Bone marrow involvement by subcutaneous panniculitis-like T-cell lymphoma: a report of three cases.

Subcutaneous panniculitis-like T-cell lymphoma is a rare subtype of cutaneous T-cell lymphoma. Virtually all cases are confined to the subcutaneous adipose tissue. In this report, we describe the first small series of subcutaneous panniculitis-like T-cell lymphoma (three patients) with bone marrow involvement. All patients presented with skin or soft tissue nodules, fever, and constitutional symptoms, and were diagnosed with subcutaneous panniculitis-like T-cell lymphoma based on the characteristic morphologic and immunophenotypic features of the subcutaneous lesions. Bone marrow core biopsies in these cases showed focal involvement by lymphoma with pathologic features similar to those seen in the diagnostic biopsies. Our observations suggest bone marrow involvement by subcutaneous panniculitis-like T-cell lymphoma does occur, and can be identified histologically and confirmed using standard immunohistochemistry. Our findings raise awareness of bone marrow involvement in this rare entity. However, the incidence and significance of bone marrow involvement in subcutaneous panniculitis-like T-cell lymphoma requires further evaluation.

Primary cutaneous and systemic anaplastic large cell lymphoma: clinicopathologic aspects and therapeutic options.

Anaplastic large cell lymphoma (ALCL) is a biologic and clinically heterogenous subtype of T-cell lymphoma. Clinically, ALCL may present as localized (primary) cutaneous disease or widespread systemic disease. These two forms of ALCL are distinct entities with different clinical and biologic features. Both types share similar histology, however, with cohesive sheets of large lymphoid cells expressing the Ki-1 (CD30) molecule. Primary cutaneous ALCL (C-ALCL) is part of the spectrum of CD30+ lymphoproliferative diseases of the skin including lymphomatoid papulosis. Using conservative measures, 5-year disease-free survival rates are > 90%. The systemic ALCL type is an aggressive lymphoma that may secondarily involve the skin, in addition to other extranodal sites. Further, systemic ALCL may be divided based on the expression of anaplastic lymphoma kinase (ALK) protein, which is activated most frequently through the nonrandom t(2;5) chromosome translocation, causing the fusion of the nucleophosmin (NPM) gene located at 5q35 to 2p23 encoding the receptor tyrosine kinase ALK. Systemic ALK+ ALCLs have improved prognosis compared with ALK-negative ALCL, although both subtypes warrant treatment with polychemotherapy. Allogeneic and, to a lesser extent, autologous stem cell transplantation play a role in relapsed disease, while the benefit of upfront transplant is not clearly defined. Treatment options for relapsed patients include agents such as pralatrexate (Folotyn) and vinblastine. In addition, a multitude of novel therapeutics are being studied, including anti-CD30 antibodies, histone deacetylase inhibitors, immunomodulatory drugs, proteasome inhibitors, and inhibitors of ALK and its downstream signaling pathways. Continued clinical trial involvement by oncologists and patients is imperative to improve the outcomes for this malignancy.

A phase II clinical trial of intensive chemotherapy followed by consolidative stem cell transplant: long-term follow-up in newly diagnosed mantle cell lymphoma.

Mantle cell lymphoma (MCL) is associated with high relapse rates and poor survival when treated with conventional chemotherapy, with or without rituximab. We report the long-term follow-up of a phase II clinical trial using a new intensive multiagent chemotherapeutic regimen [cyclophosphamide, teniposide, doxorubicin and prednisone (CTAP) alternating with vincristine and high-dose methotrexate and cytarabine (VMAC)] in newly diagnosed MCL. Following 4-6 cycles of CTAP/VMAC induction, patients aged < or =65 years proceeded to consolidative autologous haematopoietic stem cell transplantation (auto-HSCT), while patients < or =55 years who had a HLA-identical sibling received allogeneic-HSCT (busulfan/cyclophosphamide conditioning for both). Twenty-five untreated MCL patients enrolled on the protocol between 1997 and 2002. Among evaluable patients, overall response rate (ORR) was 74% following induction chemotherapy. Seventeen patients received HSCT (autologous-13/allogeneic-4). On intent-to-treat analysis, ORR for patients who received consolidative HSCT was 100% (complete remission 76%). Therapy was well-tolerated with 4% treatment-related mortality (including HSCT). The 5-year event-free-survival (EFS) and overall survival (OS) for all patients was 35% and 50% respectively. Furthermore, at 66-months median follow-up, the 5-year EFS and OS for patients who received consolidative auto-HSCT was 54% and 75% respectively. Patients who received auto-HSCT had improved outcomes compared to no auto-HSCT (EFS P = 0.001; OS P = 0.0002). CTAP/VMAC induction followed by consolidative auto-HSCT for newly diagnosed MCL is associated with high ORR and durable survival.

