Expression of lymphocyte homing receptors and vascular addressins in low-grade gastric B-cell lymphomas of mucosa-associated lymphoid tissue.

In this study, we examined lymphocyte homing receptor and vascular addressin expression in a case of primary gastric B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) with a secondary intestinal spread. We compared the findings with that observed in B cells of normal MALT and MALT acquired as a consequence of Helicobacter pylori-associated gastritis and other low-grade gastric B-cell MALT lymphomas. The neoplastic B cells in the gastric tumor were alpha 4 beta 7-, CD62L+, whereas the intestinal secondary was alpha 4 beta 7+, CD62L-. Incubation of isolated tumor cells from the stomach by H. pylori generated T-cell-dependent proliferation of neoplastic B cells and induced expression of alpha 4 beta 7 integrin similar to the intestinal tumor. These observations indicate that reversal of homing receptor profile in the gastric tumor by antigen specific stimulation may be responsible for secondary intestinal dissemination. In normal stomach and normal MALT, alpha 4 beta 7 and CD62L expression reflected the differentiation of the B cell. Plasma cells were alpha 4 beta 7+, CD62L-, whereas a subset of memory B cells were alpha 4 beta 7-, CD62L+. Homing receptor expression in MALT lymphoma B cells was heterogeneous, however, in line with their memory B-cell phenotype in the majority of cases, the neoplastic B cells were alpha 4 beta 7-, CD62L+. Neoplastic plasma cells were always alpha 4 beta 7+, CD62L-. The venules in normal gastric mucosa expressed mucosal addressin cell adhesion molecule-1 but not peripheral lymph node addressin. In normal MALT, H. pylori-associated follicular gastritis and MALT lymphomas high endothelial venules coexpressed mucosal addressin cell adhesion molecule-1 and peripheral lymph node addressin. These findings suggest expression of lymphocyte homing receptors by B cells and vascular addressins by mucosal venules are similar in normal MALT and MALT lymphomas, and factors controlling normal mucosal B-cell traffic are also operational in MALT lymphomas.     

Loss of expression of alpha4beta7 integrin and L-selectin is associated with high-grade progression of low-grade MALT lymphoma.

Expression of adhesion molecule in low-grade B-cell mucosa-associated lymphoid tissue (MALT) lymphoma of the gastrointestinal tract has been reported in recent years, but these reports have primarily focused on low-grade gastrointestinal MALT lymphoma. In this study, we examined the lymphocytic homing receptor alpha4beta7 integrin, L-selectin, and VLA-4 and mucosal addressin cell adhesion molecule-1 (MAdCAM-1) in low-grade lymphoma of the gastrointestinal tract and other organs such as the ocular adnexa and thyroid. We also observed changes in the expression pattern associated with high-grade transformation. Neoplastic cells in the gastrointestinal low-grade lymphoma and the low-grade component of high-grade MALT lymphoma were found to be alpha4beta7 integrin(+), L-selectin(+), whereas the gastrointestinal high-grade component and diffuse large B-cell lymphoma were found to be alpha4beta7 integrin(-), L-selectin(-). High endothelial venules in the gastric MALT lymphomas expressed MAdCAM-1. In the ocular adnexa low-grade MALT lymphoma, most cases were alpha4beta7 integrin(-), L-selectin(+); and in the thyroid, most cases of both low- and high-grade MALT lymphoma were alpha4beta7 integrin(-), L-selectin(-). These findings show that alpha4beta7 integrin and L-selectin may play an important role in the lymphocyte homing of gastrointestinal low-grade MALT lymphoma and in the loss of alpha4beta7 integrin expression throughout the course of high-grade progression.     

Characterization of tumor-infiltrating T lymphocytes in B-cell lymphomas of mucosa-associated lymphoid tissue.

