Cutaneous b-cell lymphomas of follicular and marginal zone types: use of Bcl-6, CD10, Bcl-2, and CD21 in differential diagnosis and classification

Cutaneous follicular lymphomas (FLs) and cutaneous B-cell lymphomas of extranodal marginal zone (MZL)/mucosal-associated lymphoid tissue (MALT) type may have morphologic overlap, despite the fact that they are thought to be of distinct derivation (germinal center vs. postgerminal center). The problem is compounded by the reported absence of bcl-2 expression by many cutaneous FLs, leading to speculation that cutaneous FL may be unrelated to nodal FL. The authors analyzed the expression of the germinal center-associated antigens bcl-6 and CD10 and of bcl-2 in 18 cutaneous B-cell lymphomas (10 FLs and eight MZLs), in relationship to CD21+ follicular structures, to clarify the relationship of nodal to cutaneous FLs and to explore the value of these antigens in differential diagnosis. The authors studied 10 cutaneous FLs (seven primary and three secondary) and eight MZLs (six primary and two secondary). The FLs (found in six men and four women age 45-75 years) involved the trunk (n = 3) and scalp, face and neck (n = 7). The MZLs (found in five women and three men age 34-81 years) involved the trunk (n = 4), face and neck (n = 2), and arm (n = 2). Immunostaining for CD21, bcl-6, CD10, and bcl-2 allowed the delineation of compartments within the tumors and yielded distinct patterns of staining in FL and MZL. In both follicular and interfollicular/diffuse areas of FL the neoplastic cells were bcl-6+ (10 of 10), often CD10+ (seven of 10, four of seven primary), and bcl-2+ (nine of 10, six of seven primary). Only three of seven cases (one of five primary) had bcl-2 rearrangement detectable by polymerase chain reaction. In the MZLs, the neoplastic B-cells were bcl-6-, CD10-, and bcl-2+ (eight of eight). Three patterns of CD21+ follicles were identified in MZL: reactive germinal centers, uniformly bcl-6+, CD10+, and bcl-2- (five of eight MZLs); colonized follicles, both bcl-6-, bcl-2+, and L26+ cells, and bcl-6+ and bcl-2- cells (five of eight MZLs); and expanded/colonized follicular dendritic cell meshworks, bcl-6- and bcl-2+ B cells with rare residual bcl-6+ and bcl-2- cells (four of eight MZLs). The authors conclude that cutaneous FLs express bcl-6 uniformly, usually express CD10 and bcl-2, and have a follicular pattern similar to nodal FL and consistent with a germinal center origin. The immunophenotype of cutaneous FL is distinct from that of cutaneous MZL, which is negative for bcl-6 and CD10. Colonized follicles in MZL, identified by CD21+ follicular dendritic cell meshworks, contained numerous bcl-6- and bcl-2+ B cells, and were readily distinguished from neoplastic follicles in FL. Conversely, CD21- interfollicular and diffuse areas in FLs contained bcl-6+ and CD10+ cells, which were not seen in diffuse areas of MZLs. Thus, the combination of bcl-2, bcl-6, and CD21 staining is useful for the distinction of cutaneous MZL from cutaneous FL.     

Peripheral T-cell lymphoma with follicular involvement and a CD4+/bcl-6+ phenotype

A truly follicular pattern is thought to be restricted to B-cell lymphomas. We observed a prominent follicular growth pattern in three cases of nodal peripheral T-cell lymphomas, of which two were initially diagnosed as follicular lymphomas. All three patients were male, ranged in age from 50 to 70 years, and had generalized lymphadenopathy at the time of diagnosis. The follicles were sharply demarcated in two cases and large and vague in one case; in all cases, they contained abundant follicular dendritic cells. Neoplastic cells were small to medium, with irregular cleaved or round nuclei and clear cytoplasm, which was abundant in one case. Lymphoma cells in all cases were CD4+ CD8- CD57- bcl-6, with CD10 coexpression in 2 cases. Clonal rearrangement of the gamma chain of the T-cell receptor gene was demonstrated in each case. These cases expand the differential diagnosis of lymphomas with a follicular growth pattern and suggest that neoplastic T cells may have the capacity to induce or home to follicular structures.     

Peripheral T-cell lymphoma with distinct perifollicular growth pattern: a distinct subtype of T-cell lymphoma?

