胃肠道弥漫性大B细胞淋巴瘤免疫表型与预后的研究

目的 探讨胃肠道弥漫性大B细胞淋巴瘤(diffuse large B-cell lymphoma,DLBCL)免疫表型与患者预后的关系.方法 收集2000年6月至2007年6月我院普外科收治的胃肠道DLBCL63例,应用免疫组化方法检测抗体CD10、Bcl-6和MUM1在胃肠道DLBCL中的表达,并根据检测结果进行分型.结果 本组63例中CD10表达阳性13例,Bcl-6阳性53例,MUM1阳性52例.根据检测结果将胃肠道DLBCL分为生发中心B细胞型(GCB型)17例(27%),非GCB型46例(73%).GCB型局部淋巴结受累患者的比例(35%)显著低于非GCB型(70%)(P＜0.05);肿瘤大小及浸润深度在两种亚型之间的差异无统计学意义.CD10表达阳性者的中位生存时间(76个月)显著长于阴性者(24个月)(P＜0.01);GCB型胃肠道DLBCL患者的中位生存时间(76个月)显著长于非GCB型(28个月)(P＜0.05);接受CHOP化疗方案的患者中GCB型的中位生存时间(76个月)显著长于非GCB型(24个月)(P＜0.05);8例术后接受利妥昔单抗联合CHOP方案治疗的患者中GCB型和非GCB型各4例,目前均存活(22～47个月).结论 胃肠道DLBCL的免疫表型与局部淋巴结是否受累密切相关;CD10表达阳性者的生存时间显著长于阴性者;胃肠道DLBCL免疫表型分型对患者预后判断具有重要意义.     

B-cell posttransplant lymphoproliferative disorders in heart and/or lungs recipients: clinical and molecular-histogenetic study of 17 cases from a single institution

BACKGROUND: Posttransplantation lymphoproliferative disorders (PTLDs) are heterogeneous lymphoid proliferations representing a major complication of solid organ transplant. This study details the clinicopathological and molecular features of 17 B-cell PTLDs observed in a single center series of 988 heart and/or lung transplant recipients. METHODS: Cases were classified according to World Health Organization lymphoma classification and tested for Epstein-Barr Virus (EBV), clonality, histogenetic phenotypic (CD10, Bcl-6, MUM1, CD138), and genotypic (immunoglobulin and BCL-6 genes somatic hypermutation) markers. RESULTS: This series of 17 PTLDs included: two B-cell monoclonal polymorphic PTLDs and 15 B-cell monomorphic PTLDs (13 diffuse large B-cell lymphomas [DLBCL] and 2 Burkitt lymphomas [BL]). EBV was detected in 9/17 cases. A monoclonal immunoglobulin variable (IGV) genes rearrangement was documented in 17/17 cases; IGV somatic hypermutation was found in 88% of cases, indicating a prevalent origin from germinal center (GC)-experienced B cells. Using immunophenotypic markers, three histogenetic profiles were identified: a) CD10/bcl-6/MUM1/CD138, mimicking GC B-cells; b) CD10-/bcl-6+/MUM1+/CD138-, reminiscent of B-cells at the latest phases of GC reaction; and c) CD10-/bcl-6-/MUM1+/CD138+/-, consistent with preterminally differentiated B-cells. CONCLUSIONS: Correlation between morphology, histogenesis, and EBV status demonstrated a high degree of homogeneity in the two GC-related groups, mostly including EBV-negative cases with BL and DLBCL-centroblastic features; the third group, consisting of post GC EBV-positive cases, was histologically less homogeneous, as it included polymorphic PTLDs and DLBCL with immunoblastic and anaplastic features. The EBV-negative cases with GC histogenetic phenotype showed a slightly better outcome; however, such less aggressive prognostic trend was not confirmed by statistical analysis.     