B-cell lymphomas of mucosa-associated lymphoid tissue invariably contain large numbers of reactive tumor-infiltrating T cells. In the stomach, these lymphomas develop secondary to Helicobacter pylori infection, and clinical and in vitro studies have shown that their growth depends on help provided by H. pylori-specific T cells. In this study we characterized tumor-infiltrating T cells in low- and high-grade B-cell lymphomas of mucosa-associated lymphoid tissue using immunohistochemistry. In most cases, CD4+ T cells dominated and almost all T cells were CD45RO+ memory cells. In 11 of 13 cases studied, the proliferating T cells were CD4+ and no proliferation was observed in the CD8+ subset. In low-grade lymphomas, between 7 and 24% of T cells expressed CD40L whereas no CD40L expression was observed in the majority of high-grade tumors. Examination of homing receptor profile showed that both alpha 4 beta 7 integrin+ and L-selectin+ T cells were present. Examination of T cell diversity by a panel of antibodies against different T-cell receptor V beta regions and by analysis of T-cell receptor genes using polymerase chain reaction suggested that the T cells in these tumors were polyclonal. These results show that low-grade B-cell lymphomas of mucosa-associated lymphoid tissue contain a significant population of activated helper T cells that may be important in supporting tumor growth.     

bcl-10蛋白异常表达对黏膜相关淋巴组织结外边缘区B细胞淋巴瘤的诊断价值

目的探讨bcl-10蛋白表达对黏膜相关淋巴组织结外边缘区B细胞淋巴瘤（MALT淋巴瘤）的诊断价值。方法收集140例不同部位的MALT淋巴瘤,包括胃38例、眼眶35例、肠16例、皮肤15例、涎腺15例、肺14例、甲状腺3例、其他部位4例。对照：10例扁桃体反应性滤泡增生（RFH）、5例眼眶的淋巴组织增生和143例非MALT淋巴瘤、不同类型的非霍奇金淋巴瘤（NHL）,包括20例NK／T细胞淋巴瘤、20例滤泡性淋巴瘤（FL）、20例间变性大细胞淋巴瘤（ALCL）、20例淋巴结内弥漫大B细胞淋巴瘤（DLBCL）、10例原发胃DLBCL、13例淋巴结边缘区淋巴瘤（NMZL）、12例套细胞淋巴瘤（MCL）、11例脾脏边缘区淋巴瘤（SMZL）、6例血管免疫母细胞性T细胞淋巴瘤（AITL）、6例外周T细胞淋巴瘤（PTCL）、3例B．小淋巴细胞淋巴瘤（B-SLL）、1例淋巴浆细胞性淋巴瘤（LPL）和1例浆细胞瘤。免疫组织化学EnVision法检测bcl-10蛋白;免疫组织化学双标记法检测CD20与bcl-10的共表达。结果在扁桃体RFH中,bel-10蛋白呈中等强度表达于生发中心B细胞质中,套细胞不表达,边缘区细胞和副皮质区T细胞呈弱表达。在眼眶淋巴组织增生中,2例bel-10阴性,3例主要呈淋巴滤泡生发中心B细胞质阳性,与扁桃体RFH的表达类似。在非MALT淋巴瘤的其他类型NHL中,除3例（3／10）原发胃DLBCL呈胞核阳性外,其余均未见胞核表达;在不同NHL中的胞质阳性分别为：结内（12／20）和胃（7／10）DLBCL、FL和ALCL（16／20）、PTCL（5／6）、AILT（6／6）、NMZL（13／13）、SMZL（11／11）、B-SLL（3／3）和浆细胞瘤（1／1）,11例MCL呈胞质可疑阳性,20例NK／T细胞淋巴瘤和1例LPL阴性;在部分淋巴瘤中可见肿瘤性细胞表达而反应性小淋巴细胞不表达：MALT淋巴瘤之bcl-10的总表达率为92．1％（129／140）,其中54．3％（76／140）胞质阳性,37．9％（53／140）胞核阳性;但不同部位之胞核阳性率有所不同。在MALT淋巴瘤中,bcl-10蛋白核强表达最常见于眼眶（25．7％,9／35）;除出现异常bcl-10胞核表达外,约20％有反应性滤泡的病例呈生发中心失表达。双标记显示bcl-10阳性细胞为CD20阳性细胞,但CD20阳性细胞多于bcl-10阳性细胞。结论（1）淋巴细胞增生性病变中bcl-10蛋白普遍表达,细胞质表达可出现在多数NHL和反应性增生中,但在淋巴瘤中呈肿瘤细胞表达而反应性细胞不表达,提示bcl-10异常可能与部分淋巴瘤的形成有关;（2）细胞核内bcl-10异常表达主要见于MALT淋巴瘤;眼眶、肺等部位的胞核强阳性和生发中心阴性的特殊模式,对MALT淋巴瘤的诊断及其与反应性病变的鉴别诊断有一定辅助意义。     