Nine cases of peripheral T-cell lymphoma were identified in this study showing a distinctive growth pattern with partial distortion of the lymph node structure and prominent infiltration predominantly of marginal zones by medium-sized cells with clear cytoplasm and significant nuclear atypia. In the paracortical T-zone, there was a marked proliferation of high endothelial venules. Plasmocytosis and capsular fibrosis were other distinctive features. On immunohistochemistry, the lymphomas proved to be of T-helper cell origin (CD3+, CD4+, CD5+/-, CD8-, TIA1-) and proliferation was most prominent in the marginal zone of the regressive B-cell follicles. These cases have a characteristic morphology that may be sufficient to differentiate them as a variant from other peripheral T-cell lymphomas of the "not otherwise specified" group and to include them in the list of currently recognized lymphomas. Because of the distinct perifollicular growth pattern and incomplete effacement of the lymph node architecture, the differential diagnosis consists mainly of marginal zone B-cell lymphoma and reactive lesions.     

BCL-2 is consistently expressed in hyperplastic marginal zones of the spleen,abdominal lymph nodes,and ileal lymphoid tissue

BCL-2 is an antiapoptotic protein overexpressed in follicular lymphomas, principally as a result of the t(14;18)(q32;q21), and useful in distinguishing follicular lymphoma (usually BCL-2 positive) from follicular hyperplasia (BCL-2 negative). BCL-2 is also overexpressed in other lymphoma types without the t(14;18), including marginal zone B-cell lymphoma, because of other, poorly understood mechanisms. It has been suggested that BCL-2 immunoreactivity can distinguish between malignant (BCL-2 positive) and reactive (BCL-2 negative) marginal zone B cells. In this study, we evaluated 26 spleen, 10 abdominal lymph node, and 3 ileum specimens with marginal zone B-cell hyperplasia for BCL-2 expression immunohistochemically. We also analyzed these cases using polymerase chain reaction methods to evaluate for the presence of clonal rearrangements of the immunoglobulin heavy chain gene (IgH) using consensus V FRIII and J region primers, and the t(14;18) involving both the major breakpoint and the minor cluster regions of the bcl-2 gene. All (100%) cases of splenic, abdominal lymph node, and ileal marginal zone hyperplasia displayed strong BCL-2 reactivity in the marginal zone B cells. In all cases analyzed, IgH polymerase chain reaction demonstrated a polyclonal pattern, and bcl-2/JH DNA fusion sequences were not detected. Our results indicate that BCL-2 is consistently expressed by reactive marginal zone B cells of the spleen, abdominal lymph nodes, and ileal lymphoid tissue and should not be used as a criterion for discriminating between benign and malignant marginal zone B-cell proliferations involving these sites.     

Expression of bcl-6 and CD10 in primary mediastinal large B-cell lymphoma: evidence for derivation from germinal center B cells?

Primary mediastinal large B-cell lymphomas (LBCLs) constitute a unique subtype of diffuse LBCLs, with distinct clinical, immunophenotypic, and morphologic features. These lymphomas are thought to originate from the thymus, and it has been hypothesized that they derive from a population of B lymphocytes normally present in the thymic medulla. Most diffuse LBCLs harbor somatic mutations in their immunoglobulin genes, suggesting that they have been exposed to the germinal center. To investigate the possible relationship of mediastinal LBCLs to germinal center B cells, we analyzed the expression of bcl-6 and CD10 in 19 mediastinal LBCLs, using an immunoperoxidase technique on formalin-fixed tissue. We found that 19 of 19 (100%) mediastinal LBCLs were bcl-6+ and 6 of 19 (32%) mediastinal LBCLs were CD10+. Because mediastinal LBCLs usually lack BCL-6 gene rearrangement or mutations, expression of bcl-6 and CD10 in these tumors tends to support a germinal center derivation.     

T-cell-rich B-cell lymphomas. A clinicopathologic study of 19 cases.

