Follicular lymphoid hyperplasia of the oral cavity representing progressive transformation of germinal center

Follicular lymphoid hyperplasia (FLH) of the oral cavity is a rare and poorly understood lymphoproliferative disorder. We present a case of FLH of the oral cavity presenting with progressive transformation of germinal center (PTGC). The patient was a 49-year-old Japanese woman presenting with a hard mass in the right cheek. The resected specimen contained numerous lymphoid follicles with active germinal centers and a portion of the lymphoid follicles exhibited PTGC. The PTGCs contained a few large lymphoid cells resembling lymphocytic and histiocytic Reed-Sternberg cells of nodular lymphocyte-predominant Hodgkin lymphoma. The PTGC was surrounded by groups of epithelioid cells. In situ hybridization studies demonstrated strong expression of Epstein-Barr virus (EBV)-encoded small RNA in scattered large lymphoid cells in the PTGC. Although the etiology of FLH of the oral cavity remains unclear, the present case suggests that a subset of FLH of the oral cavity appears to be an EBV-associated lymphoproliferative disorder.     

Localized lymphoid hyperplasia of the rectum representing progressive transformation of the germinal center. A report of two cases

Histologically, benign lymphoid hyperplasia (BLH) of the rectum is usually characterized by large lymphoid follicles with active germinal centers, and a narrow surrounding mantle zone and marginal zone. We present two cases of BLH of the rectum demonstrating progressive transformation of the germinal center (PTGC). The patients were 50- and 71-year-old Japanese women. Colonoscopy demonstrated small sessile polyps in both cases. The resected specimen contained numerous lymphoid follicles with active germinal centers and a portion of the lymphoid follicles exhibited PTGC. The area showing PTGC contained a few large lymphoid cells resembling lymphocytic and histiocytic Reed-Sternberg cells of nodular lymphocyte-predominant Hodgkin lymphoma. These PTGC contained small- to-medium clusters of epithelioid cells in both cases. In situ hybridization studies demonstrated scattered Epstein-Barr virus (EBV)-encoded small RNA-positive medium and large lymphoid cells and crypt epithelium in both lesions. EBV may be involved in the etiology of a subset of BLH of the rectum. However, reactivity of lymphoid cells for EBV has been reported in lymphoid tissues in a high percentage of "normal" individuals. The etiology of BLH of the rectum remains unclear.     

A B-cell lymphoma-associated chromosomal translocation in a progressive transformation of germinal center

Progressive transformation of germinal center (PTGC) is a pattern of lymph node reactive hyperplasia. It can also be the predominant pattern in a hyperplastic lymph node known as florid PTGC. It is characterized histologically by the expansion of the mantle zone lymphocytes into both the adjacent sinusoids and germinal centers. The lymphocytes destroying the germinal centers are predominantly B cells, with a minor population of T cells. Morphologically, it can be confused with nodular lymphocyte-predominant Hodgkin disease (NLPHD) because of its nodular pattern and because of the presence of large cells that can be incorrectly identified as lymphocytic and histiocytic cells. A relationship between PTGC and NLPHD remains unclear, and many authors have suggested that PTGC can represent a precursor lesion of NLPHD. Here we report the first karyotype obtained in PTGC, in a 12-year-old boy. It shows a t(3;22)(q27;q11) translocation, probably involving the BCL6 gene. This translocation has previously been described in diffuse large B-cell lymphomas and in NLPHD with BCL6 rearrangement. This finding offers an insight into a possible tumorigenic pathway from PTGC to NLPHD. Further studies will be required to confirm this hypothesis.     

Follicular hyperplasia, follicular lysis, and progressive transformation of germinal centers. A sequential spectrum of morphologic evolution in lymphoid hyperplasia

We studied mantle B-cell and T-cell ingression in hyperplastic follicles (HFs), follicular lysis (FL), and progressive transformation of germinal centers (PTGC) in 19 paraffin-embedded, H&E-, bcl-2-, CD20-, and CD3-stained lymph nodes. We enumerated the T cells (CD3+) and mantle B cells (bcl-2+/CD3-) per 100 cells in 5 high-power fields of each entity (mean +/- SD). Compared with HF, FL had increased numbers of T cells migrating into germinal centers (39.8 +/- 10.0 vs 25.8 +/- 7.8; P < .0001). and a mild increase of mantle B cells (12.3 +/- 11.4 vs 2.1 +/- 1.6; P < .001). PTGC showed an increase of T-cell ingression compared with HF (36.5 +/- 12.1 vs 25.8 +/- 7.8; P < .0001) and more migration of mantle B cells into the follicle than FL (41.0 +/- 22.5 vs 12.3 +/- 11.4; P < .0001). T cells and mantle B cells ingress in FL and PTGC, although the mantle B-cell component predominates in the latter, suggesting that follicular hyperplasia, FL, and PTGC constitute an evolutionary spectrum in resolution of lymphoid hyperplasia with sequential ingression of T cells followed by mantle B cells. The maintenance of bcl-2 expression in mantle B cells in PTGC may cause differential diagnostic pitfalls in florid PTGC vs follicular lymphoma, particularly the so-called floral variant.     