Primary follicular lymphoma of the small intestine: alpha4beta7 expression and immunoglobulin configuration suggest an origin from local antigen-experienced B cells

Primary follicular lymphoma of the gastrointestinal tract (GI-FL) is a rare so far poorly studied entity. We analyzed four FL cases located in the small intestine and duodenum to gain insight in their pathogenesis and to find an explanation for their low tendency to disseminate outside the GI tract. GI-FLs resemble nodal FLs with respect to morphology and expression of typical GC markers such as CD10, CD38, and BCL-6. We established that the high levels of the anti-apoptosis protein BCL-2 in the tumor cells are in all cases due to a t(14;18) involving the immunoglobulin heavy chain and BCL-2 loci. Detailed immunoglobulin gene analyses on microdissected tissue samples further supported the GC-cell derivation: GI-FLs carry extensively mutated variable heavy-chain genes. The mutation patterns indicated that at some time point in development stringent antigen receptor-based selection processes must have occurred. Interestingly, three of four neoplasms expressed surface IgA, an immunoglobulin class typical of the mucosal immune system and seldom found in nodal FL. In contrast to nodal FLs, the GI-FLs expressed the alpha4beta7 integrin, an established mucosa-homing receptor also expressed by normal intestinal B and T lymphocytes and by low-grade mucosa-associated lymphoid tissue lymphomas. However, the chemokine receptor CXCR3, expressed on low-grade mucosa-associated lymphoid tissue lymphomas, was not detected on the GI-FLs or on nodal FLs. The combined data suggests that primary FL of the small intestine is a distinct entity that originates from local antigen-responsive B cells.     

Heterogeneity of protein kinase C beta(2) expression in lymphoid malignancies

AIMS: Protein kinase C (PKC) beta is an important regulator of lymphoid survival and its expression has been shown to be altered in lymphomas. The aim was to determine the expression of PKC beta(2) in various subtypes of lymphoproliferative diseases by immunohistochemistry. METHODS AND RESULTS: One hundred and forty archival samples representing various subtypes of lymphoproliferative diseases were analysed. Certain subtypes, such as mantle cell, lymphocytic or follicular lymphoma, were found to express PKC beta(2) in > 90% of the samples. In follicular lymphomas, the follicular lymphomatous areas were constantly labelled, whereas residual germinal centres remained negative. In follicular hyperplasia, PKC beta(2)+ cells were found in the mantle and marginal zones. Most angioimmunoblastic T-cell lymphomas, lymphoblastic T-cell lymphomas and marginal zone/mucosa-associated lymphoid tissue (MALT) lymphomas were labelled with anti-PKC betaII antibody, but the pattern of expression was more heterogeneous in these subtypes. A minority of diffuse large B-cell lymphomas were stained and most plasma cell malignancies were negative. None of the cases of Hodgkin's disease and anaplastic large cell lymphoma expressed PKC beta(2). CONCLUSIONS: PKC beta(2) expression varies significantly among lymphoproliferative diseases. In our series, the highest level of expression was found in mantle cell lymphomas and chronic lymphocytic lymphoma.     

CCR6 is a functional chemokine receptor that serves to identify select B-cell non-Hodgkin's lymphomas