Hypoxia inducible factor-alpha activation in lymphoma and relationship to the thioredoxin family.

Hypoxia inducible factors (HIFs) activate oncogenic pathways, while thioredoxins (Trx), including Trx1 and Trx reductases-1 and -2 (TrxR1 and TrxR2), promote HIF-alpha stabilization. In immunoblotting studies in lymphoma cell lines we found that Raji and SUDHL4 cells exhibited normoxic HIF-2alpha protein stabilization. Five cell lines showed increased TrxR1 expression, while only Namalwa, HF1 and SUDHL4 had Trx1 and TrxR2 activation. Tissue microarrays in diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) identified different HIF expression among histological subgroups (e.g. 44% DLBCL vs. 11% of FL cases with moderate-to-high expression of HIF-1alpha and HIF-2alpha, P = 0.0017). These data demonstrate that HIF and the thioredoxin family are abnormally activated in lymphoma.

Instability of immunophenotype in plasma cell myeloma.

Little information has been reported describing antigen stability in plasma cell myeloma. In this study, the expression frequency and stability of 2 potential therapeutic targets, CD20 and CD52, along with the frequently aberrantly expressed CD56 antigen, were evaluated by flow cytometric analyses in 56 patients with plasma cell myeloma. Of the 56 patients, 23 (41%) showed immunophenotype change, including CD56 in 6 cases, CD20 in 7 cases, and CD52 in 17 cases. Combined CD56/CD52 change was seen in 3 cases and combined CD20/CD52 in 4 cases. No correlation was found between immunophenotype change and age, sex, stage, plasma cell morphologic features, extent of marrow involvement, time between analyses, type of therapy, or response to therapy. Immunophenotype shift was more common in patients with IgA than in patients with IgG paraprotein. Recognition of lack of stability in immunophenotype may be important, especially in antigen-directed treatment decisions and when specific phenotypes are used to detect residual disease.

CD23+ mantle cell lymphoma: a clinical pathologic entity associated with superior outcome compared with CD23- disease.

Mantle cell lymphoma (MCL) commonly lacks expression of CD23. However, a significant minority of MCLs express CD23, as assessed by flow cytometric immunophenotyping (FCIP). The aims of our study were to investigate the expression of CD23 by FCIP in patients with MCL and to correlate CD23 expression with pathologic and clinical parameters, including outcome. We studied 53 patients with untreated MCL who had CD23 expression determined by FCIP. At diagnosis, 14 MCLs (26%) were CD23+ at all tissue sites, whereas 33 (62%) were CD23-, and 6 (11%) had discordant CD23 expression among different tissue sites. Patients with CD23- MCL had extranodal disease more commonly compared with patients with CD23+ MCL. Moreover, with 57-month median follow-up, the 4-year event-free and overall survival rates for CD23+ MCL were 45% and 75%, respectively, compared with 19% and 51% for CD23- MCL. In multivariate Cox regression analysis, CD23 status and leukemic-phase MCL were the most important factors predicting outcome.

Chronic lymphocytic leukemia FISH panel: impact on diagnosis.

Interphase fluorescence in situ hybridization (FISH) is an alternative to conventional chromosome analysis of chronic lymphocytic leukemia (CLL) cells. We analyzed 172 samples from 136 possible CLL cases using a FISH panel. Reflex testing with probes to CCND1, BCL2, BCL3, BCL11A, c-MYC, MALT1, and a break-apart immunoglobulin heavy chain (IGH) probe was done if more than 2 signals for 14q32 occurred. For 111 cases, there were sufficient data for analysis. Of 111 cases, 81 (72.9%) had 1 or more genetic abnormalities. The most frequent abnormality was 13q-, followed by trisomy 12, 11q-, and 17p-. In 13 cases, there were IGH abnormalities. Two cases with CCND1/IGH fusion were reclassified as mantle cell lymphoma. Four CLL cases had IGH fusion with BCL2, BCL3 (2 cases), and BCL11A; no fusion partner was detected in 7 cases. Morphologic features were atypical for CLL in 2 cases with IGH fusion (BCL11A and BCL3). The FISH CLL panel is useful to identify prognostic aberrations and to clarify diagnosis in cases with unusual morphologic features.