T-cell-rich B-cell lymphomas (TCRBCLs) are recently described, unusual non-Hodgkin's lymphomas that have a diffuse morphology, a predominance of reactive T-cells, and a minority of neoplastic B-cells. The clinical and pathological features of 19 TCRBCLs, all of which demonstrated B-cell clonality, are presented. These lymphomas generally affected older patients by widespread disease and usually were nodal in origin. Treatment varied, but continuous complete remissions (eight patients) were achieved only in those receiving chemotherapy directed at intermediate-grade lymphomas. Although morphologically heterogeneous, all cases resembled peripheral T-cell lymphomas (PTCLs); several TCRBCLs also contained Reed-Sternberg-like cells. Flow cytometry or frozen-section immunoperoxidase failed to detect monotypic immunoglobulin (Ig) in eight of eight cases tested. In contrast, paraffin immunoperoxidase was very useful diagnostically, showing large L26 (CD20-associated) positive cells scattered singly or in small clusters among numerous small T-cells (UCHL1[CD45RO] positive) in all cases. Monotypic cytoplasmic Ig was present in 16 of 19 cases, one of which exhibited plasmacytic differentiation. Southern blot analysis demonstrated relatively faint Ig JH and/or JK bands, indicating a small monoclonal B-cell population in nine of 11 cases, one of which also showed a bcl-2 rearrangement. No T-cell receptor gene rearrangements were observed. These results showed that TCRBCLs may be easily confused with PTCLs or occasionally confused with Hodgkin's disease. TCRBCLs are probably heterogeneous biologically; some cases are of follicular center cell origin. These lymphomas respond to chemotherapy directed at intermediate-grade lymphomas, apparently have a better prognosis than PTCLs, and seem to represent morphological variants of different types of large B-cell lymphomas.     

Immunohistochemical study of the regional lymph nodes in gastric cancer

Immunohistochemical study with various monoclonal antibodies against the mononuclear cell surface antigen was performed on the regional lymph nodes of gastric cancer through Avidin-Biotin Complex (ABC) method. In the paracortical area (P.C.) of those lymph nodes without the metastasis of gastric cancer, T cells were dominant, and OKT3 positive (OKT3+) cells and OKT4+ cells were diffusely present, while OKT8+ cells were occasionally recognized. In the sinus, subsets of the above T cells, and OKT9+ cells and OKT10+ cells were observed. In the germinal center (G.C.), mantle zone (M.Z.) and primary follicle (P.F.), which were B cell regions, OKIa1+ cells and Leu12+ cells were diffusely present. OKB7+ cells, OKT9+ cells, OKT10+ cells and Leu7+ cells were also noted in G.C.. Leu8+ cells were observed in M.Z. and P.F.. OKIa1+ cells were occasionally noted in P.C. and sinus. In the lymph nodes with the metastasis, decrease of OKT4+ cells and increase of OKT8+ cells were noted in comparison to the lymph nodes without the metastasis. Using the tissue double fluorescence staining method, it was found that about half of the OKT4+ cells were helper T cells. The majority of OKT8+ cells were identified as cytotoxic T cells or their precursors. By preoperative endoscopic administration of OK-432 or PSK into the tumor, the IL-2 receptor+ cells, or OKM1+ cells and OKT4+ cells increased in the regional lymph nodes and the antitumor activity was intensified.     

Primary and secondary cutaneous diffuse large B-cell lymphomas: a multiparameter analysis of 25 cases including fluorescence in situ hybridization for t(14;18) translocation

Although primary cutaneous diffuse large B-cell lymphomas (DLBCLs) except for those of the leg are grouped together with primary cutaneous follicle center cell lymphoma in the European Organization for Research and Treatment of Cancer classification of primary cutaneous lymphomas, they typically lack the usual phenotypic profile of follicular lymphoma. Whether they are truly of follicular center cell origin, have a molecular pathogenesis similar to nodal follicular lymphoma, or have any biologic features that distinguish them from secondary DLBCL involving skin remains uncertain. To address these issues, a retrospective multiparameter study of 25 patients including clinical, histologic, immunophenotypic, and cytogenetic analyses was performed. A classic CD10+, bcl-6+ follicular center cell profile was found in 10 (40%) cutaneous DLBCL (2 of 11 primary, 5 of 8 secondary, 3 of 6 unclassified) with bcl-2 expression seen only in the nonprimary cases. Of the remaining cases, 14 cases (56%) were CD10-, bcl-6+, bcl-2+/- (9 primary) and one case (4%) was CD10-, bcl-6-, bcl-2+ (0 primary). Fluorescence in situ hybridization analysis showed a t(14;18) in 0 of 9 primary and 3 of 5 secondary cases. Primary cases were frequently found in the head/neck region, whereas secondary cases were more common on the trunk and extremities. Patients with primary disease were all alive, usually having received only local therapy, at a median follow-up of 19 months. Most secondary cases were treated with chemotherapy with only one untreated patient dead of disease at a median follow-up of 5 months. Primary cutaneous DLBCLs therefore appear to be distinctive as they have fewer features of follicular lymphoma than do secondary cases. Nevertheless, some appear to be of follicular center cell origin, even though they probably have a different molecular pathogenesis than most nodal follicular lymphomas.     

