Lenalidomide in combination with vorinostat and dexamethasone for the treatment of relapsed/refractory peripheral T cell lymphoma (PTCL): report of a phase I/II trial.

Given the poor outcome of relapsed and refractory peripheral T cell lymphoma (PTCL), we explored a combination of lenalidomide, vorinostat, and dexamethasone to test the feasibility of this therapy in relapsed and refractory PTCL. Eight patients were accrued: two peripheral T cell lymphoma, unspecified; five angioimmunoblastic T cell lymphoma; and one ALK-negative anaplastic large-cell lymphoma. A dose escalation of lenalidomide (days 1-21, q28) was planned using a 3 + 3 design. As two patients treated with 10 mg/day experienced dose-limiting toxicity (thrombocytopenia grade 3, stroke grade 4), the primary end point of our trial was reached; the maximal tolerable dose of lenalidomide was 5 mg/day (level -I). Adverse events grade ≥3 were observed as thrombocytopenia (23 %), leukocytopenia (15 %), anemia (8 %), and neutropenia (8 %). One complete remission (10.3 months), one partial remission (11.3 months), one stable disease (11.9 months), and four progressive disease (overall response rate 25 %) were observed. The median progression-free survival was 2.2 months and the median OS was 6.7 months. In conclusion, the poor results obtained with lenalidomide in combination with vorinostat and dexamethasone provide no arguments that could justify further investigation of this drug combination for the treatment of relapsed PTCL.

Bortezomib in plasmablastic lymphoma: a case report and review of the literature.

BACKGROUND: Plasmablastic lymphoma (PBL) is an aggressive subtype of non-Hodgkin's lymphoma (NHL). While classically associated with the human immunodeficiency virus (HIV), cases of PBL in immunocompetent patients have been increasingly described. PBL shares common morphological and immunohistochemical features with diffuse large B-cell lymphoma (DLBCL) and multiple myeloma (MM). Due to the rarity of PBL, there is no current consensual standard therapy available. As a result, PBL treatment is mirrored after aggressive NHL regimens. One of the newly emerged therapeutic options for PBL is bortezomib, which is a proteasome inhibitor and a cornerstone in MM therapy. In recently published cases, bortezomib has shown promising results in PBL. CASE REPORT: In this report, we describe a patient with HIV-negative PBL who dramatically responded to bortezomib after failing several other lines of therapy. We also review 4 other, similar cases reported in the literature. RESULTS AND CONCLUSION: We conclude that bortezomib resulted in rapid and dramatical responses regardless of the line of therapy. Although most of these responses were not sustained, bortezomib represents a new therapeutic option for PBL that should be further explored in larger clinical trials.

Plasmablastic lymphoma of the stomach in an HIV-negative patient.

Plasmablastic lymphoma (PBL) is a rare B-cell neoplasm with an aggressive clinical behavior that predominantly occurs in the oral cavity of human immunodeficiency virus (HIV)-positive patients. However, it has recently been recognized that PBLs can also affect individuals without HIV infection, and suggested that these neoplasms show different clinicopathological characteristics between HIV-positive and -negative patients. Herein we describe a case of gastric PBL in a female HIV-negative patient. The tumor was composed of a diffuse and cohesive proliferation of large neoplastic cells, which resembled immunoblasts or plasmablasts with a starry sky appearance. Immunophenotypically, the neoplastic cells were diffusely positive for CD138, MUM1, IgM, and BOB-1, and negative for CK, LCA, CD3, CD20, CD79a, Pax5, kappa, lambda, CD30, ALK, S-100, HMB-45, MPO, and HHV-8. The MIB-1 index was nearly 100%. Epstein-Barr virus-encoded RNA in situ hybridization was negative. A monoclonal immunoglobulin heavy chain gene rearrangement was detected in polymerase chain reaction (PCR) and heteroduplex analyses. A combination of PCR-based analysis of immunoglobulin gene rearrangement and immunohistochemistry can be useful to substantiate the diagnosis by utilizing routine paraffin-embedded tissue sections, because PBL in the setting of extra-oral localization and immunocompetence is a diagnostic challenge, given its rarity, morphology, and absence of CD20 expression.

Paying more than lip service to an oral lesion: a case of plasmablastic lymphoma.

Plasmablastic lymphoma (PBL) is a variant of lymphoma originally described in the oral cavity of patients with advanced HIV. Our patient developed PBL despite well-controlled HIV and a CD4 count greater than 800 cells/µl. A drug interaction with an inhaled corticosteroid and ritonavir likely contributed to the development of this malignancy through increased immune suppression.

Unusual presentation of gastric plasmablastic lymphoma in HIV-negative patient.