Several recent studies have revealed important contributions of chemokines and their receptors to the development and progression of both hematopoietic and nonhematopoietic neoplasms. The chemokine receptor CCR6 is unusual in that it mediates leukocyte chemotaxis in response to a single chemokine, CCL20 (macrophage inhibitory factor-3alpha), as well as in response to a family of antimicrobial peptides termed "beta-defensins." CCR6 is critical for mucosal immunity, and expression of the receptor is tightly regulated on hematopoietic cells. Here we characterize the expression of CCR6 on B cells and B-cell non-Hodgkin's lymphomas. We demonstrate that CCR6 expression is limited to cells comprising the mantle and marginal zones of the secondary lymphoid tissues and serves to identify the majority of mantle cell, marginal zone, and mucosa-associated lymphoid tissue lymphomas. Furthermore, we show that CCR6 serves as a functional chemokine receptor when expressed by neoplastic cells. Finally, we establish that the cognate ligand for CCR6 is present on mucosal epithelium infiltrated by neoplastic cells in select extranodal lymphomas. Thus, CCR6 is a useful new marker identifying a subset of B-cell non-Hodgkin's lymphomas and likely contributes to the localization of select extranodal lymphomas at mucosal sites.     

Expression of classical protein kinase C subspecies in non-neoplastic lymphocytes and non-Hodgkin's lymphomas: an immunohistochemical study

It is generally accepted that phosphorylation plays a pivotal role in the cellular response of cell differentiation and proliferation. Immunohistochemical expression of classical protein kinase C (cPKC) subspecies (alpha, beta and gamma) in eight reactive lymphoid tissues, three normal spleens and 149 non-Hodgkin's lymphomas was examined. cPKC beta was observed primarily in the mantle zone B cells, but appeared as very faint staining in Ki-67 positive proliferated B cells in the germinal centers of secondary lymph follicles. In contrast to the reactive state, high levels of cPKC subspecies were recognized in the majority of 149 cases of non-Hodgkin's lymphoma, including those thought to have arisen from germinal center cells such as follicular lymphoma. The expression of cPKC alpha was found in higher frequency in T cell lymphomas than B cell lymphomas (P < 0.01) by the Chi-squared test. High levels of cPKC alpha were present only in high grade or highly aggressive lymphomas, showing the highest incidence in the small non-cleaved cell type, according to the International Working Formulation and National Cancer Institute (P < 0.01). cPKC gamma was not detected in normal lymphoid cells and was expressed in only four cases of non-Hodgkin's lymphomas. It is presumed that cPKC alpha and beta have a relationship to cell activation and proliferation of lymphoid cells of reactive and neoplastic states. It might be considered that the expression of cPKC alpha may have a relationship with aggressiveness in non-Hodgkin's lymphomas.     

Cytology and immunophenotyping of low- and intermediate-grade B-cell non-Hodgkin's lymphomas with a predominant small-cell component: a study of 56 cases

Diagnosis of non-Hodgkin's lymphomas based on cytologic evaluation of fine-needle aspirates and body cavity fluids has gained increasing acceptance. However, the accurate diagnosis and classification of low- and intermediate-grade B-cell lymphomas with a predominant small-cell population still present a diagnostic challenge. In this study, we reviewed the cytology and immunophenotype of 56 cases of low- and intermediate-grade non-Hodgkin's B-cell lymphomas composed of predominantly small cells, with histologic correlation in all cases. These cases consisted of 23 small lymphocytic lymphomas (SLL), 15 follicular center lymphomas (FCL), grade I (small cell predominant), 8 lymphoplasmacytoid lymphomas (LPL), 6 mantle-cell lymphomas (MCL), and 4 marginal zone lymphomas (MZL) including mucosa-associated lymphoid tissue (MALT) lymphoma. Histologic comparison was available in all cases. A cytologic diagnosis of malignant lymphoma was made in 46 (82%) cases. Based on cytomorphology and immunophenotyping of cytologic material, 39 (85%) cases were correctly classified using the Revised European and American Lymphoma classification. In 7 (11%) cases, which included 3 FCLs, 2 MALT lymphomas, and 2 SLLs, the findings were atypical but not diagnostic of lymphoma. There were 3 (5%) false-negative cases. They were 2 SLLs and a FCL. Immunophenotyping done in 4 "atypical" cases was noncontributory. No marker studies were done in the remaining "atypical" case and all false-negative cases. We conclude that cytology, when used in conjunction with immunophenotyping, can accurately diagnose and in most instances subclassify low- and intermediate-grade B-cell non-Hodgkin's lymphoma with a predominant small-cell population.     

Expression of heat-shock protein-90 in non-Hodgkin's lymphomas.