Sinonasal lymphoma: a clinicopathologic analysis of 58 cases from the Massachusetts General Hospital.

Few large series compare lymphomas of the nasal cavity with those of the paranasal sinuses. We studied the cases of 58 patients, 34 males and 24 females, aged 7 to 92 years (mean, 57 years), who had lymphoma involving the nasal cavity or paranasal sinuses. Thirty-three patients had diffuse large B-cell lymphoma (DLBCL). Twenty-three were male and 10 were female, with an age range of 7 to 91 years (mean, 63 years); two were HIV-positive. Only 2 of 11 cases tested (one in an HIV-positive patient and one of lymphomatoid granulomatosis type) were Epstein-Barr virus (EBV)-positive. Thirty (91%) involved paranasal sinuses, 10 with nasal involvement, whereas three cases had nasal, but not sinus, involvement. At last follow-up, 16 (67%) were free of disease 7 to 169 months later (mean, 65 months), and 8 (33%) had died of disease 2 to 166 months later (mean, 45 months). Seventeen patients had nasal-type natural killer (NK)/T-cell lymphoma. There were 10 women and 7 men, aged 27 to 78 years (mean, 48 years). Thirteen of 14 were EBV-positive. Sixteen patients had nasal involvement, eight with sinus involvement. Eleven (73%) of 15 were alive and well 6 to 321 months later (mean, 139 months), three (20%) died of lymphoma 1, 11, and 12 months later, and one (7%) is alive with disease. There was one case each of marginal zone B-cell lymphoma, Burkitt's lymphoma, Burkitt-like lymphoma, peripheral T-cell lymphoma of unspecified type, and adult T-cell lymphoma/leukemia. In an additional three cases, the lymphomas were composed predominantly of large cells, but no immunophenotyping could be performed for subclassification. In 19 cases (17 DLBCLs, 1 Burkitt-like lymphoma, and 1 lymphoma of uncertain lineage), presenting symptoms included complaints related to the eyes. In 16 cases (13 DLBCLs, 1 Burkitt-like lymphoma, 1 nasal NK/T-cell lymphoma, and 1 lymphoma of uncertain lineage), the orbit was invaded by lymphoma. In our series, the most common lymphoma to arise in the sinonasal area is DLBCL, followed by nasal NK/T-cell lymphoma. Comparison of these two types of lymphoma showed that lymphomas involving sinuses without nasal involvement were predominantly DLBCLs (20 of 21), whereas nasal cavity lymphomas without sinus involvement were usually NK/T-cell type (8 of 11) (p = 0.000125). Compared with patients with DLBCL, patients with nasal NK/T-cell lymphoma were overall younger, with a lower male-to-female ratio. Lymphomas of B-cell lineage were more likely to be associated with symptoms related to the eyes (p < 0.0005) and to have extension to the orbit (p < 0.01) than were lymphomas of T- or NK-cell lineage. In contrast to results of Asian studies in which nasal NK/T-cell lymphoma has a very poor prognosis, our nasal NK/T-cell lymphomas had an outcome similar to that of DLBCL.     

Clinical relevance of three subtypes of primary sinonasal lymphoma characterized by immunophenotypic analysis