Plasmablastic lymphoma (PBL) has initially been described as a rapidly progressive and almost invariably fatal diffuse large-cell lymphoma with plasmablastic features, exclusively involving the jaw and oral mucosa in HIV-positive patients. Although its clinical features may help in differential diagnosis, an extra-oral localization in a patient without HIV makes it more difficult to suspect clinically. We describe a very rare case of gastric PBL primarily involving stomach in a middle age man without an HIV infection. A biopsy was performed and its findings revealed a diffuse, monomorphous proliferation of the tumor cells with features of immunoblasts, MUM-1, EMA, and lambda light chains positive. Serology was negative for the human immunodeficiency virus (HIV), HBsAg, and hepatitis C virus infection. The patient started treatment with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy, but unfortunately died before the second cycle was given. To our knowledge, this is the second case of gastric PBL presented in HIV-negative patients. The findings in this case suggest that PBL should be included in the differential diagnosis of gastrointestinal tumors.

Uniform expression of Notch1, suppressor of B-cell-specific gene expression, in plasmablastic lymphoma.

CONTEXT: Although the loss of B-lineage-specific gene expression is a distinctive feature of plasmablastic lymphoma, the underlying mechanism remains poorly understood. A candidate for this mechanism is Notch1 signaling, which interferes with the activity of B-cell-specific transcription factors E2A and early B-cell factor and positively regulates the mammalian target of rapamycin (mTOR) pathway. OBJECTIVE: To explore the mechanism of loss of B-cell phenotype by correlating expression of B-cell markers with that of Notch1 and downstream targets of the mTOR pathway in plasmablastic lymphoma. DESIGN: A combination of flow cytometric and immunohistochemical immunophenotyping techniques was used on 9 cases of plasmablastic lymphoma to correlate loss of B-cell markers with expression of Notch1 and downstream activation of the mTOR pathway. These results are compared with 5 cases of primary effusion lymphoma and 21 cases of plasma cell myeloma. RESULTS: Plasmablastic lymphoma cases exhibit nearly complete loss of B-cell-associated markers and uniform expression of Notch1, with a predominantly nuclear staining pattern. There is a concurrent activation of the mTOR pathway, indicated by expression of mTOR targets eukaryotic initiation factor 4E-binding protein 1 and phosphorylated ribosomal protein S6 in most cases. Similar results are seen in cases of primary effusion lymphoma and plasma cell myeloma. CONCLUSIONS: These findings suggest that activation of Notch1 may be involved in suppression of B-cell-specific gene expression and global loss of the B-cell phenotype in plasmablastic lymphoma, similar to primary effusion lymphoma and plasma cell myeloma. Thus, there might be a role for the Notch1 and mTOR pathways in the pathogenesis and therapy of plasmablastic lymphoma.

HIV-negative plasmablastic lymphoma: not in the mouth.

Plasmablastic lymphoma (PBL) is an aggressive variant of non-Hodgkin lymphoma initially reported in the oral cavity of HIV-positive individuals. Since its original description, several cases have been reported in patients who do not have HIV infection. However, despite its recognition as a distinct subtype of diffuse large B-cell lymphoma several years ago, comprehensive reviews of this entity are lacking. A MEDLINE search through June 2010 was performed to identify cases with a pathologic diagnosis of HIV-negative PBL based on morphology and minimal immunohistochemical criteria. Our study included a total of 76 cases. The median age was 57 years (range, 1 to 90 years) with a male-to-female ratio of 1.7. Seventy-four percent of cases did not have an apparent association with immunosuppression, 18% had a concurrent lymphoproliferative or autoimmune disorder and 9% developed PBL after solid organ transplantation. Oral involvement was observed in 21%, advanced stage in 60%, Epstein-Barr virus-encoded RNA expression was positive in 45% and Ki-67 expression of greater than or equal to 80% in 61% of the cases. Chemotherapy was documented in 43 patients, from which 43% received the cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP)-like regimens. The median and the 2-year overall survival for the whole group were 9 months and 10%, respectively. Patients who had HIV-negative PBL have distinct clinicopathological characteristics, such as short overall survival and lower rates of oral involvement and Epstein-Barr virus-encoded RNA expression than the previously reported in HIV-positive patients.

Bilateral acute angle-closure associated with systemic lymphoma: a report of 2 cases.

Bilateral acute angle-closure is a rare occurrence. When the central anterior chambers are shallow, it is often associated with systemic disease. We present 2 patients with atypical bilateral acute angle-closure as the presentation of systemic lymphoma. In these patients, angle closure may be caused by a uveal effusion or swelling of the ciliary body. If an atypical bilateral acute angle-closure attack cannot be attributed to a drug reaction or a bilateral iatrogenic cause, the patient should be evaluated for an associated systemic disease. In some patients, the acute angle-closure cannot be fully resolved until the underlying disease is treated. This report discusses the spectrum of presentations and the various diseases that have been associated with bilateral acute angle-closure.