Heat-shock protein-90 (HSP90) inhibitors are currently being used in phase I clinical trials for treating patients with a variety of neoplasms including lymphomas. Using immunohistochemical methods, we assessed for HSP90 expression in 412 cases of non-Hodgkin's lymphoma. In B-cell lymphomas, HSP90 was moderately to strongly expressed in all cases of Burkitt's lymphoma (5/5, 100%), and in subsets of follicular lymphoma (17/28, 61%), diffuse large B-cell lymphoma (27/46, 59%), nodal marginal zone B-cell lymphoma (6/16, 38%), plasma cell neoplasms (14/39, 36%), small lymphocytic lymphoma/chronic lymphocytic leukemia (3/9, 33%), mantle cell lymphoma (12/38, 32%) and lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia (3/10, 30%). HSP90 was weakly expressed in six of 14 (43%) cases of extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue. In T-cell lymphomas, HSP90 was moderately to strongly expressed in subsets of anaplastic large-cell lymphoma (14/24, 58%; 9/12 ALK+ and 5/12 ALK-), precursor-T-cell lymphoblastic leukemia/lymphoma (20/65, 31%), unspecified peripheral T-cell lymphoma (8/43, 23%) and angioimmunoblastic T-cell lymphoma (2/17, 12%). HSP90 was weakly expressed in seven of 58 (12%) cases of mycosis fungoides. We conclude that HSP90 is commonly expressed in a subset of many types of B- and T-cell lymphoma. These data suggest that many lymphoma types are suitable targets for modulation of HSP90 activity, and that HSP90 inhibitors are a potential investigational therapy for lymphoma patients.     

Marginal zone B-Cell lymphoma among primary B-Cell lymphoma of Waldeyer's ring: histopathologic and immunohistochemical study of 16 tonsillectomy specimens

Two subtypes of marginal zone B-cell lymphoma (eg, mucosa-associated lymphoid tissue [MALT] type and splenic type) have been reported in the lymph node. To determine the presence or absence of marginal zone B-cell lymphoma of MALT type and the splenic type among Waldeyer's ring (WR) lymphomas, 16 tonsillectomy specimens were studied. Ten cases (63%) were marginal zone B-cell lymphoma. Among marginal zone B-cell lymphoma, 7 were the MALT type and the remaining 3 cases of marginal zone B-cell lymphoma were the splenic type. Moreover, 4 cases of 7 MALT-type lymphomas contained numerous large cells (diffuse large B-cell lymphoma arising from a low-grade marginal zone B-cell lymphoma of MALT type). The low incidence of primary mucosa-associated lymphoid tissue type lymphoma of WR in previous reports may be because it is difficult to correctly identify the characteristic histologic findings of MALT-type lymphoma because of the small biopsy size.     

Study of vimentin expression in non-Hodgkin's lymphoma using paraffin sections.

Human non-Hodgkin's lymphomas were studied by means of an avidin-biotin complex immunoperoxidase method using several monoclonal antibodies against the intermediate filament protein, vimentin. The study cases were 61 B-cell lymphomas (including 2 plasmacytomas) and 30 T-cell lymphomas (including 8 cases of mycosis fungoides). Twelve of the 61 B-cell lymphomas were positive for vimentin, and were composed of extrafollicular-center cells such as immunoblastic and plasmacytoid cells. On the other hand, lymphomas of follicular center cell origin were negative for vimentin. All cases of T-cell lymphoma except for 14 (all of 9 AILD-type lymphomas, all of 4 lymphoblastic lymphomas and one diffuse mixed small/large lymphoma) were positive for vimentin. Although vimentin expression appeared to be influenced by various conditions such as the proportion of T- and B-cell subsets, or B-cell proliferation rate, follicular center cells were constantly negative for vimentin.     

Expression of lymphocyte homing receptor antigen in non-Hodgkin's lymphoma.

