Immunoblastic morphology but not the immunohistochemical GCB/nonGCB classifier predicts outcome in diffuse large B-cell lymphoma in the RICOVER-60 trial of the DSHNHL.

The survival of diffuse large B-cell lymphoma patients varies considerably, reflecting the molecular diversity of tumors. In view of the controversy whether cytologic features, immunohistochemical markers or gene expression signatures may capture this molecular diversity, we investigated which features provide prognostic information in a prospective trial in the R-CHOP treatment era. Within the cohort of DLBCLs patients treated in the RICOVER-60 trial of the German High-Grade Lymphoma Study Group (DSHNHL), we tested the prognostic impact of IB morphology in 949 patients. The expression of immunohistochemical markers CD5, CD10, BCL2, BCL6, human leukocyte antigen (HLA)-DR, interferon regulatory factor-4/multiple myeloma-1 (IRF4/MUM1), and Ki-67 was assessed in 506 patients. Expression of the immunohistochemical markers tested was of modest, if any, prognostic relevance. Moreover, the Hans algorithm using the expression patterns of CD10, BCL6, and interferon regulatory factor-4/multiple myeloma-1 failed to show prognostic significance in the entire cohort as well as in patient subgroups. IB morphology, however, emerged as a robust, significantly adverse prognostic factor in multivariate analysis, and its diagnosis showed a good reproducibility among expert hematopathologists. We conclude, therefore, that IB morphology in DLBCL is likely to capture some of the adverse molecular alterations that are currently not detectable in a routine diagnostic setting, and that its recognition has significant prognostic power.

Plasmablastic lymphomas with light chain restriction - plasmablastic extramedullary plasmacytomas?

BACKGROUND: It is diagnostically difficult to differentiate plasmablastic lymphomas (PBLs) from plasma cell neoplasms with plasmablastic differentiation. Plasmablastic lymphomas are currently classified as 'PBL of the oral mucosa' and 'PBL with plasmacytic differentiation'. METHODS: Forty-five cases of PBL were retrieved from the Departments of Oral Pathology of the Universities of Pretoria and Limpopo, South Africa. Clinical features and HIV status were recorded and each case was classified as 'PBL of the oral mucosa type' or as 'PBL with plasmacytic differentiation'. Immunohistochemistry included: CD45, CD3, CD20, CD79a, CD38, CD138, MUM1, Ki-67 and kappa and lambda light chains. Positivity was recorded based on the percentage of positive staining cells as focal (5-20%); intermediate (20-70%) or diffuse (>70%). In situ hybridization was performed for Epstein-Barr virus (EBV) and HHV-8. Results were recorded as positive or negative. RESULTS: All cases showed some degree of plasmacytic differentiation. All were negative for CD20 with reactive T cells detected with CD3. Diffuse and strong positive staining was found with Ki-67 and MUM1, but variable immunoreactivity was found with CD79a, CD45, CD38 and CD138. Twenty cases (47%) showed light chain restriction. Epstein-Barr virus was detected in 44/45 cases and HHV-8 in none. CONCLUSIONS: The morphological classification of PBLs is not valid as all cases showed some degree of plasmacytic differentiation. We propose that PBLs with light chain restriction be reclassified as 'plasmablastic extramedullary plasmacytomas' and managed accordingly. The rest represents true PBLs. The true nature of these neoplasms as an entity should be further investigated with molecular and genetic studies.

Diffuse large B-cell lymphomas with plasmablastic/plasmacytoid features are associated with TP53 deletions and poor clinical outcome.

To define reproducible criteria for subgroups of diffuse large B-cell lymphomas (DLBCL), including lymphomas with plasmablastic/plasmacytoid features (PB/PC-Fs), we investigated 66 DLBCL; the samples were categorized as either centroblastic (CB), immunoblastic (IB) or PB/PC-F applying standardized morphologic criteria. Blinded specimens were reviewed by three independent pathologists. The final consensus classification included 44 CB (67%), seven IB (10%) and 15 PB/PC-F (23%). The interobserver agreement between two centers (Vienna, Würzburg) was 93.5%. Most PB/PC-F were CD20+, cIgM+, MUM-1+, CD138+/-, bcl-6-, corresponding to an activated B-cell phenotype. Immunoglobulin-V(H) gene mutation analysis was consistent with a germinal or postgerminal center-cell origin. By fluorescence in situ hybridization analysis, 11/13 (85%) PB/PC-F had a monoallelic TP53 deletion. The pretreatment characteristics of patients with PB/PC-F included a tendency for more B symptoms, extranodal disease and a higher IPI. Importantly, PB/PC-F were resistant to standard chemotherapy (complete remission rate 47%, relapse rate 71%) and even autologous stem-cell transplantation. The median overall survival (OS) (14 months, P<0.002) and disease-free survival (6 months, P=0.02) were significantly shorter compared to patients with CB and IB. The OS difference was pronounced within the low and low-intermediate IPI risk group (P<0.001). Our data indicate a strong association of plasmablastic/plasmacytoid morphology with TP53 deletions, poor response to chemotherapy and short survival.