SIRT1 expression is associated with poor prognosis of diffuse large B-cell lymphoma

Sirtuin1 (SIRT1) is a nicotinamide adenine dinucleotide-dependent deacetylase. Recently, it is suggested that SIRT1 may be involved in the development of malignant tumors including mouse lymphoma. Therefore, we investigated the prevalence and the prognostic impact of SIRT1 expression in diffuse large B-cell lymphoma (DLBCL). Immunohistochemical expression of SIRT1, p53, bcl2, CD10, bcl6, and multiple myeloma-1 (MUM1) were evaluated by using a 2 mm core from 104 DLBCL patients for tissue microarray. Positive expression of SIRT1 was seen in 74% (77/104) of patients. In total DLBCL patients, SIRT1 and p53 expression were significantly associated with shorter overall survival (OS) by univariate analysis (P=0.001 and P=0.011, respectively). SIRT1 was also an independent prognostic factor by multivariate analysis (P=0.01). According to the expression patterns of CD10, bcl6, and MUM1, germinal center B cell (GCB) types were represented in 38 cases (37%) and non-GCB types were represented in 66 cases (63%). In the GCB type, only p53 expression was associated with a significantly shorter OS (P=0.032). In the non-GCB type, expression of SIRT1 correlated with shorter OS by univariate analyses (P=0.005) and multivariate analyses (P=0.049). In conclusion, we showed that SIRT1 expression is a clinically significant prognostic indicator for DLBCL patients.     

Impact of Epstein-Barr virus in monomorphic B-cell posttransplant lymphoproliferative disorders: a histogenetic study

The heterogeneity of the posttransplant lymphoproliferative disorders (PTLDs) is well recognized. However, in contrast to other immunodeficiency-associated lymphomas or diffuse large B-cell lymphomas in general, studies of the histogenetic spectrum of the large category of monomorphic B-cell cases have been more limited, produced conflicting results, and have paid little attention to the impact of Epstein-Barr virus (EBV). Therefore, 30 monomorphic B-cell PTLD from 27 patients were analyzed using EBER in situ hybridization for EBV and a panel of antibodies directed against CD20, CD3/bcl-6, CD10, MUM-1/IRF4, CD138, and bcl-2. The results were correlated with the histopathologic features and clinical outcome. All PTLD were CD20 with 23% CD10, 53% bcl-6, 67% MUM-1/IRF4, 13% CD138, 83% bcl-2 and 67% EBV. 30% of the PTLD had a germinal center (GC) profile (CD10, bcl-6, MUM-1/IRF4, CD138), 53% a "late GC/early post-GC" profile (CD10, bcl-6, MUM-1/IRF4, CD138), 13% a post-GC profile (CD10, bcl-6, MUM-1/IRF4, CD138) and 3% an indeterminate profile (all markers negative). EBV positivity was associated with MUM-1/IRF4 expression (P=0.005) and with a non-GC phenotype (P=0.01). All CD138 cases were EBV. The cases with a GC phenotype were the most likely to resemble transformed GC cells (P=0.023). No statistically significant survival differences could be documented between those with a GC versus non-GC phenotype. These results highlight the broad histogenetic spectrum of monomorphic B-cell PTLD. They demonstrate the association of EBV positivity with a non-GC phenotype and suggest that EBV PTLD are more like lymphomas that arise in immunocompetent individuals. The lack of a demonstrable correlation with survival may relate to the relatively small number of cases studied.     

Critical evaluation of Bcl-6 protein expression in diffuse large B-cell lymphoma of the stomach and small intestine

Diffuse large B-cell lymphoma (DLBCL) of the gastrointestinal tract is heterogeneous, including mucosa-associated lymphoid tissue (MALT) origin and non-MALT, and they are indistinguishable. MALT lymphoma is a tumor of a post-germinal center (GC) memory B-cell origin, which is negative for Bcl-6 protein expression in low-grade but may become positive in high-grade tumors. Because Bcl-6 expression patterns in lymphoma of GC and non-GC B-cell origins have recently been characterized and CD10 is generally regarded as a specific marker for GC B cells, we critically evaluated gastric and small intestinal DLBCLs to see whether it is possible to identify tumor of GC B-cell origin by immunostaining in archival specimens. High-grade MALT lymphoma (H-ML) of the stomach (n = 20) was defined by the presence of a concomitant lymphoepithelial lesion and/or follicular colonization; and DLBCLs de novo, both gastric (n = 31) and intestinal (n = 21), were defined by the absence of the above features. Immunostaining for Bcl-6 and CD10 was done using formalin-fixed, paraffin-embedded sections and was examined independently by three pathologists. Staining for Bcl-6 was positive (>10% of tumor cells) in 55 of 72 cases. However, two distinct patterns were recognized among those positive: diffusely dense (>75%) and sporadic (<75%). The former was further characterized by a consistency of Bcl-6+ tumor cell density at any given area, resembling the staining pattern of the GC or follicular lymphoma (FL) (GC/FL pattern), whereas the latter was, besides less dense population, by variable density from area to area. The GC/FL pattern was observed in 36% and 38% of gastric and intestinal DLBCLs de novo, respectively, but in none of the gastric H-ML. CD10 was positive in 12 of 71 cases (17%), all coexpressing Bcl-6. CD10+ tumors were more frequent in the intestinal (33%) than in gastric DLBCLs ( approximately 15%). Significantly, CD10 expression was observed in three gastric H-MLs, including one that displayed a distinct lymphoepithelial lesion. In conclusion: 1). tumors showing a diffusely dense pattern of Bcl-6 expression should be distinguished from those showing a sporadic pattern; for the former most likely represents the tumor of GC B-cell derivation, and the latter non-GC, including MALT lymphoma; 2). tumor of GC B-cell origin thus defined accounted for about one third of gastric as well as intestinal DLBCLs de novo but none of the gastric H-ML; and 3). CD10 expression can be seen in MALT lymphomas and should not be used as the marker for GC B cells.     

