were seen. The combination of gemcitabine with standard (R)CHOP results in significant but acceptable hematologic toxicity. Maximal tolerated dose of gemcitabine is 800 mg/m2 given on days 1 and 8 every 3 weeks. In this small group of patients, addition of gemcitabine did not seem to improve outcomes. The use of gemcitabine in previously untreated patients with aggressive NHL results occasionally in severe, potentially fatal, pulmonary toxicity. Therefore, further exploration of this combination does not seem to be warranted.

Differential gene expression in murine large cell B-cell lymphoma metastatic variants

Previous studies from this laboratory have characterized RAW117-P murine large cell B-cell lymphoma and its in vivo selected highly malignant and liver metastatic RAW117-H10 subline for their biological and biochemical properties. In this study, to understand the molecular basis of low and high metastatic behavior of these variant sublines, we have investigated the molecular phenotypes of these cells using differential display techniques and cDNA array analysis. Differential display analysis indicated a significant difference in expression of several genes between these two metastatic variant lymphoma cells. Further analyses of these cells using microarray showed an increased expression of several genes including uPAR1, CRE-BP1, Chop-10, IGF, insulin-like growth factor-IA, STAT6, Cyclin-D1, Cyclin-E, ERBB-3, Alpha NGF, Kruppel-like factor LKLF, (P)19INK4 in metastatic RAW117-H10 cells compared to parental RAW117-P cells. On the other hand, MIP1beta, CD14 antigen, Cathepsin B and MOD are expressed more in RAW117-P cells compared to RAW117-H10 cells. Differential expression of the selected genes was confirmed using semiquantitative RT-PCR techniques. The combination of plasminogen activator and its receptor and IGF-like growth factors, cell cycle regulatory molecules and transcription factors might provide an ideal environment for RAW117-H10 cells to metastasize to distant organs and colonize. Thus these results identify certain differentially expressed genes that are involved in the metastatic properties of these lymphoma cells and lay foundation for further in depth analyses to use this information to develop therapy for metastatic lymphoma.

Familial occurrence of sequential B-cell lymphoma and myeloproliferative disease

Dear Editor, A 68-year-old man (case 1) presented with multiple 3-cm scalp nodules. A punch biopsy showed an infiltrate of pleomorphic medium to large size CD20+ve lymphoid cells, compatible with follicular large cell B-cell lymphoma (Fig. 1a). Bilateral marrow staging, complete blood counts, and whole body computerized tomography (CT) were negative. A remission was achieved with R-CEOPx 6 (rituximab, cyclophosphamide, epirubicin, vincristine, and prednisolone). Two years later, he developed polycythemia vera (Fig. 1b; PV: hemoglobin (Hb) 20.6 g/dl, white cell count (WCC) 8.3×10/l, platelet count (Plt): 758×10/l) with Jak2 V617F mutation detected in blood but not in the archival biopsy specimens [1]. He was put on hydroxyurea for 3 years when his 103-year-old father was noticed to have bilateral cervical lymphadenopathy and a monoclonal IgGλ paraprotein 16.7 g/l (case 2). An excision biopsy showed CD20+ve, CD10−ve lymphoplasmacytic lymphoma (Fig. 1c). Bilateral marrow staging and complete blood counts were normal and a CT scan showed no hepatosplenomegaly. He was treated with rituximab four times and chlorambucil (2 mg daily×3 months), with resolution of lymph nodes and monoclonal gammopathy. Three months later, however, he presented with persistent leukocytosis (Hb: 9.6 g/dl, WCC: 18.3×10/l, Plt: 93×10/l). A marrow biopsy showed markedly hypercellular particles with dysplastic megakaryocytes and ring sideroblasts (Fig. 1d) compatible with myeloproliferative disease (MPD-unclassified). Cytogenetic study, Jak2 mutation, and tumor marker screening were negative. Despite rising WCC, he remained asymptomatic (Hb: 8.6 g/dl,WCC 32.5×10/l, Plt: 62×10/l) but died of cerebrovascular accident 1 year from initial presentation. Four siblings and three offspring of case 1 had no evidence of lymphoma, Jak2 mutation, or hematological abnormality. To the best of our knowledge, this is the first familial occurrence of lymphoma followed by t-MPD. The genetic markers for familial lymphoma and familial MPD are both unknown. Similar to our cases, both entities show genetic anticipation [2, 3], and the individual lymphoma and MPD entities may be discordant [4]. Therapy-related MPD, PV, and CML after lymphoma treatment has occasionally been reported [5–7]. Although this may be a chance association, lymphoma patients may have genetic predisposition to MPD. Low levels of Jak2 mutation have been detected in lymphoma marrow specimens [8]. Patients with myeloid malignancies also have increased familial risk of lymphoma and vice versa [9]. Hence, a genetic link between familial lymphoma and familial MPD is also possible. It is interesting to note that with prolonged and detailed follow-up, more idiopathic MPD cases actually turn out to be familial in nature [3]. The recognition of these index families with distinct patterns of malignancies may be invaluable to future research on disease pathogenesis for both entities. Ann Hematol (2008) 87:931–932 DOI 10.1007/s00277-008-0503-y