In man, lymphocyte binding to high endothelial venules (HEVs) involves specific 85-95 kd cell surface glycoprotein(s) recognized by the monoclonal antibodies Hermes-1 and Hermes-3. These putative "homing receptor" molecule(s) are believed to play an important role in the normal regulation of lymphocyte circulation. To investigate the possibility that homing receptors also play a role in the biology of lymphoid malignancies, the authors studied over 300 cases of non-Hodgkin's lymphoma by immunohistologic staining with Hermes-1 and -3, antibodies that define two distinct epitopes on the gp 85-95 putative homing receptor molecules. Furthermore, they directly compared expression of the Hermes-3 antigen with clinical extent of disease in 57 patients with diffuse large cell lymphoma. They found that staining of the various subtypes of lymphoma was heterogeneous, and in general correlated with patterns of expression seen in benign lymphoid populations. Essentially all normal lymphoid populations examined, except germinal center B cells and most cortical thymocytes, bear a high level of homing receptor antigen. Similarly, nearly all peripheral T-cell lymphomas, diffuse small cell lymphomas of B lineage, and plasma cell tumors were positive for homing receptor antigen (95%, 97%, and 100%, respectively). Small noncleaved cell, follicular, and diffuse large cell lymphomas of B lineage, tumors having morphologic or immunologic features resembling germinal center cells, frequently failed to express Hermes-defined epitopes (81%, 41%, 25% Hermes-3-, respectively). Antigen expression in T-lymphoblastic lymphomas strongly correlated with immunophenotypic subtypes: only 8% of CD4+/CD8+ were Hermes-1+ versus 86% of CD4-/CD8- and 43% of CD4+/CD8-. Hermes-3 expression by cases of diffuse, large cell lymphoma which showed generalized lymph node involvement (a pattern strongly suggestive of HEV-mediated spread; 100% Hermes-3+, mean intensity 3.4) was higher than that of cases with localized or multifocal, contiguous involvement (consistent with lymphatic spread; 69% Hermes-3+, mean intensity 2.2), but these differences did not achieve statistical significance. The results indicate that homing receptor antigen expression, although perhaps necessary for wide-spread blood-borne lymphoma dissemination to lymphoid sites, is not in and of itself sufficient to predict such behavior in this subtype of lymphoid malignancy.     

Primary gastric lymphoma—a tumour of mucosa-associated lymphoid tissue. A histological and immunohistochemical study of 36 cases

A series of 36 cases of non-Hodgkin's lymphoma of the stomach have been analysed using routine histological techniques and immunohistochemistry. All cases were categorized as follicle centre cell lymphomas. Apart from two cases who had nodal lymphomas followed by gastric lymphomas, all cases appeared to represent primary lymphoma of mucosa-associated lymphoid tissue. It is proposed that the morphology and behaviour of these tumours reflect their origin from gut-associated lymphoid tissue. Physiologically well-differentiated examples show monotypic plasmacytic differentiation. Infiltration of gastric glands by follicle centre cells forming characteristic lympho-epithelial lesions is, we believe, a pathognomonic feature of primary gastric lymphoma. The spread of these tumours is within the mucosa-associated lymphoid tissues involving, in particular, the nasopharynx and lung but seldom spreading to peripheral lymph nodes or bone marrow. This concept of gastric lymphomas as primary neoplasms of gut-associated lymphoid tissue has important implications with respect to the investigation and treatment of this disease.     

Follicular dendritic cells in extranodal non-Hodgkin lymphomas of MALT and non-MALT type