Clinicopathologic features of ileocolonic malignant lymphoma: analysis according to colonoscopic classification.

BACKGROUND: The aims of this study were to classify primary ileocolonic lymphomas according to colonoscopic findings and to determine the clinicopathologic relationship according to classes. METHODS: Thirty-two patients (22 men, 10 women; age range 29 to 75 years) with primary malignant lymphoma of the terminal ileum and/or colorectum were studied. The clinicopathologic features were evaluated according to colonoscopic findings. RESULTS: Thirty-six lesions in 32 patients were endoscopically classified as follows: fungating (14, 39%), ulcerofungating (11, 31%), infiltrative (5, 14%), ulceroinfiltrative (4, 11%), and ulcerative (2, 6%). Location of the lesions was as follows: terminal ileum, 15 (42%); colorectum, 14 (39%); both regions, 7 (19%). The most common histopathologic types were diffuse large cell (22, 69%) and large cell immunoblastic (5, 16%). There was no relationship between the endoscopic findings and histologic types. In 9 patients (28%), the clinical manifestation was intussusception, and all were found endoscopically to have the fungating type lesion. CONCLUSIONS: Primary ileocolonic lymphomas can be classified endoscopically into fungating, ulcerative, infiltrative, ulcerofungating, and ulceroinfiltrative types. Among these, fungating and ulcerofungating are the most frequent. Intussusception is a common clinical finding in ileocolonic lymphomas, occurring mainly in patients with the fungating type of lesion.

Diffuse large B-cell lymphoma: a clinicopathologic analysis of 444 cases classified according to the updated Kiel classification.

The purpose of this study was: to compare the survival of diffuse large B-cell lymphomas (DLBCL) stratified according to the up-dated Kiel classification. A retrospective study of a cohort of 1378 cases was organized in 1996 by the Non-Hodgkin's Lymphoma Classification Project, and the DLBCL were classified according to the updated Kiel classification. The distribution of the different types and subtypes was as follows: centroblastic (CB, 85.4%), composed of the polymorphic (CB-PM, 58.6%), monomorphic (CB-MM, 17.1%) and multilobated (CB-ML, 9.7%) subtypes; immunoblastic (IB, 11.2%), with (8.3%) or without (2.9%) plasmacytoid differentiation; and anaplastic large cell lymphoma (ALCL) of B-cell type (3.4%). The rate of diagnostic agreement between pathologists was 78% for CB and 65% for IB lymphoma. The 5-year overall survival (OAS) for the entire group was 47% and the 5-year failure-free survival (FFS) was 42%. No significant differences in survival were found between the three major groups (CB, IB, ALCL). However, the 5-year OAS and FFS of patients with DLBCL not containing immunoblasts (CB-MM+CB-ML) was 51 and 52%, respectively, and was significantly better than the survival of those containing immunoblasts (CB-PM+IB+ALCL), which was 44 and 38% (p = 0.06 and p = 0.037), respectively. These results did not appear to be due to differences in the clinical features of the two groups, and was most significant for patients with low stage or low risk disease. However, histologic subtyping was not an independent risk factor for the entire group by multivariate analysis. In conclusion, patients with CB-MM and CB-ML (without immunoblasts) had a significantly better OAS and FFS than those with CB-PM, IB and ALCL (with immunoblasts). Therefore, we conclude that additional studies are still needed to further evaluate the importance of immunoblastic differentiation in DLBCL.

Lymphoid neoplasms in HIV-positive individuals in India.

The HIV epidemic in the Asian subcontinent has a significant impact on India. Patients with AIDS have an increased risk of developing non-Hodgkin lymphoma (NHL). In this study, we have investigated the pattern of distribution of lymphoid neoplasms and also studied the Epstein-Barr virus (EBV)-association and p53 expression in 35 HIV-positive patients from India. The biopsy samples were studied for histology and for expression of CD20, CD3, CD15, CD30, light chains, CD138, bcl-6, epithelial membrane antigen, EBV-latent membrane protein-1, and p53 protein. In situ hybridization was performed with digoxigenin-labeled anti-sense EBV-encoded nuclear RNA-1 (EBER-1) probe. Polymerase chain reaction (PCR) was performed on DNA extracted from paraffin sections for EBV-subtype analysis. The 35 cases included 7 cases of Hodgkin disease (HD), 4 cases of plasmacytoma (PL), and 24 cases of NHL. Among the cases of NHL, 3 were Burkitt lymphoma (BL), 4 were diffuse large B-cell lymphoma (DLBL) of centroblastic type (CBL), 10 were DLBL of immunoblastic type (IBL), 4 were high-grade B-cell lymphoma (unspecified) and the rest were other subtypes. EBV-association was noted in all cases of HD, 2 of 3 BL, and 3 of 10 IBL. PCR analysis of the EBNA-3C gene revealed amplimers corresponding to type A. A p53 protein overexpression was noted in 6 of 10 IBLs, 1 of 3 BLs, 2 of 3 CBLs, and 5 of 7 cases of HD. This is the first reported study of lymphoid malignancies in HIV-positive individuals from India.