BACKGROUND: The purpose of this study was to investigate the clinical relevance of subtypes categorized by immunophenotypic analysis in primary sinonasal lymphomas. METHODS: Eighty patients with localized non-Hodgkin's lymphoma involving the nasal cavity and/or paranasal sinuses were divided into three subtypes on the basis of their immunohistochemical findings: (A) B-cell lymphoma (n = 19), (B) T-cell lymphoma (n = 27), and (C) natural killer (NK)/T-cell lymphoma (n = 34). The clinicopathologic profiles, immunophenotypic data, patterns of treatment failure, and survival data among the three patient groups were retrospectively compared. RESULTS: The nasal cavity was the predominant site of involvement in T-cell and NK/T-cell lymphoma, whereas sinus involvement without nasal disease was common in B-cell lymphoma. Systemic B symptoms were frequently observed in NK/T-cell lymphoma. Almost all patients with NK/T-cell lymphoma showed a strong association with the Epstein-Barr virus by in situ hybridization studies. Sixty-five patients (81%) patients achieved complete remission after initial treatment, but 36 (55%) of these subsequently experienced treatment failure. Although there were no significant differences in locoregional failure rates among the patients of the three groups, distant failure was far more common in B-cell or NK/T-cell lymphoma than in T-cell lymphoma (p =.005). Most B-cell lymphoma cases showed a predilection for sites of systemic failure in the nodal and extranodal sites below the diaphragm, such as the paraaortic lymph nodes or the gastrointestinal (GI) tract, whereas patients with NK/T-cell lymphoma showed an increased risk of systemic dissemination to the skin, testes, or GI tract, including the development of hemophagocytic syndrome. The 5-year actuarial and disease-free survival rates for all patients were 57% and 51%, respectively. Of the three subtypes of primary sinonasal lymphomas, T-cell lymphoma seemed to carry the most favorable prognosis and NK/T-cell lymphoma the worst. (The 5-year actuarial survival rate was 57% for B-cell lymphoma, 80% for T-cell lymphoma, 37% for NK/T-cell lymphoma; p =.02, log-rank.) By univariate and multivariate analyses, immunophenotype was identified as the most important prognostic factor. CONCLUSIONS: Our data indicate that the three subtypes of primary sinonasal lymphomas classified by immunohistochemical studies exhibit different clinical profiles, different patterns of failure, and different treatment outcomes. Given these observations, it is concluded that the recognition of these distinct subsets, diagnosed on the basis of immunophenotypic study, is very important and clinically relevant in predicting their potential behavior and prognosis.     

Correlation between immuno-morphological parameters of regional lymph nodes and the mortality of patients with stage I and II bronchial squamos cell carcinoma

Histological changes in tracheobronchial and bronchopulmonary lymph nodes of patients with operable (i.e. stages T 0/2, N 0/1, M0) bronchogenic squamous cell carcinoma were examined histometrically. Out of 29 patients 10 survived less than 12 months and 19 lived longer than two years after surgery. Quantitive methods were employed for measuring structural changes in lymph node sections at the histological and cellular level. The following parameters reflecting both cellular and humoral immune responses correlated with survival: relative numbers of large lymphoid cells and mitotic figures in the paracortical "thymus dependent") area; volume of the follicular (predominantly B-cell) cortex and volume of germinal centers. Pronounced accumulation of histiocytes or dust-loaded marcrophages in the paracortex and presence of "empty" lymph sinusoids (i.e. without sinushistiocytosis) correlated inversely with survival. Besides the theoretical importance and considerations of a documented immune response, such data could help in identifying high risk groups within the same stage of bronchogenic carcinoma of a given type.     

Epstein-Barr virus negative clonal plasma cell proliferations and lymphomas in peripheral T-cell lymphomas: a phenomenon with distinctive clinicopathologic features

Clonal B-cell populations have been described in peripheral T-cell lymphomas (PTCL) as secondary Epstein-Barr virus (EBV) driven B-cell expansions that may evolve to an overt B-cell lymphoma. EBV-negative B-cell proliferations associated with T-cell lymphomas are uncommon and not well characterized. We studied 15 patients who developed an EBV-negative B-cell proliferation or malignant lymphoma associated with PTCL. The T-cell tumors were 8 PTCL, not otherwise specified, 4 angioimmunoblastic T-cell lymphomas, and 3 cutaneous PTCL. The B-cell component was intermingled with the PTCL in all patients and it was classified as clonal/monotypic plasma cell proliferation in 8 lesions, clonal/monotypic large B-cell proliferation in 4 patients, and B-cell lymphoma with plasmacytic/plasmablastic differentiation in 3 patients. Two patients had 2 clonally unrelated plasma cell proliferations associated with the same PTCL. All cases showed cytoplasmic Ig light chain restriction. Clonal IgH and T-cell receptor rearrangements were detected in 11/12 and 11/13 cases examined, respectively. EBV, cytomegalovirus, and HHV-8 were not observed in any of the examined cases. Sequential samples in 7 patients showed persistence of the PTCL and the B-cell component in 4, the PTCL without the B-cell lymphoma in 2, and progression of the B-cell neoplasm in 1. Patients followed an aggressive clinical course similar to conventional PTCL. In conclusion, EBV-negative clonal or mononotypic B-cell proliferations in patients with PTCL present with a spectrum of lesions ranging from plasma cell proliferations to overt lymphomas with plasmacytic/plasmablastic features. The distinctive features of these patients suggest that these lesions represent a specific phenomenon in PTCL.     