Extranodal lymphomas of the thyroid (n=19), kidney (n=15) and testis (n=30) were investigated histologically and immunohistochemically for follicular dendritic cell pattern using the monoclonal antibody Ki-FDC1P. This recognizes follicular dendritic cells in paraffin sections. Follicular dendritic cells were most predominant in lymphomas of the thyroid. These thyroid lymphomas showed the morphological features of mucosa-associated lymphoid tissue (MALT) type lymphomas in 18 of 19 cases and were classified as high-grade malignant lymphoma of MALT type with evidence of a low-grade malignant component (n=18). Ten of these cases contained destroyed reactive follicles of follicular dendritic cells. In 6 of these 10 cases follicular dendritic cells occurred in a pattern of tumour-associated abortive follicle type. The remaining lymphoma of the thyroid was an immunoblastic lymphoma of B-cell type showing no detectable follicular dendritic cells. In extranodal lymphomas of non-MALT type follicular dendritic cells occurred in only two cases where immunocytoma involved the kidney. Malignant lymphomas of the kidney (chronic lymphocytic leukaemia,n=2; immunocytoma,n=4; centroblastic lymphoma,n=9) and of the testis (immunocytoma,n=2; centroblastic lymphoma,n=27; immunoblastic lymphoma of B-cell type,n=1) revealed no characteristics of MALT type lymphoma, cytologically or with respect to follicular dendritic cells. Classical lymphoepithelial lesions formed by centrocyte-like cells, a hallmark of MALT, occurred exclusively in thyroid lymphomas of MALT type. Although occurrence of classical lymphoepithelial lesions formed by centrocyte-like cells was limited to thyroid lymphomas of MALT type, a growth pattern of lymphoid blasts, with formation of lesions mimicking lymphoepithelial lesions superficially, was found in 6 of 27 testicular centroblastic lymphomas. Follicular dendritic cells in non-Hodgkin's lymphomas of MALT type show distinct follicular patterns not found in other extranodal lymphomas such as those found in the kidney and testis.     

BAFF-R, the major B cell-activating factor receptor, is expressed on most mature B cells and B-cell lymphoproliferative disorders

B cell-activating factor receptor (BAFF-R) is one of three known receptors for BAFF, a critical regulator of B- and T-cell function. In mice, BAFF-R is required for B-cell maturation and survival, and in mice and humans, the overproduction of BAFF is associated with autoimmune disease. We sought to determine the normal pattern of BAFF-R expression at specific stages of B- and T-cell development and whether this pattern of expression corresponds with related B- and T-cell neoplasms. Most circulating human B cells and a small subset of T cells are BAFF-R-positive. In reactive lymphoid tissues, BAFF-R is expressed by B cells colonizing the mantle zones, by a subset of cells within germinal centers, and rare cells in the interfollicular T-cell zone. BAFF-R is also expressed by B cells colonizing the splenic marginal zone. Seventy-seven (78%) of 116 cases of B-cell lymphoproliferative disorders were BAFF-R-positive by immunohistochemical and/or flow cytometric immunophenotypic analysis, including most cases of mantle cell lymphoma, follicular lymphoma, marginal zone lymphoma, chronic lymphocytic leukemia, hairy cell leukemia, and diffuse large B-cell lymphoma. In contrast, cases of precursor B lymphoblastic lymphoma, Burkitt lymphoma, and nodular lymphocyte-predominant Hodgkin lymphoma exhibit weak to negative staining for BAFF-R. All cases of classical Hodgkin lymphoma and T-cell lymphomas were BAFF-R-negative, including all cases of anaplastic large cell lymphoma, adult T-cell leukemia/lymphoma, angioimmunoblastic T-cell lymphoma, and peripheral T-cell lymphoma, unspecified. These findings highlight BAFF-R as a marker of both normal and neoplastic B cells and raise the possibility that BAFF-R expression is necessary for the survival of a subset of neoplastic B lymphocytes analogous to its known role in promoting normal B-cell maturation and survival.     

Paediatric marginal zone lymphoma and hyperplasia

Marginal zone lymphomas (MZL) are low-grade B-cell lymphomas arising from post-germinal memory B-cells occurring in adults with a slight female predilection. They are sub-categorized into nodal (NMZL), extra-nodal/mucosa-associated lymphoid tissue (MALT) and splenic (SMZL). MALT lymphomas are the most common (70%) followed by SMZL (20%) and NMZL (10%). Histologic transformation into aggressive B-cell lymphoma can rarely occur. MZL is extremely uncommon in the paediatric population and unlike in adults, is predominantly nodal. Paediatric NMZL (pNMZL) is an indolent, low-grade lymphoma with unique clinical and morphologic features. In contrast paediatric MALT lymphoma and SMZL are extremely uncommon and resemble their adult counterparts. Paediatric marginal zone lymphomas must be differentiated from paediatric-type follicular lymphoma (PFL) and marginal zone hyperplasia (MZH) of lymph nodes and mucosa-associated lymphoid tissue. This review summarizes the pathogenesis, morphology, genetic features of paediatric MZL and marginal zone hyperplasia. Recognition of these entities is important to avoid unnecessary therapy.     