Primary Diffuse Large B-Cell Lymphoma of the Oral Cavity: Germinal Center Classification

Primary lymphomas of the oral cavity are rare and the most frequent type is diffuse large B-cell lymphoma (DLBCL). Recently, several reports have highlighted the value of classifying DLBCL into prognostically important subgroups, namely germinal center B-cell like (GCB) and non-germinal center B-cell like (non-GCB) lymphomas based on gene expression profiles and by immunohistochemical expression of CD10, BCL6 and MUM-1. GCB lymphomas tend to exhibit a better prognosis than non-GCB lymphomas. Studies validating this classification have been done for DLBCL of the breast, CNS, testes and GI tract. Therefore we undertook this study to examine if primary oral DLBCLs reflect this trend. We identified 13 cases (age range 38–91 years) from our archives dating from 2003–09. IHC was performed using antibodies against germinal center markers (CD10, BCL6), activated B-cell markers (MUM1, BCL2) and Ki-67 (proliferation marker). Cases were sub-classified as GCB subgroup if CD10 and/or BCL6 were positive and MUM-1, was negative and as non-GCB subgroup if CD10 was negative and MUM-1 was positive. Immunoreactivity was noted in 2/13 cases for CD10, in 12/13 for BCL6, in 8/13 for MUM-1, and in 6/13 for BCL2. Therefore, 8/13 (58%) were sub-classified as non-GCB DLBCLs and 5/13 (42%) as GCB subgroup. All tumors showed frequent labeling with Ki-67 (range 40–95%). Four of the 8 patients with non-GCB subgroup succumbed to their disease, with the mean survival rate of 16 months. Two patients in this group are alive, one with no evidence of disease and another with disease. No information was available for the other 3 patients in this group. Four of the 5 patients in the GCB subgroup were alive with no evidence of disease and one patient succumbed to complications of therapy and recurrent disease after 18 months. In conclusion, our analysis shows that primary oral DLBCL predominantly belongs to the non-GCB subgroup, which tends to exhibit a poorer prognosis. These findings could allow pathologists to provide a more accurate insight into the potential aggressive behavior and poorer prognosis of these lymphomas.     

Pyothorax-associated lymphoma: a peculiar clinicopathologic entity derived from B cells at late stage of differentiation and with occasional aberrant dual B- and T-cell phenotype

We report 12 European cases of pyothorax-associated lymphomas occurring 30-67 years following artificial pneumothorax for pleuropulmonar tuberculosis. Eleven patients presented with a localized pleural tumor mass, whereas one patient also had liver involvement. Histologic examination showed a diffuse proliferation of large lymphoid cells with frequent plasmacytoid differentiation (n = 8), expressing CD20 (n = 10), CD79a (n = 11), and/or CD138 (n = 5) B-cell antigens. Aberrant expression of T-cell markers (CD2, CD3, CD4) was noted in five cases. The B-cell origin of lymphoma cells was confirmed by the demonstration of immunoglobulin light chain restriction or clonal B cell population in six cases. In 11 of 12 cases in situ hybridization disclosed Epstein-Barr virus genome in most tumor cells and immunohistochemistry a type III LMP-1+/ EBNA-2+ latency profile. HHV-8/ORF73 antigen was not detected in all tested cases (n = 11). All investigated cases (10 of 10) disclosed a uniform CD10-/BCL-6-/MUM1+/CD138+/- phenotype, consistent with a derivation from late germinal center (GC)/post-GC B cells. Clinical outcome was poor with a median survival time of 5 months. Only one patient was in complete remission after 34 months. This study further confirms that pyothorax-associated lymphoma represents a distinct clinicopathologic entity among diffuse large B-cell lymphoma, which is characterized by a peculiar clinical presentation, frequent plasmacytoid features, and a strong association with EBV. Moreover, we show that this lymphoma entity likely originates from B cells at a late stage of differentiation and occasionally shares an aberrant dual B/T phenotype.     