Surface immunoglobulin positive lymphoblastic leukemia in adults; a genetic spectrum.

Precursor B-lymphoblastic leukemia is typically surface immunoglobulin (sIg) negative. Although rare cases of sIg+ precursor lymphoblastic leukemia are recognized, sIg+ leukemia often represent leukemic phase of Burkitt lymphoma or other non-Hodgkin lymphoma such as blastic mantle cell lymphoma. This study reports four adults, two women (56 and 58 years old) and two men (35 and 41 years old) with lymphoblastic leukemia that displayed lambda, surface immunoglobulin restriction (sIg+). The leukemic cells were all dim CD45 positive with side scatter light characteristic of blasts. Two cases were positive with the blasts associated with antigens TdT and CD34. Genetic abnormalities were detected in all cases and in three cases included abnormalities commonly present in precursor lymphoblastic leukemia. Translocation (1;19) (q23;p13) was present in the first case. Deletion of the 3' region of the mixed lineage leukemia (MLL) gene at chromosome 11q23 as well as t(14;18) were detected in the second case. In the 3rd case, a BCR-ABL fusion gene was detected as part of a complex abnormal karyotype. Translocation (1;19)(q23;p13) was present in one case. Deletion of the 3' region of the mixed lineage leukemia (MLL) gene at chromosome 11q23 as well as t(14;18) were detected in one case. BCR-ABL fusion gene was detected as part of a complex abnormal karyotype in one case. These cases illustrate that lymphoblastic leukemias occurring in adults exhibit a morphologic, immunophenotypic as well as a genetic spectrum and represent either non-Hodgkin lymphoma or precursor lymphoblastic leukemia. A multi-parameter approach including flow cytometric and genetic studies is crucial in separating these cases.

Classical Hodgkin's lymphoma presenting with tongue involvement: a case report and review of the literature.

We report an unusual case of mixed cellularity classical Hodgkin's lymphoma with prominent involvement of the base of the tongue at diagnosis. In situ hybridization findings for Epstein-Barr virus were positive. Waldeyer's ring involvement by Hodgkin's lymphoma is uncommon with < 200 cases reported in the English literature and only 5 previous reports of Hodgkin's lymphoma involving the tongue.

Characterization of tissue findings in bone marrow biopsy specimens with small monoclonal B-cell populations.

OBJECTIVES: Bone marrows (BMs) with incidentally identified, small monotypic B-cell populations (MBPs) were evaluated. METHODS: BM aspirates with MBPs representing 5% or less of total events by flow cytometry, less than 5.0 × 10(9)/L B cells in blood, and no history of lymphoma or MBP with a different phenotype from prior lymphoma were selected. Clinical, immunophenotypic, and histologic findings were evaluated. RESULTS: Forty-one of 3,052 BMs had MBPs at 5% or less of total events (median, 1%); 17 were females and 24 were males aged 30 to 87 years (median, 73 years). The MBPs were CD5- in 24, CD5+ resembling chronic lymphocytic leukemia (CLL) in 13, and CD5+ unlike CLL in four. Eighteen of 40 had lymphoid aggregates (LAs) with mostly T cells or a mixture of B and T cells, but three cases had B-cell-rich LAs. CONCLUSIONS: Unlike monoclonal B lymphocytosis in blood, MBPs in BMs were more commonly CD5-. Forty-five percent of BMs had LAs; none were interpreted as lymphoma, although three were suspicious for B-cell lymphoma.

Post-transplant lymphoproliferative disease (PTLD): risk factors, diagnosis, and current treatment strategies.