Primary hepatic (extranodal) lymphoma: utility of [(18)F]fluorodeoxyglucose-PET/CT.

Primary hepatic lymphoma is extremely rare. Although the utility of fluorodeoxyglucose (FDG)-positron emission tomography (PET) for imaging extranodal lymphoma has been reported, there is very little literature describing its use in primary hepatic lymphoma. This case report demonstrates the effect of FDG-PET/computed tomography (CT) in a case of unifocal primary hepatic lymphoma and its usefulness in the assessment of treatment response.

Concurrent classical Hodgkin lymphoma and plasmablastic lymphoma in a patient with chronic lymphocytic leukemia/small lymphocytic lymphoma treated with fludarabine: a dimorphic presentation of iatrogenic immunodeficiency-associated lymphoproliferative disorder with evidence suggestive of multiclonal transformability of B cells by Epstein-Barr virus.

A small fraction of patients with chronic lymphocytic leukemia/small lymphocytic lymphoma develop Epstein-Barr virus-positive B-cell lymphoproliferative disorders. These Epstein-Barr virus-B-cell lymphoproliferative disorders are thought to be related to immune suppression induced by fludarabine/other chemotherapeutic regimens. As in other immunodeficiency-associated lymphoproliferative disorders, these disorders demonstrate a heterogeneous histological spectrum that ranges from polymorphic to monomorphic to classical Hodgkin lymphoma-like lesions. We report a case of concurrent classical Hodgkin lymphoma and plasmablastic lymphoma in a patient with chronic lymphocytic leukemia/small lymphocytic lymphoma treated with fludarabine. Both classical Hodgkin lymphoma and plasmablastic lymphoma were positive for Epstein-Barr virus-encoded RNA, whereas classical Hodgkin lymphoma was also positive for Epstein-Barr virus- latent membrane protein 1, suggesting a different viral latency. Immunoglobulin gene rearrangement studies demonstrated distinct clones in the plasmablastic lymphoma and chronic lymphocytic leukemia/small lymphocytic lymphoma. These findings suggest biclonal secondary lymphomas associated with iatrogenic immunodeficiency. Epstein-Barr virus-B-cell lymphoproliferative disorders in the setting of chronic lymphocytic leukemia/small lymphocytic lymphoma, in particular those arising after chemotherapy, should be separated from true Richter's transformation, and be categorized as (iatrogenic) immunodeficiency-associated lymphoproliferative disorder.

A meta-analysis of highly active anti-retroviral therapy for treatment of plasmablastic lymphoma.

BACKGROUND AND OBJECTIVES: Plasmablastic lymphoma is a recently described B-cell derived lymphoma. The prognosis of plasmablastic lymphoma patients is usually poor. We performed a systematic review of the literature on the use of highly active anti-retroviral therapy (HAART) and the prognosis of plasmablastic lymphoma. METHODS: A comprehensive search of relevant databases, including Medline, Embase, the Cochrane Controlled Trials Register, the Cochrane Library, and the Science Citation Index yielded ten randomized controlled trials. Trials were divided into two groups according to therapy. The rates of plasmablastic lymphoma were analyzed using a fixed-effects model. Sensitivity analyses (on publication type, statistical model) were performed to further detect and evaluate clinically significant heterogeneity. Tests of survival for plasmablastic lymphoma were also performed by using Kaplan-Meier method. RESULTS: Meta-analysis result showed that the prognosis of plasmablastic lymphoma patients was statistically different in the patients receiving HAART in addition to chemotherapy and/or radiotherapy than in the patients receiving the chemotherapy and/or radiotherapy alone (pooled relative risk=3.04; P=.03). Survival analyses also displayed a statistically significant difference (chi-square=6.22, P=.013). CONCLUSION: HAART in addition to chemotherapy and/or radiotherapy is effective in improving the prognosis of plasmablastic lymphoma. However, the small sample sizes increase the likelihood of bias in the studies in this meta-analysis, and therefore, the results should be taken cautiously.

Prognostic factors in chemotherapy-treated patients with HIV-associated Plasmablastic lymphoma.