CD10 and BCL-6 expression in paraffin sections of normal lymphoid tissue and B-cell lymphomas

In this study the authors explored the value of immunostaining for follicular center B-cell markers, BCL-6 and CD10, in paraffin sections as a tool for the differential diagnosis of B-cell lymphomas. The cases studied comprised reactive lymphoid hyperplasia (RLH; n = 19), follicular lymphoma (FL; n = 50), low-grade mucosa-associated lymphoid tissue (MALT) lymphoma (n = 24), mantle cell lymphoma (n = 19), splenic marginal zone lymphoma (n = 13), diffuse large B-cell lymphoma (DLBCL; n = 54), Burkitt's lymphoma (BL; n = 20), nodular lymphocyte predominance Hodgkin's disease (NLPHD; n = 16), and classic Hodgkin's disease (CHD; n = 13). In RLH, CD10 and BCL-6 were expressed almost exclusively by the follicular center cells. In contrast in FL, the expression of CD10 (39/50) and BCL-6 (34/36) was seen in both follicular and interfollicular neoplastic B cells. Marginal zone/MALT lymphomas and mantle cell lymphoma were always negative. In DLBCL the expression was variable for both CD10 (21/54) and BCL-6 (39/47), with some tumors, including cases of transformed follicular lymphoma (9/10), coexpressing CD10 and BCL-6, and others expressing only BCL-6, and a small group expressing neither marker, possibly reflecting the underlying primary pathogenetic events such as the rearrangement of BCL-2 or BCL-6 genes. BL was always both CD10 and BCL-6 positive. In NLPHD the L&H cells expressed BCL-6 (11/13) but not CD10, whereas in CHD BCL-6 expression was seen in half of the cases. This study demonstrates that both CD10 and BCL-6 are reliable markers of follicular center B-cell differentiation. CD10 and BCL-6 immunostaining have an important role in differential diagnosis of FL from RLH and other low-grade B-cell lymphomas. The results also suggest that a CD10/BCL-6 expression pattern may be helpful in identifying main subsets of DLBCL. However, additional studies comparing genotype with immunophenotype are required.     

Diffuse large B-cell lymphomas with plasmablastic differentiation represent a heterogeneous group of disease entities

Plasmablastic lymphoma was initially described as a variant of diffuse large B-cell lymphoma (DLBCL) involving the oral cavity of HIV+ patients and characterized by immunoblastic morphology and a plasma cell phenotype. However, other lymphomas may exhibit similar morphologic and immunophenotypic features. To determine the significance of plasmablastic differentiation in DLBCL and examine the heterogeneity of lymphomas with these characteristics, we examined 50 DLBCLs with low/absent CD20/CD79a and an immunophenotype indicative of terminal B-cell differentiation (MUM1/CD38/CD138/EMA-positive). We were able to define several distinct subgroups. Twenty-three tumors were classified as plasmablastic lymphoma of the oral mucosa type and showed a monomorphic population of immunoblasts with no or minimal plasmacytic differentiation. Most patients were HIV+ and EBV was positive in 74%. Eleven (48%) cases presented in the oral mucosa, but the remaining presented in other extranodal (39%) or nodal (13%) sites. Sixteen cases were classified as plasmablastic lymphoma with plasmacytic differentiation. These were composed predominantly of immunoblasts and plasmablasts, but in addition exhibited more differentiation to mature plasma cells. Only 33% were HIV+, EBV was detected in 62%, and 44% had nodal presentation. Nine cases, morphologically indistinguishable from the previous group, were secondary extramedullary plasmablastic tumors occurring in patients with prior or synchronous plasma cell neoplasms, classified as multiple myeloma in 7 of the 9. Two additional neoplasms were an HHV-8+ extracavitary variant of primary effusion lymphoma and an ALK+ DLBCL. HHV-8 was examined in 39 additional cases, and was negative in all. In conclusion, DLBCLs with plasmablastic differentiation are a heterogeneous group of neoplasms with different clinicopathological characteristics that may correspond to different entities.     