Post-transplant lymphoproliferative diseases (PTLD) are heterogeneous lymphoid disorders ranging from indolent polyclonal proliferations to aggressive lymphomas that complicate solid organ or hematopoietic transplantation. Risk factors for PTLD include viral infections, degree of immunosuppression, recipient age and race, allograft type, and host genetic variations. Clinically, extra-nodal disease is common including 10-15 % presenting with central nervous system (CNS) disease. Most PTLD cases are B cell (5-10 % T/NK cell or Hodgkin lymphoma), while over one-third are EBV-negative. World Health Organization (WHO) diagnostic categories are: early lesions, polymorphic, and monomorphic PTLD; although in practice, a clear separation is not always possible. Therapeutically, reduction in immunosuppression remains a mainstay, and recent data has documented the importance of rituximab +/- combination chemotherapy. Therapy for primary CNS PTLD should be managed according to immunocompetent CNS paradigms. Finally, novel treatment strategies for PTLD have emerged, including adoptive immunotherapy and rational targeted therapeutics (e.g., anti-CD30 based therapy and downstream signaling pathways of latent membrane protein-2A).

Early posttransplant lymphoproliferative disease: clinicopathologic features and correlation with mTOR signaling pathway activation.

Early posttransplant lymphoproliferative disorders (EPTLDs) represent the first changes in posttransplant lymphoproliferative disorders (PTLDs) morphologic spectrum. EPTLD data are available mostly from case reports and series that include other types of PTLD. Fifteen EPTLDs were reviewed retrospectively. Clinical data, histopathology, clonality, and Epstein- Barr virus (EBV) status were correlated with staining intensity to an antibody for phosphorylated S6 (pS6) ribosomal protein, a downstream effector of mammalian target of rapamycin (mTOR). Median time from transplantation to EPTLD was 50 months (range, 7-135 mo). EPTLDs involved tonsil and/or adenoids (n = 11) and lymph nodes (n = 4), all of which were nonclonal and EBV-encoded RNA-positive. Most (n = 11) were plasmacytic hyperplasia and florid follicular hyperplasia (n = 4). All regressed with reduced immunosuppression, and had increased pS6 staining compared with normal tonsil (P = .002, F test). EPTLDs developed later than previously reported, involved mostly tonsils/adenoids, were EBV-encoded RNA (EBER) positive, showed increased pS6, and had excellent clinical outcome with reduction of immunosuppression.

Hypoxia-inducible factor-1 {alpha} expression predicts superior survival in patients with diffuse large B-cell lymphoma treated with R-CHOP.

PURPOSE Hypoxia-inducible factor (HIF) controls the expression of genes in response to hypoxia, as well as a wide range of other cellular processes. We previously showed constitutive stabilization of HIF-1alpha in the majority of patients with diffuse large B-cell lymphoma (DLBCL). To our knowledge, the prognostic significance of HIF in lymphoma has never been investigated. PATIENTS AND METHODS We studied the immunohistochemical protein expression of HIF-1alpha on tissue microarrays from 153 patients with DLBCL treated in sequential cohorts with cyclophosphamide, doxorubicin, oncovin, and prednisone (CHOP) or rituximab-CHOP (R-CHOP) from 1999 to 2002. Results were correlated with patient outcome. Results Median follow-up for all patients was 80 months. Among all patients, HIF-1alpha was expressed in 62% of germinal center and 59% of non-germinal center patients. With HIF-1alpha analyzed as a dependent variable, there were no survival differences in CHOP-treated patients. In the R-CHOP group, however, HIF-1alpha protein expression correlated with significantly improved progression-free survival (PFS) and overall survival (OS). Five-year PFS for HIF-1alpha-positive patients was 71% v 43% for HIF-1alpha-negative patients (P = .0187), whereas 5-year OS was 75% and 54%, respectively (P = .025). In multivariate analysis with International Prognostic Index criteria, HIF-1alpha remained a significant predictor for PFS (P = .026) and OS (P = .043). Compared with other biomarkers, HIF-1alpha correlated only with BCL6 (P = .004). In terms of gene expression, we found several common gene associations of HIF-1alpha and the stromal-1 signature with genes predominantly involved in regulation of the extracellular matrix (eg, BGN, COL1A2, COL5A1, and PLOD2). CONCLUSION The expression of HIF-1alpha protein is an important independent favorable prognostic factor for survival in patients with DLBCL treated with R-CHOP.

T-cell non-Hodgkin lymphoma.