BACKGROUND: Plasmablastic lymphoma (PBL) is a variant of diffuse large B-cell lymphoma commonly seen in the oral cavity of HIV-infected individuals. PBL has a poor prognosis, but prognostic factors in patients who have received chemotherapy have not been adequately evaluated. METHODS: An extensive literature search rendered 248 cases of PBL, from which 157 were HIV(+). Seventy cases with HIV-associated PBL that received chemotherapy were identified. Whenever possible, authors of the original reports were contacted to complete clinicopathological data. Univariate analyses were performed calculating Kaplan-Meier estimates and compared using the log-rank test. RESULTS: The mean age was 39 years, with a male predominance. The mean CD4(+) count was 165 cells/mm(3). Advanced clinical stage was seen in 51% and extraoral involvement was seen in 43% of the cases. The expression levels of CD20 and Epstein-Barr virus-encoded RNA were 13% and 86%, respectively. The overall survival duration was 14 months. In a univariate analysis, early clinical stage and a complete response to chemotherapy were associated with longer survival. There was no apparent difference in survival with regimens more intensive than cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). CONCLUSIONS: Patients with HIV-associated PBL have a poor prognosis. Prognosis is strongly associated with achieving a complete clinical response to CHOP or CHOP-like chemotherapy. The role of more intensive regimens is currently unclear. Further research is needed to improve responses using novel therapeutic agents and strategies.

[Febrile cellulitis surrounding a scar revealing a large immunoblastic B-cell lymphoma]. / Dermohypodermite fébrile péricicatricielle révélatrice d'un lymphome B immunoblastique à grandes cellules.

BACKGROUND: Secondary skin sites of lymphoma appear in the advanced stages of the disease. We report the first case of a pericicatricial skin infiltration, mimicking febrile dermohypodermitis, revealing diffuse immunoblastic large B-cell non-Hodgkin's lymphoma. PATIENTS AND METHODS: Four months after decompressive cervical laminectomy, a 56-year-old man presented an inflammatory pericicatricial patch evoking cellulitis in a setting of hyperthermia and lymphadenopathy. Blood cultures and bacteriological analysis of skin biopsy samples were negative. The images showed infiltration of the soft subcutaneous areas and polyadenopathy. Two weeks later, several subcutaneous nodules appeared on the trunk. Histological analysis and immunolabelling pointed to immunoblastic large B-cell non-Hodgkin's lymphoma. A clone of B lymphocytes CD45+, CD20+, CD79a+, Bcl2+, CD5+, MUM1+, CD3-, CD10-, CD23- and Bcl6- was seen. The remainder of the extension examination was negative. CHOP-rituximab polychemotherapy resulted in complete regression of all lesions, notably the inflammatory cervical plaque. DISCUSSION: Secondary skin manifestations of lymphoma are generally non-specific (pruritus, ichthyosis, purpura, etc.) rather than specific in terms of lymphoid infiltration. As in our patient, certain cutaneous sites of lymphoma may have a misleading clinical presentation, histological analysis alone was able to provide a conclusive diagnosis. In our patient, the highly specific infiltration seen around the entire scar could either suggest a Koebner phenomenon or point to a role of the cutaneous aggression within the development of an inflammatory process contributing to pericicatricial infiltration by lymphoid cells. Locoregional invasion from the osseous part of the cervical spine and not macroscopically diagnosed during neurosurgery could also be responsible.

Primary meningeal CNS lymphoma treated with intra-arterial chemotherapy and blood-brain barrier disruption.

Diffuse large B-cell lymphoma of the meninges is a particularly rare form of primary CNS lymphoma. We report a case of a 63-year-old woman found to have primary meningeal lymphoma (PML) with dural and leptomeningeal involvement whom we treated with multiple cycles of intra-arterial (IA) methotrexate, intravenous (IV) etoposide phosphate, and IV cyclophosphamide after reversible osmotic blood-brain barrier disruption (BBBD). Improvement was evident on gadolinium-enhanced brain MRI one month into therapy. At 67 months post-diagnosis there is no evidence of CNS disease. After completing her therapy regimen, she remained disease-free for 34 months, when stage IV diffuse large B-cell lymphoma was discovered in her left adrenal gland and right thigh. Following six cycles of rituximab and CHOP treatment, she is presently in complete remission. IA methotrexate and reversible osmotic BBBD without radiation therapy may be an effective therapy for treating PML.

Plasmablastic lymphoma in the orbit: case report.

Plasmablastic lymphoma (PBL) is a rare entity most commonly identified in the oral cavity of immunodeficient patients. The immunophenotype of this condition shows a poor expression for B-cell markers but, in contrast, a strong reactivity for well-differentiated plasma cells markers, such as CD138, CD38, and epithelial membrane antigens. PBL survival is limited due to its highly aggressive local and metastatic behavior and poor response to treatment. Although it can involve different organs, there have been only a few cases involving the ocular adnexa. We describe a case of atypical rapidly progressive pre-septal brawny induration affecting the right orbit in a patient with HIV-related lymphoma.