超音波内視鏡下吸引細胞診(EUS-FNA）が有用であった膵悪性リンパ腫の1例

A 57-year-old woman was admitted to the hospital because of obstructive jaundice. Abdominal computed tomography and ultrasonography showed a homogeneous mass 7cm in diameter at the head of the pancreas. Gamma-scintigraphy showed uptake in the head of the pancreas. Histological diagnosis was obtained by endoscopic ultrasoundscopy-fine needle aspiration (EUS-FNA). The pathological and immunohistochemical studies showed diffuse lymphoma with large B-cells. We experienced a rare case of pancreatic malignant lymphoma and EUS-FNA was usefull in the diagnosis.

Monomorphic post-transplant lymphoproliferative disorder of the tongue: case report and review of literature

BackgroundPost-transplant lymphoproliferative disorder (PTLD) is a spectrum of hematological diseases arising in context of immunosuppression after organ transplantation. PTLD can involve any organ; however, it is extremely rare in oral cavity.MethodsUsing morphologic and immunophenotypic approaches we have studied a case of monomorphic PTLD of the tongue that developed in a patient following unilateral kidney and pancreas transplantation on immunosuppressive therapy. Additionally, cases of PTLD in the oral cavity were reviewed in the English literature.ResultsThe neoplasm showed large cell morphology and B-cell phenotype. In situ hybridization for Epstein-Barr virus was positive. Complete remission was obtained after decreasing immunosuppressive therapy. The patient remained in remission at 790 days' follow up.ConclusionThis rare case increased our awareness of PTLD in the oral cavity of patients following solid organ transplantation and immunosuppressive therapy.

Chylous ascites secondary to B-cell non Hodgkin's lymphoma in a patient with the acquired immune deficiency syndrome (AIDS)

In the present article we describe a patient with AIDS and chylous ascites secondary to B-cell non Hodgkin's lymphoma. A 43 years old homosexual HIV-positive man. Complained of abdominal fullness, diarrhea and a rapidly increase in abdominal girth of 1 week duration. A diagnostic paracentesis was performed and revealed a milky fluid with high triglyceride levels. All blood tests and analysis of the peritoneal fluid with polymerase chain reaction for DNA sequence of broad-range bacterial Post Voiding Residual volume, Mycobacterium tuberculosis, Kaposi Sarcoma associated Herpes virus and Epstein Barr Virus were negative. CT scan did not demonstrate any evidence for cancer. An exploratory laparotomy was thus performed. A mass spreading along the mesenteric route to the omentum was found and a debulking resection was performed. The final pathology report was of diffuse, CD20-positive, CD3-negative, Epstein Barr Virus-negative, large B-Cell non Hodgkin's lymphoma. Subsequently, he underwent five cycles of CHOP (cyclofosfamide, doxorubicin, vincristin, prednison) chemotherapy with further partial regression of the abdominal tumour. Five months after the initial diagnosis of lymphoma, the patient relapsed and was treated with high-dose BEAM (carmustine, etoposide, cytosine, arabinoside, melphalan) chemotherapy followed by CD34 stem-cell transplantations salvage therapy. This notwithstanding, the patient died due to intestinal secondary to tumor relapse 2 months later.

Aberrant phenotypes and quantitative antigen expression in different subtypes of canine lymphoma by flow cytometry

Flow cytometry may be a useful tool to analyze lymphoma samples that are obtained from fine needle aspirations (FNA). This study aimed to determine if flow cytometric analysis add more objective and standardized information on the cellularity and morphology of lymphoma cells to conventional cytology. The typical immunophenotype of different lymphoma subtypes was assessed and leukocyte marker expression was evaluated to determine which antigens were more frequently over- or under-expressed in these lymphoma subtypes. Fifty FNA lymph node samples were evaluated from canine lymphomas. Thirty-one samples were identified to be of B-cell origin, sixteen were identified to be of T/NK-cell origin and three cases were classified as acute lymphoblastic leukaemia with lymph nodes involvement. The most common B-cell lymphoma subtypes were centroblastic lymphomas, whereas three cases were atypical and classified as B-large cell pleomorphic lymphomas. Among the T/NK lymphomas, small clear cells, large and small pleomorphic mixed cells, large granular lymphocytic cells and small pleomorphic cells were identified. Aberrant phenotypes and/or antigen under/over regulation was identified in thirty out of forty-seven lymphoma cases (64%; 18/31 B-cell = 58% and 12/16 T-cell = 75%). In B-cell lymphomas the most frequent finding was the diminished expression of CD79a (45%). CD34 expression was also observed in four cases (13%). Among T-cell lymphomas the prevalent unusual phenotype was the under-expression or absence of CD45 (25%). These findings reveal flow cytometry may be useful in confirming the diagnosis of lymphoma, as the technique allows one to add useful information about morphology of the neoplastic cells and identify antigenic markers and aberrant phenotypes.