胃肠道弥漫性大B细胞淋巴瘤中之t（14;18）染色体易位及Bcl-2基因扩增的研究

目的：探讨胃肠道弥漫性大B细胞淋巴瘤（diffuse large B-cell lymphoma,DLBCL）中之染色体t（14;18）（q32;q21）易位及Bcl-2基因扩增与DLBCL亚型分类及病人预后间的关系;探讨其在胃肠道DLBCL发病中的作用机制。方法：应用荧光原位杂交（fluorescence in situ hybridization,FISH）技术检测45例胃肠道DLBCL组织中之t（14;18）（q32;q21）染色体易位及Bcl-2基因扩增情况;应用免疫组化染色法检测该45例胃肠道DLBCL中之Bcl-2蛋白的表达。结果：在45例胃肠道DLBCL病人中,10例（22%）存在t（14;18）（q32;q21）易位,10例（22%）存在Bcl-2基因扩增。t（14;18）（q32;q21）易位阳性者与阴性者间的亚型分类比例差异有统计学意义（P〈0.01）。Bcl-2基因扩增阳性者与阴性者间之生存时间差异有统计学意义（P〈0.05）。而t（14;18）（q32;q21）染色体易位及Bcl-2基因扩增与Bcl-2蛋白表达间均属无关（P〉0.05）。结论：t（14;18）（q32;q21）染色体易位与胃肠道DLBCL的免疫表型分类相关,生发中心B细胞（germinal center B cell-like,GCB）型与非GCB型间存在分子遗传学差异。而检测Bcl-2基因扩增对判断胃肠道DLBCL病人的预后具有重要意义。     

Diffuse large B-cell lymphoma of bone: an analysis of differentiation-associated antigens with clinical correlation

Twenty-nine patients with diffuse large B-cell lymphomas presenting with bone involvement, including 18 localized primary bone lymphomas (group 1), 2 multifocal primary bone lymphomas (group 2), and 9 patients with extraskeletal disease at diagnosis (group 3), were studied. The tumors were subclassified according to the criteria of the WHO classification and evaluated by immunohistochemistry for expression of antigens associated with germinal center (GC) and non-GC stages of B-cell differentiation (bcl-6, CD10, MUM-1, VS38c, CD138, bcl-2, and CD44). The presence of a BCL-2/IgH gene rearrangement was investigated by polymerase chain reaction. All cases were characterized by similar clinicopathologic and morphologic features and had similarly good overall outcome. The patients (23 males, 6 females, median age 44 years) had tumors in long bones (14), axial skeleton (8), limb girdles (3), and multiple sites (4). Most tumors (24) were centroblastic, with multilobated cells in 12 cases. Almost half of the tumors (14 of 29, 48%) were bcl-6+CD10+ (GC-like), 9 of 29 cases (31%) were bcl-6+CD10- (indeterminate phenotype), and 6 of 29 cases (21%) were CD10-bcl-6- (post-GC like). The indeterminate phenotype was seen only in primary bone lymphoma. MUM-1 was frequently expressed in GC-like and non-GC-like categories. We found no evidence of plasmacytic differentiation by CD138, and VS38c immunoreactivity was distinctly rare (2 of 29 cases). CD44 was detected in 6 tumors, all CD10-. Bcl-2 was expressed by 70% of the tumors, but only 1 of 23 cases tested had a Bcl-2/JH rearrangement by polymerase chain reaction. A survival analysis showed that GC-like tumors had a longer overall survival duration compared with non-GC-like tumors (P = 0.0046). In conclusion, a GC-like immunophenotype characterizes roughly half of large B-cell lymphomas of bone and is associated with an improved survival.     