Primary effusion lymphoma: a distinct clinicopathologic entity associated with the Kaposi's sarcoma-associated herpes virus.

We recently discovered the Kaposi's sarcoma-associated herpes virus (KSHV/HHV-8) in an uncommon and unusual subset of AIDS-related lymphomas that grow mainly in the body cavities as lymphomatous effusions without an identifiable contiguous tumor mass. The consistent presence of KSHV and certain other distinctive features of these body cavity-based lymphomas suggest that they represent a distinct entity. We tested this hypothesis by investigating 19 malignant lymphomatous effusions occurring in the absence of a contiguous tumor mass for their clinical, morphologic, immunophenotypic, viral, and molecular characteristics, KSHV was present in 15 of 19 lymphomas. All four KSHV-negative lymphomatous effusions exhibited Burkitt or Burkitt-like morphology and c-myc gene rearrangements and, therefore, appeared to be Burkitt-type lymphomas occurring in the body cavities. In contrast, all 15 KSHV-positive lymphomatous effusions exhibited a distinctive morphology bridging large-cell immunoblastic lymphoma and anaplastic large-cell lymphoma, and all 12 cases studied lacked c-myc gene rearrangements. In addition, these lymphomas occurred in men (15/15), frequently but not exclusively in association with HIV infection (13/15), in which homosexuality was a risk factor (13/13), presented initially as a lymphomatous effusion (14/15), remained localized to the body cavity of origin (13/15), expressed CD45 (15/15) and one or more activation-associated antigens (9/10) in the frequent absence of B-cell-associated antigens (11/15), exhibited clonal immunoglobulin gene rearrangements (13/13), contained Epstein-Barr virus (14/15), and lacked bcl-2, bcl-6, ras and p53 gene alterations (13/15). These findings strongly suggest that the KSHV-positive malignant lymphomatous effusions represent a distinct clinicopathologic and biologic entity and should be distinguished from other malignant lymphomas occurring in the body cavities. Therefore, we recommend that these malignant lymphomas be designated primary effusion lymphomas (PEL), rather than body cavity-based lymphomas, since this term describes them more accurately and avoids their confusion with other malignant lymphomas that occur in the body cavities. We further recommend that these PEL be considered for inclusion as a new entity in the Revised European-American Lymphoma Classification.

[Immunophenotyping and clinical manifestations of NHL in Jilin Province and Akita county].

This was a comparative study of NHL in Jilin Province, China (JPC) and Akita county, Japan (ACJ). A total with 219 cases of their clinical features analyzed. The results indicated that in both areas, B-NHL predominated with a B to T cell ratio of 5.1 : 1 (JPC) and 2.4 : 1 (ACJ) respectively. Histologically B-NHL of defuse large-cell type was most commonly seen, the frequency of which was higher in JPC (61.5%) than in ACJ (37.2%). However, immunoblastic B-NHL was of common occurence in ACJ (26 out of 91 cases). In contrast, immunoblastic lympaoma of T cell lineage was very common in both areas, accounting for a half of all T-NHL. Most of the patients were treated with CHOP or COPP protocol, but the responses differred between the two phenotypes of NHL. Patients with B-NHL responded favorably to chemotherapy, with complete response (CR) in 54 of 70 treated cases (77.0%) in ACJ and 47 of 82 treated cases (57.3%) in JPC. The 3-year disease-free survial rate was 44% and 37%, respectively. The response to treatment in T-NHL patients was inferior with a CR rate of 59% in JPC cases. Only 2 in each series of patients kept the remission over 1 year.

Lymph node classification systems in cutaneous T-cell lymphoma. Evidence for the utility of the Working Formulation of Non-Hodgkin's Lymphomas for Clinical Usage.