Multiple perineal sinuses in non-hodgkin's lymphoma

A 60 years old male presented with a 10 years history of chronic discharging perineal sinuses with inguinal lymphadenopathy. Biopsy of the inguinal lymph node revealed follicular B-cell non-Hodgkin's lymphoma while the biopsy of the sinuses was non-specific. It was diagnosed as a case of primary nodal NHL with secondary cutaneous manifestations of multiple perineal sinuses (paraneoplastic dermatosis). After two courses of chemotherapy, the discharge from the sinuses disappeared and the lesions healed by scarring.     

Clinicopathologic Features of B-Cell Lineage Neoplasms With Aberrant Expression of CD3: A Study of 21 Cases

CD3 expression by immunohistochemistry was historically considered restricted to T-lineage or NK-lineage neoplasms but recently has been reported in rare cases of mature B-cell neoplasms, frequently in association with Epstein-Barr virus. Here, we describe the pathologic features of 21 B-cell lineage neoplasms that express CD3 protein by immunohistochemistry: 12 diffuse large B-cell lymphomas (DLBCLs); 2 plasmablastic lymphomas (PBLs); 4 plasma cell neoplasms; 2 Burkitt lymphomas; and 1 nodal follicular lymphoma, grade 3A. CD20 expression was negative or only partially positive in 13/21 cases. Epstein-Barr virus was positive in 3/20 tested cases (2 PBLs and 1 DLBCL). All tested neoplasms (14/14) had clonal immunoglobulin gene rearrangements, and no clonal T-cell gene rearrangements were detected (0/14). The 12 DLBCLs segregated into 2 main groups: 7 demonstrated features of plasmacytic differentiation but did not meet criteria for PBL, and 5 had anaplastic features. In addition to morphology, other features shared among the DLBCLs with plasmacytic differentiation, the plasma cell neoplasms, and the PBLs included extranodal presentation, cytoplasmic localization of CD3, and lack of expression of other T-cell antigens in most cases. In contrast, DLBCLs with anaplastic features and the single follicular lymphoma coexpressed multiple T-cell antigens in a predominantly membranous pattern and presented with nodal disease in a relatively younger patient population. Our data expand the spectrum of morphologic, phenotypic, and clinical features of B-cell neoplasms aberrantly expressing CD3. As these neoplasms often lack typical expression of B-cell antigens, knowledge of these features will help avoid misclassification.     

FAS gene mutation in a case of autoimmune lymphoproliferative syndrome type IA with accumulation of gammadelta+ T cells

A 6-month-old girl presented to the hospital with cervical lymphadenopathy and hepatosplenomegaly. She was known to have an enlarged spleen, anemia, and thrombocytopenia since the age of 1 month. A lymph node biopsy showed a diffuse proliferation of blasts with few remnants of follicles. The blasts were CD3+CD57+CD4-CD8-, consistent with the usual autoimmune lymphoproliferative syndrome phenotype. However, these double negative T cells stained positive for gammadelta T-cell receptors, whereas double negative T cells in patients with autoimmune lymphoproliferative syndrome usually bear alphabeta T-cell receptor. Mutation analysis of the FAS gene revealed a mutation in the death domain of the FAS gene, which is a frequent finding in patients with autoimmune lymphoproliferative syndrome. Based on these results, the diagnosis of autoimmune lymphoproliferative syndrome was established. RT-PCR analysis of the affected lymph node tissue revealed a strong upregulation of interleukin 10 and a moderate upregulation of interferon-gamma expression compared with normal tissue. Our findings indicate that autoimmune lymphoproliferative syndrome can result in a prominent proliferation of gammadelta+ double negative T cells. It is important to distinguish this benign polyclonal proliferation from neoplastic gammadelta+ T-cell proliferations, such as hepatosplenic gammadelta T-cell lymphomas. Factors contributing to the accumulation of these gammadelta+ double negative T cells may be an unidentified infection in combination with the young age of onset in this patient.     