Micronodular T-cell/histiocyte-rich large B-cell lymphoma of the spleen: histology,immunophenotype, and differential diagnosis

Occasionally, primary large B-cell lymphomas (LBLs) arising in the spleen present with a micronodular pattern involving the splenic white pulp but sparing the red pulp. Histologically, the nodules contain scattered large B cells in a background of numerous T cells and histiocytes. They can cause substantial difficulty in histologic diagnosis as the morphology can mimic reactive and inflammatory lesions as well as other lymphoid neoplasms. In this study, we examined the histology and immunophenotype of the micronodular T-cell/histiocyte-rich LBL (MTLBL) of the spleen with a view to establish the characteristics that may be helpful in diagnosis. Paraffin-embedded material from 17 cases of MTLBL was studied. Clinical features and histology were reviewed and immunohistochemistry was performed for immunoglobulins, CD20, CD79a, CD3, CD68, CD10, BCL6, BCL2, OCT-2, epithelial membrane antigen, CD30, CD138, and EBV markers. The median age of presentation was 56 years, and the most frequent presenting features were anemia and B symptoms. All cases showed a micronodular pattern of involvement. The tumor nodules comprised a mixture of numerous CD3+ T cells and CD68+ histiocytes and scattered large CD20+ B cells with immunoglobulin light chain restriction. They were positive for BCL6 and OCT2 but negative for CD10, CD138, and EBV markers. There was variable expression of epithelial membrane antigen, Bcl-2, and CD30. No follicle dendritic cell meshwork infrastructure underlying the nodules could be demonstrated by staining for CD21 or CD35 antigens. The prognosis was poor; seven of the 12 cases with follow-up were dead within 2 years. MTLBL is unique variant of T-cell/histiocyte-rich diffuse LBL, characterized by primary splenic presentation and a micronodular architecture. The main differential diagnoses include granulomatous inflammation, Hodgkin's lymphoma, follicular lymphoma, and peripheral T-cell lymphomas.     

Primary central nervous system lymphoma in Korea: comparison of B- and T-cell lymphomas

The great majority of primary central nervous system lymphoma (PCNSL) is known to be of B-lineage, with T-cell PCNSL (T-PCNSL) accounting for <5%. We report an unusually high incidence of T-cell lymphoma among the PCNSLs originated in a large general-care hospital in the metropolitan Seoul area. PCNSLs (n = 42) accrued from April 1995 through June 2001 were reviewed for histologic and clinical features, and immunohistochemical staining was done for CD3, CD20, CD4, CD8, Bcl-6, and CD10. Clonal rearrangements of the TCR-gamma and IgH genes were studied with semi-nested PCR in all seven cases of T-PCNSL and seven of 35 B-cell PCNSL (B-PCNSL). Formalin-fixed, paraffin-embedded specimens were used in all these studies. By immunohistochemical staining and molecular studies, seven cases (16.7%) were diagnosed as T-PCNSL, each displaying clonal rearrangement of the TCR-gamma gene, and 35 (83.3%) as B-PCNSL. Radiologically, T-PCNSL was significantly correlated with the superficial and subcortical lobar location (p <0.001), solitary mass formation (p = 0.001), presence of rim enhancement (p <0.001), and peritumoral edema (p = 0.029). Involvement of cerebrospinal fluid was observed only in B-PCNSL (n = 17) but not in T-PCNSL (p = 0.010). Histologically, T-PCNSL was characterized by a population of mixed predominantly small- and occasionally medium-sized cells (p <0.001), which were loosely scattered without forming a solid mass (p = 0.024), and perivascular infiltration was frequent (p = 0.007), in contrast to predominantly large cells of B-PCNSL, i.e., diffuse large B-cell lymphoma (DLBCL), in which the cells tended to aggregate to form monomorphous sheets (p = 0.024). In T-PCNSL, staining for CD8 was positive in five, including one with coexpression of CD4, and two were negative for CD4 and CD8. Of 24 DLBCLs tested, the pattern of Bcl-6+ tumor cells was diffusely dense, similar to that of the germinal center in nine cases (37.5%), with coexpression of CD10 in three of the nine cases. T-PCNSL accounted for 16.7% of the PCNSLs; thus, in Korea it may not be as rare as previously known. The T-PCNSL presented with certain clinical and pathologic features that were distinct from B-PCNSL and displayed preponderance of CD8 expression. DLBCL of the germinal center B-cell derivation defined by bcl-6 expression comprised 37.5% of DLBCL of the brain.     