BACKGROUND: This study was undertaken to compare three classification schemes used to evaluate lymph nodes (LN) obtained from patients with cutaneous T-cell lymphoma (CTCL): a modified Rappaport classification, the National Cancer Institute-Veterans Administration (NCI-VA) classification based on the relative numbers of cerebriform cells in the paracortical areas, and the Dutch classification based on the presence of cerebriform cells with large nuclei in mycosis fungoides (MF) and diffuse infiltration by cerebriform cells in Sézary syndrome. METHODS: A study set of 195 LN obtained from patients with CTCL (MF, Sézary syndrome, and nonepidermotropic T-cell lymphomas) and 14 LN from patients with benign dermatoses was reviewed independently by three groups of pathologists familiar with each classification system. RESULTS: Each classification system provided useful prognostic information. However, contrary to prior reports, no significant difference in survival was apparent in patients with uneffaced LN when classified according to the NCI-VA (LN0-2 versus LN3) or Dutch (Gr0-1 versus Gr2) ratings. In addition, all classification systems demonstrated a poor survival time associated with effaced LN. By combining results from the modified Rappaport and Dutch classifications, three prognostic groups could be identified based on cell morphology: a low-grade category with a small cell histologic subtype (median survival time, 40 months); a high-grade immunoblastic subtype (median survival time, 9 months) composed of cells with an oval nucleus containing a large, usually solitary central nucleolus; and an intermediate-grade category composed of all cases without the distinctive small cell and immunoblastic morphologies (median survival time, 26 months). CONCLUSIONS: The authors propose that clearly involved LN in CTCL can be categorized on the basis of cell morphology into prognostic groups analogous to what has been proposed for the Working Formulation for Non-Hodgkin's Lymphomas for Clinical Usage.

Noncutaneous T-cell lymphomas. Recognition of a lymphoma type (large cell anaplastic) with a relatively favorable prognosis.

BACKGROUND: The clinical relevance of the updated Kiel classification for T-cell lymphomas is discussed. Large series with long-term follow-up are needed to investigate the clinical relevance of a separation into high- and low-grade T-cell lymphomas, based on the Kiel classification. METHODS: The clinicopathologic data of 97 consecutive noncutaneous T-cell lymphomas, diagnosed in the Comprehensive Cancer Center Amsterdam, between July 1, 1985, and December 1, 1990, were reviewed and analyzed for their prognostic significance. RESULTS: Immunohistochemistry contributed substantially in the diagnosis of T-cell lymphoma. Using the updated Kiel classification, many difficulties occurred in classifying these lymphomas. Only large cell anaplastic lymphoma (LCAL) and lymphoblastic lymphoma (LBL) were classified with a high degree of confidence. Variables associated with prolonged survival were classified as LCAL and low stage of disease (Stage I and II) at clinical presentation. Multivariate survival analysis revealed that subtype (grouped as LCAL versus non-LCAL) was selected as the most significant variable, closely followed by stage of disease at clinical presentation (grouped as Stage I/II versus Stage III/IV). LCAL was associated with a significantly better survival than were all other types of high-grade T-cell lymphoma (P = 0.018) and tended to be associated with a better survival than low-grade T-cell lymphoma (P = 0.067). No significant differences in survival were found between the other types of T-cell lymphoma or between high- and low-grade T-cell lymphomas as classified according to the updated Kiel classification. Other variables, such as sex and age (younger than 60 years versus older than 60 years) had no significant influence on survival time. CONCLUSIONS: This study indicates that the clinical relevance of classifying primary noncutaneous T-cell lymphomas according to the updated Kiel classification is limited because only a diagnosis of LCAL has prognostic relevance in predicting survival.

Clinical significance of morphologic subdivision in diffuse large cell lymphoma.

Although diffuse large cell lymphomas can be morphologically divided into large cell (DLC) and immunoblastic (IBL) subtypes, the clinical significance of this subdivision remains controversial. The initial diagnostic materials from 85 patients with recorded diagnoses of diffuse large cell lymphoma who were treated at Stanford between 1975 and 1986 with cyclophosphamide, doxorubicin (Adriamycin; Adria Laboratories, Columbus, OH), vincristine, and prednisone (CHOP); methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone (M-BACOD); or methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin (MACOP-B) chemotherapy were retrospectively reviewed by a panel of hematopathologists and classified according to morphologic criteria of the Working Formulation. Based on the criterion of agreement of two of three observers, 60 patients were classified as having DLC, 19 as having IBL, and the lymphomas in 6 patients could not be additionally classified. No significant differences in complete response (CR) rate, freedom from disease progression (FFP), or overall survival were found between the DLC and IBL groups. There was also no significant difference in prognosis between DLC cases additionally subclassified as large cleaved cell (16 patients) and those with large non-cleaved cell (36 patients). Although IBL is considered to be a high-grade lymphoma, the authors concluded that it does not differ significantly in prognosis from DLC lymphoma and, therefore, does not justify a modified treatment selection based on IBL morphologic type alone. Definitive evaluation of the prognostic significance of morphologic subdivision may require a larger cohort of uniformly treated patients.