PD-1, a follicular T-cell marker useful for recognizing nodular lymphocyte-predominant Hodgkin lymphoma

The nodularity and presence of T-cell rosettes surrounding the neoplastic cells has been described as a defining feature of nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL). We have explored the potential diagnostic value of a new marker (NAT105) that recognizes the antigen PD-1 in a series of 152 cases diagnosed as nodular sclerosis Hodgkin lymphoma, mixed cellularity Hodgkin lymphoma, lymphocyte-rich classic Hodgkin lymphoma, NLPHL, and T-cell/histiocyte-rich B-cell lymphoma (T/HRBCL). All the cases were immunostained with a panel of antibodies against CD10, bcl-6, CXCL13, CD57, and PD-1 (NAT-105). The series includes a set of cases diagnosed as NLPHL with diffuse areas, and a group of borderline cases with features between those of NLPHL and T/HRBCL. Results show that PD-1 (NAT-105) is an excellent immunomarker not only of follicular T-cell rosettes in NLPHL, but also of a subset of lymphocyte-rich classic Hodgkin lymphomas. However, it is not a unique and defining feature of NLPHL. The presence of PD-1-positive (NAT-105) T-cell rosettes seems to be an additional useful feature in the differential diagnosis of NLPHL and T/HRBCL, which is normally a controversial and difficult task. The standard T/HRBCL cases lack follicular T-cell rosettes, whereas most of the borderline cases between the 2 entities have follicular T-cell rosettes, thus suggesting a closer relation with NLPHL.     

Primary cutaneous CD4+ small/medium-sized pleomorphic T-cell lymphoma expresses follicular T-cell markers

Cutaneous CD4 small/medium-sized pleomorphic T-cell lymphoma (CSTCL) is a cutaneous T-cell lymphoma defined by a predominance of small-to-medium-sized CD4 pleomorphic T cells, with a favorable clinical course. Cases are also characterized by the presence of a rich infiltrate of reactive B cells. Recently, it has been reported that follicular helper T cells (TFH cells) display a distinct gene expression profile, positive for PD-1, CXCL13, and BCL-6. We report for the first time the expression of PD-1 and other TFH cell markers in CSTCLs and discuss its biologic significance. Sixteen CSTCLs were included in this study, and also 20 reactive inflammatory conditions, 10 primary cutaneous marginal zone, 10 follicular center lymphomas, and 5 primary CD30 cutaneous lymphomas. They were immunohistochemically analyzed for a large panel of markers. Double immunoperoxidase labeling of paraffin sections was performed for PD-1, OCT-2, and BCL-6. Clonal Ig and T-cell receptor rearrangements and Epstein-Barr virus-encoded RNA expression were also evaluated. Morphologic and clinical data were reviewed. Histologic examination showed a dense polymorphic lymphoid infiltrate throughout the dermis. Atypical large CD4 cells were positive for PD-1, CXCL13, and BCL-6 in all cases, and were attached in small clusters, or formed rosettes around CD30/OCT-2+ B blast cells. Epstein-Barr virus was not apparent in any of the cases. A dominant T-cell clone was identified in 14 cases, whereas polymerase chain reaction IgH gene rearrangement studies showed that all cases were polyclonal. None of the patients had lymphadenopathy or showed any evidence of systemic disease, nor did they have any previous history of mycosis fungoides or drug reactions. FTH cell markers are not exclusive to angioimmunoblastic lymphadenopathy but may also be seen in neoplastic cells of CSTCLs. Moreover, these findings suggest that B-cell stimulation by FTH could also take place in some cutaneous T-cell lymphomas.     

Primary cutaneous follicular lymphoma: a clinicopathologic and molecular study of 16 cases in support of a distinct entity