原发性乳腺淋巴瘤8例临床病理分析并文献复习

目的:探讨乳腺淋巴瘤的临床病理学特点及诊断要点。方法:收集2009年1月—2015年3月确诊为乳腺淋巴瘤的病例资料,进行临床资料、病理形态学及免疫组化分析,并结合文献对该病的诊断及鉴别诊断进行讨论。结果:8例均为女性,发病年龄35~82岁,6例位于左乳,1例右侧,1例双侧。多数表现为无痛性肿块,边界较清,可活动。7例为弥漫大B细胞淋巴瘤(DLBCL),1例为黏膜相关淋巴组织淋巴瘤(MALT),免疫组化染色均表达CD20、CD79a,7例MUM1阳性,4例Bcl-2阳性。治疗后4例患者获随访3~25个月,均健在。结论:乳腺淋巴瘤少见,常见类型为DLBCL,确诊依赖组织病理学和免疫组化染色。提高对乳腺淋巴瘤的认识,对避免误诊是至关重要的。     

Polyclonal rabbit antithymocyte globulin triggers B-cell and plasma cell apoptosis by multiple pathways

BACKGROUND: Polyclonal antithymocyte globulin (ATG) is widely used as an anti-T-cell agent for induction and treatment of acute cellular rejection in solid organ transplantation. The authors recently demonstrated that rabbit (r) ATG can be used in combination with plasmapheresis to effectively treat antibody-mediated renal allograft rejection. This observation suggested that rATG may have anti-B cell activity. METHODS: The authors tested the complement-independent, apoptosis-inducing properties of rATG on CD27- naive B cells, CD40 ligand-activated B cells, and plasma cells in vitro by annexin V staining, subdiploid DNA content, caspase activation, and loss of mitochondrial membrane polarity. Potential surface targets for rATG were assayed by competitive inhibition of monoclonal antibody binding. RESULTS: Rabbit ATG strongly induced apoptosis in vitro against naive, activated B cells and bone marrow resident plasma cells at clinically relevant concentrations (1-100 ng/mL). The authors found rATG activity against numerous B-cell surface proteins and observed that crosslinking of CD30, CD38, CD95, CD80, and HLA-DR likely accounts for this activity. F(ab)2 fragments of rATG showed 90% of the activity of the intact molecule, suggesting participation of the Fc fragment. Inhibition of caspase- and cathepsin-dependent apoptotic pathways partially inhibits rATG-induced B-cell apoptosis. Immunohistochemical staining of pediatric thymi demonstrated the presence of CD20+ B cells and CD138+ plasma cells within the thymic parenchyma, which accounts for the anti-B-cell activity in rATG. CONCLUSIONS: Polyclonal rATG induces complement-independent apoptosis of naive, activated, and plasma B cells. This effect appears to involve the caspase- and cathepsin-mediated apoptosis pathways.     

Keratin 17 expression correlates with tumor progression and poor prognosis in gastric adenocarcinoma

Background

Keratin 17 (K17) is regarded as a basal/myoepithelial cell keratin and is known to be inducible in activated keratinocytes. The high frequency of K17 expression in pancreaticobiliary nonmucinous adenocarcinoma or basal-like breast carcinoma has previously been described. However, its expression in gastric cancer (GC) is controversial.

Methods

We investigated the clinicopathological features and prognostic significance of 192 patients with GC by immunohistochemical staining of tissue microarrays. Analysis of epithelial markers including K17, K14, and K5/6, cell cycle-associated proteins p53, Ki-67, and 14-3-3 sigma, and mucinous phenotype markers including CD10, CDX2, MUC5AC, and MUC6 was performed.

Results

Cytoplasmic expression of K17 was observed in 95 (49.5?%) of 192 patients with GC. K17 expression positively correlated with lymph node metastasis (P?=?0.003) and advanced stages of the disease (P?=?0.014). K17 expression was significantly correlated with 14-3-3 sigma expression (P?<?0.001) and CD10 expression (P?=?0.015). The overall survival rates of patients with K17-positive GC were significantly lower than those with negative K17 expression (50.5 vs. 71.1?%, P?=?0.004). Univariate analysis revealed that K17 expression confers a poor prognosis in patients with GC (P?=?0.004), and it was also an independent prognostic factor in multivariate analysis (P?=?0.049).