T-cell non-Hodgkin lymphomas (NHLs) are uncommon malignancies. The current WHO/EORTC classification recognizes 9 distinct clinicopathologic peripheral T-cell NHLs. These disorders have unique characteristics and require individualized diagnostic and therapeutic strategies. Tremendous progress has been made in recent years in the understanding of the pathogenesis of these disorders. Specific chromosomal translocations and viral infections are now known to be associated with certain lymphomas. In this review, we describe their clinical and pathologic features. We also discuss the use of molecular studies in the diagnostic work-up of T-cell lymphomas. Because of the rarity of these disorders and the lack of well-designed clinical trials, the treatment of peripheral T-cell NHLs is often challenging. Additional studies are required to learn more about the biology of these diseases, which may lead to more optimal and possibly targeted therapies.

Leukemic phase of B-cell lymphomas mimicking chronic lymphocytic leukemia and variants at presentation.

Six cases of non-Hodgkin B-cell lymphoma that mimicked either chronic lymphocytic leukemia (CLL) or a CLL variant at presentation are reported. The patients ranged from 54 to 89 years and included three females and three males. All six patients had prominent peripheral blood lymphocytosis at presentation; the initial morphologic impression was CLL in three cases, CLL/prolymphocytic leukemia (PLL) in two cases, and PLL in one. Five patients had bone marrow biopsies; each showed a lymphoid infiltrate in a focally random, interstitial, and/or diffuse pattern. Flow cytometric immunophenotyping showed CD20-positive B cells with surface immunoglobulin (Ig) light chain restriction in all six patients. The five cases resembling CLL or CLL/PLL had at least a subset of CD5-positive B cells, whereas CD5 was absent in the one case that resembled PLL. CD23 was positive in three of the four cases studied that resembled CLL or CLL/PLL; CD79b was positive in three, FMC7 was positive in two, and surface Ig and CD20 were brightly positive in three. A t(11;14) (q13;q32) was found in four cases that resembled CLL or CLL/PLL; they were subsequently diagnosed as mantle cell lymphoma. The remaining two cases mimicking CLL or PLL were diagnosed as lymphomas of follicle center origin with leukemic phase based on the presence of t(14;18) (q32;q21). Thus although the morphology of these six cases resembled CLL or variants, and immunophenotyping by flow cytometry showed overlapping features, genetic studies enabled distinction of these leukemic non-Hodgkin lymphoma from chronic lymphocytic leukemia or variants.

Long-term survival of a patient with human immunodeficiency virus infection and Hodgkin's lymphoma.

When patients infected with human immunodeficiency virus (HIV) are found to have Hodgkin's lymphoma (HL), it is generally advanced, with involvement of extranodal sites including bone marrow, spleen, and liver, and prognosis tends to be unfavorable. We present the case of a 38-year-old white man who had HIV and HL diagnosed in 1990. Despite presenting with stage IV HL, having recurrence of HL after initially attaining remission, and being hospitalized on several occasions for opportunistic infections, he ultimately achieved complete remission of HL and is alive 9 years after initial diagnosis. This case illustrates that although unusual, prolonged survival of an HIV-infected patient with HL associated with poor prognostic features is possible.

Post-transplant plasma cell myeloma and polymorphic lymphoproliferative disorder with monoclonal serum protein occurring in solid organ transplant recipients.

Post-transplant lymphoproliferative disorders are mostly Epstein-Barr virus-related, B-cell tumors that develop as a consequence of immunosuppressive therapy in recipients of solid organ or bone marrow transplants. These disorders range from reactive, polyclonal plasmacytic hyperplasia to those that are morphologically and genotypically indistinguishable from typical non-Hodgkin's lymphomas. Plasma cell myeloma occurring after solid organ transplantation is rare. We report three plasma cell myeloma post-transplant lymphoproliferative disorder cases and one polymorphic, monoclonal post-transplant lymphoproliferative disorder case associated with a monoclonal serum protein. All three plasma cell myeloma post-transplant lymphoproliferative disorder cases had clinical, radiologic, and pathologic features of conventional plasma cell myeloma. The one polymorphic post-transplant lymphoproliferative disorder case was associated with an IgM monoclonal serum protein and was morphologically indistinguishable from a lymphoplasmacytic lymphoma. Three of the four cases, including the one polymorphic post-transplant lymphoproliferative disorder case, were positive for Epstein-Barr virus encoded small RNA by in situ hybridization. One patient died of plasma cell myeloma post-transplant lymphoproliferative disorder. The remaining three patients are alive: two are completely free of post-transplant lymphoproliferative disorder, and one has shown partial response to therapy. We compare the clinicopathologic features of these cases with those in the literature.