Primary cutaneous B-cell lymphomas displaying a prominent follicular growth pattern are rare and remain poorly defined, particularly in terms of the frequency of detection of t(14;18) and whether or not, as a group, they represent an entity distinct from follicular lymphoma arising in lymph nodes. The morphologic, immunophenotypic, and clinical features of 16 cases of primary cutaneous follicular lymphoma, identified during a review of all PCBCL in the Scotland and Newcastle Lymphoma Group database, were studied and the number of cases harboring t(14;18) assessed by polymerase chain reaction using primers to the major breakpoint cluster region. Comparisons were made with stage I follicular lymphoma arising in lymph nodes and follicular lymphoma secondarily involving the skin. All cases of primary cutaneous follicular lymphoma had undergone thorough staging, including physical examination and CT scans of chest and abdomen, with 15 of 16 cases also having bone marrow aspiration and/or trephine performed. The morphology and immunophenotype of the lesions were similar to that expected in lymph nodes. All cases displayed a follicular architecture complete with follicular dendritic cell networks and comprised an admixture of CD10 and/or bcl-6-positive neoplastic centrocytes and centroblasts with 13 of 16 cases also expressing bcl-2 protein. None harbored t(14;18), a significantly different finding compared with cases of stage I nodal follicular lymphoma (p <0.001) and secondary cutaneous follicular lymphoma (p <0.039). Relapses occurred in five of 15 patients with a median time to first relapse of 20 months (range 1-73 months; mean 27.2 months). These were multiple in two patients and involved extracutaneous sites in two patients. The propensity for relapse was similar to that in a comparative cohort of stage I nodal follicular lymphoma, but the group of primary cutaneous follicular lymphoma were significantly more likely to attain complete remission; all cases of primary cutaneous follicular lymphoma were in complete remission when last seen compared with 49 of 87 patients with stage I nodal follicular lymphoma (p <0.005). No lymphoma-related deaths were encountered in 15 cases with a mean follow-up >60 months (range 5-119 months). These results support the concept of a subtype of follicular lymphoma lacking t(14;18) involving the major breakpoint cluster region, and with a propensity to arise in the skin. Despite a high relapse rate patients with primary cutaneous follicular lymphoma are more likely to achieve complete remission and may ultimately have a more favorable long-term prognosis than those with equivalent nodal disease.     

Follicular colonization in B-cell lymphoma of mucosa-associated lymphoid tissue

The formation of neoplastic B-cell follicles is universally accepted as diagnostic of a follicle centre cell (FCC) lymphoma. Low-grade B-cell lymphomas of mucosa-associated lymphoid tissue (MALT) are characterized by a diffuse infiltrate of cells of uncertain lineage known as "centrocyte-like" cells because of their resemblance to centrocytes (small cleaved cells). Some MALT lymphomas, however, contain numerous follicles and may even have a predominantly follicular appearance. These follicles may be reactive or show immunoglobulin (Ig) light-chain restriction, indicating their neoplastic nature. We have proposed that these neoplastic follicles are not composed of follicle centre cells but result from colonization of reactive follicles by CCL cells. In this study, the immunophenotype and genotype of 10 primary gastrointestinal lymphomas with a follicular component have been determined. One case exhibited the morphological, immunophenotypic, and genotypic features of FCC lymphoma (Ig light-chain restriction, CD10+, KB61 (CDw32)-, Jh, and bcl-2 gene rearrangement). Neoplastic follicles in the remaining nine cases, which showed the features of MALT lymphoma, were of a different phenotype (Ig light-chain restriction, CD10- KB61(CDw32)+), and these lymphomas showed Jh but not bcl-2 gene rearrangement. Taken in conjunction with the morphological features, these findings suggest that in these cases the neoplastic follicles formed as the result of colonization of previously reactive follicles by neoplastic CCL cells. Thus, not all lymphomas containing neoplastic follicles are of FCC origin. Follicular colonization, as seen in low-grade MALT lymphomas, is likely to be a recapitulation of an as yet undescribed normal immunological phenomenon that may involve marginal zone B cells.     

SHP-1 expression by malignant small B-cell lymphomas reflects the maturation stage of their normal B-cell counterparts.

SHP-1 is a protein phosphotyrosine phosphatase that plays an important role in modulating intracellular signaling, which regulates cell activation, proliferation, differentiation, and migration. It is a negative regulator of signal transduction induced by a number of cell receptors. Our immunohistochemical examination of paraffin-embedded reactive lymph nodes and lymphoid tissues revealed that B lymphocytes in follicle germinal centers do not express SHP-1. A weak staining of the B cells in the germinal center light zones was detected when an ultrasensitive amplification system was used. In contrast, normal B cells in mantle and marginal zones as well as interfollicular B lymphocytes and plasma cells displayed strong immunoreactivity. This pattern of SHP-1 expression was repeated in small B-cell lymphomas. All cases of mantle cell lymphoma (12 of 12), marginal zone lymphoma (10 of 10), and chronic lymphocytic leukemia/small lymphocytic lymphoma (13 of 13) expressed SHP-1 protein. However, only 1 of 30 cases of grade 1 follicle center cell lymphoma expressed SHP-1. Our observations highlight the biologic functions of SHP-1 and demonstrate that the SHP-1 expression pattern by small B-cell lymphomas reflects the maturation stage of their normal cell counterparts. These results indicate that determination of SHP-1 expression may help in the differential diagnosis of small B-cell lymphomas.