Conclusions

K17 expression is correlated with tumor progression in GC and may serve as a biomarker for poor prognosis.     

Diffuse large B-cell lymphoma with extra Bcl-2 gene signals detected by FISH analysis is associated with a "non-germinal center phenotype"

Amplification and translocation of the Bcl-2 gene has been detected in a certain subset of diffuse large B-cell lymphomas (DLBCL). The correlations among Bcl-2 protein expression, gene translocation or amplification, and the molecular signature determined by cDNA array are poorly understood. This study examined 25 cases with de novo nodal DLBCL. Interphase fluorescence in situ hybridization (FISH) analysis was performed to evaluate the Bcl-2 gene using IGH/BCL2 and CEP18 centromere probes (Vysis). When extra Bcl-2 gene signals were observed in each tumor cell and when these signals were in proportion to the extra CEP18 probe signals, we regarded the findings as indicating the presence of an additional chromosome 18; when extra Bcl-2 signals were observed but additional CEP18 signals were not, we regarded the findings as indicating the presence of gene amplification. A panel of 3 antigens (CD10, Bcl-6, and MUM-1) was applied to categorize each case as either a "germinal center B-cell (GCB) phenotype" or a "non-GCB phenotype." Of the 25 cases examined, 8 cases (32%) were classified as "GCB phenotype" and 17 cases (68%) were classified as "non-GCB phenotype." A FISH analysis revealed that t(14;18) was detected in 2 of the 8 cases (25%) with the "GCB phenotype" but in none of the 17 "non-GCB phenotype" cases. Extra Bcl-2 gene signals were detected in 7 of the 25 (28%) cases examined: n = 5 for an additional chromosome 18, n = 1 for gene amplification, and n = 1 for additional chromosome 18 + gene amplification. Extra Bcl-2 gene signals were exclusively detected in DLBCL with the "non-GCB phenotype"; these cases, with the exception of one, stained strongly positive for Bcl-2. The DLBCLs with Bcl-2 protein overexpression were classified into at least two heterogeneous molecular groups, based on the results of the FISH analysis.     

Clinicopathologic reassessment of primary cutaneous B-cell lymphomas with immunophenotypic and molecular genetic characterization

Primary cutaneous B-cell lymphomas (PCBLs) may have particular clinicopathologic characteristics distinct from their lymph node-based counterparts. It has been suggested that PCBLs should have a separate classification system. The aim of this study was to determine whether the Revised European-American Lymphoid Neoplasms (REAL) classification is applicable to PCBL. Thirty-nine cases of PCBL from 36 patients, consisting of 20 men and 16 women (median age 66 yrs), were included in this study. Paraffin-section immunohistochemistry for CD3, CD5, CD10, CD20, CD43, Bcl-2, Bcl-6, and cyclin D1 was performed in all cases. Immunostaining for immunoglobulin light chains was also performed on cases histologically diagnosed as extranodal marginal zone lymphoma (MZL) and primary cutaneous B-cell lymphoma unclassifiable (PCBLu). Polymerase chain reaction (PCR) analysis of t(14;18) was performed in all cases. Immunoglobulin heavy chain gene rearrangement (VDJ) was tested by PCR on all follicle center lymphoma (FCL), MZL, and PCBLu cases. The 39 cases consisted of 15 (39%) FCLs, 13 (33%) diffuse large B-cell lymphomas (DLCL), 9 (23%) extranodal MZL, and 2 cases of PCBLu. Anatomically, 59% of PCBLs occurred in the head and neck, of which approximately 57% were FCL. Five of six cases presenting on the lower extremity were DLCL. Follow-up data was available from all 39 patients with a mean of 50.8 months. All but two patients are alive with or without disease at last contact. One patient with DLCL died of lung metastases and the other DLCL patient died of sepsis as a complication of therapy. In all 15 cases of FCL, CD10 and/or Bcl-6 expression supported the follicle center origin of the neoplastic cells. In contrast to previous reports, we found that 53% (8 of 15) of primary cutaneous FCL had either Bcl-2 protein expression or t(14;18). Our data indicate that many cases of primary cutaneous FCL have Bcl-2 alterations similar to their nodal counterpart. We found that 95% (37 of 39) of PCBLs could be classified according to the REAL classification, supporting its applicability in cutaneous lymphomas.