Follicular lymphomas of the gastrointestinal tract. Pathologic features in 31 cases and bcl-2 oncogenic protein expression.

The gastrointestinal tract is the most common site for extranodal lymphomas, but follicular lymphomas involving the gut are rare. To study their pathologic features and bcl-2 expression, 31 follicular lymphomas of the GI tract were reviewed and unstained paraffin sections from 24 of the cases were immunohistochemically stained using a monoclonal antibody for the peptide product of the proto-oncogene bcl-2. The most common site of lymphoma involvement was the small intestine, especially the terminal ileum. Gastric lymphomas tended to present clinically with symptomatic ulcers and small intestinal lesions presented with obstruction. Five cases involving the terminal ileum or colon had a gross appearance of multitudinous mucosal polyps and were considered to represent examples of "multiple lymphomatous polyposis." Enhanced expression of the bcl-2 oncogenic protein was detectable in lymphoma cells in 75% of cases and at lower levels in normal lymphoid cells in most cases. Small cleaved or mixed cell lymphomas were more likely to show enhanced expression than were large cell cases. Reactive germinal centers showed no bcl-2 staining. It is concluded that follicular GI lymphomas are associated with distinctive pathological features. In their tendency to express bcl-2, these neoplasms resemble their lymph node-based counterparts. Immunohistochemical staining for enhanced bcl-2 expression is of potential diagnostic utility in distinguishing between follicular lymphoma and follicular lymphoid hyperplasia in the gastrointestinal tract. The relevance of the results to lymphoma of mucosa-associated lymphoid tissue (MALT) is discussed.     

Extranodal lymphomas of the head and neck

Malignant lymphomas represent approximately 5% of all malignant neoplasms of the head and neck and may involve nodal or extranodal sites. Nodal head and neck lymphomas are similar to other nodal sites and are not further reviewed here. The head and neck region is the second most frequent anatomical site of extranodal lymphomas (after the gastrointestinal tract). Most are non-Hodgkin's lymphomas of B-cell lineage, and overall diffuse large B-cell lymphoma is the most common type. Hodgkin's lymphoma rarely occurs in extranodal sites. Other hematologic neoplasms that commonly involve extranodal sites of the head and neck are also discussed. In this review, we begin by discussing lymphomas involving the head and neck according to anatomical site. Then we discuss specifically the pathological findings of extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue, plasmablastic lymphoma, extramedullary plasmacytoma, and extranodal natural killer/T-cell lymphoma of nasal type.     

IL-2 receptor expression in human lymphoid lesions. Immunohistochemical study of 166 cases.

Interleukin-2 (IL-2) receptor expression is a feature of T-cell activation and T-cell neoplasia. Expression of the IL-2 receptor in human lymphoid lesions was studied in a series of 166 immunophenotyped cases, including nodal and extranodal reactive lymphoid proliferations (44 cases), low-grade B-cell lymphomas (27 cases), intermediate and high grade B cell lymphomas (42 cases), peripheral T-cell lymphomas (13 cases), Hodgkin's disease (12 cases), histiocytic proliferations (15 cases), nonhematopoietic tumors (16 cases), and miscellaneous lesions (7 cases). Low levels of receptor expression were seen in reactive lymphoid lesions, low-grade B-cell lymphomas, and nonhematopoietic tumors (20%, 7%, and 25% of cases, respectively, with greater than 10% positive cells). High levels of receptor expression were seen in cases of peripheral T-cell lymphoma and histiocytic proliferations (86% and 100% of cases, respectively, with greater than 10% positive cells). Intermediate levels of expression were seen in Hodgkin's disease (including Reed-Sternberg cells) and some cases of intermediate and high-grade B-cell lymphomas (58% and 50% of cases, respectively, with greater than 10% positive cells). IL-2 receptor expression is not confined to T-cell neoplasia, but is also a feature of neoplastic and nonneoplastic histiocytic proliferations, Hodgkin's disease, and some intermediate and high-grade B-cell lymphomas. Biologic and therapeutic implications are discussed.