Regulation of germinal center B-cell differentiation

Germinal centers (GC) are the main sites where antigen-activated B-cell clones expand and undergo immunoglobulin gene hypermutation and selection. Iterations of this process will lead to affinity maturation, replicating Darwinian evolution on the cellular level. GC B-cell selection can lead to four different outcomes: further expansion and evolution, apoptosis (non-selection), or output from the GC with differentiation into memory B cells or plasma cells. T-helper cells in GC have been shown to have a central role in regulating B-cell selection by sensing the density of major histocompatibility complex (MHC):peptide antigen complexes. Antigen is provided on follicular dendritic cells in the form of immune complex. Antibody on these immune complexes regulates antigen accessibility by shielding antigen from B-cell receptor access. Replacement of antibody on immune complexes by antibody generated from GC-derived plasma cell output will gradually reduce the availability of antigen. This antibody feedback can lead to a situation where a slow rise in selection stringency caused by a changing environment leads to directional evolution toward higher affinity antibody.     

Expression of HGAL in primary cutaneous large B-cell lymphomas: evidence for germinal center derivation of primary cutaneous follicular lymphoma.

The classification of primary cutaneous large B-cell lymphoma (PCLBCL) is based on standard morphology, immunohistochemistry, and clinical presentation. There are two major subtypes in the current WHO-EORTC classification: follicle center lymphoma and diffuse large B-cell lymphoma, leg-type (DLBCL-LT). The goals of this study were to examine a series of DLBCLs to determine (1) whether the immunohistochemical paradigm of germinal center B-cell and non-germinal center B-cell types of systemic DLBCL could be applied to PCLBCL; (2) whether application of the newly described germinal center B-cell marker, human germinal center-associated lymphoma (HGAL) also discriminates between these types as a further support for germinal center B-cell origin for primary cutaneous center lymphoma; and (3) whether any of these biologic markers were of prognostic significance. To this end, 32 cases of diffuse PCLBCL (22 primary cutaneous follicular center lymphomas and 10 DLBCL-LT) were classified based on the WHO-EORTC criteria and studied for expression of CD20, BCL2, BCL6, CD10, MUM-1, and HGAL by immunohistochemistry. Results were correlated with clinical features. HGAL and BCL6 expression and germinal center B-cell phenotype were associated with primary cutaneous follicular center lymphoma. The combination of HGAL and BCL6 positivity had the highest sensitivity (88%) and specificity (100%) for predicting subtype compared to either marker alone. Both HGAL and BCL6 were associated with the germinal center B-cell phenotype. The correlation of HGAL expression with the germinal center B-cell phenotype demonstrates the role of this marker in the classification of cutaneous large B-cell lymphomas. BCL6 expression was the only immunohistochemical marker associated with overall survival. Characterizing PCLBCLs with markers of B-cell maturation stage is a useful framework for studying, classifying, and clinically stratifying these lymphomas.     

Localized lymphoid hyperplasia of the rectum resembling polypoid mucosa-associated lymphoid tissue lymphoma: a report of three cases

Histologically, benign lymphoid hyperplasia of the rectum is usually characterized by large lymphoid follicles with active germinal centers and by a narrow surrounding mantle zone and marginal zone (MZ). We report here three cases of benign lymphoid hyperplasia of the rectum associated with prominent marginal zone hyperplasia, which caused serious difficulty in the differential diagnosis from the polypoid type of mucosa-associated lymphoid tissue (MALT) lymphoma. Colonoscopy demonstrated small sessile polyps in all three cases. Histologically, the lesions were characterized by a hyperplastic germinal center and expanded MZs. The expanded MZs contained numerous monocytoid B-cells (MBC) and scattered large transformed B-cells. Initially, combined colonoscopic and histological findings strongly supported a diagnosis of polypoid MALT-type lymphoma of the rectum. However, there were neither colonized lymphoid follicles nor lymphoepithelial lesions in any of the three lesions. MBCs and large transformed B-lymphocytes were CD43- and bcl-2-. Moreover, immunohistochemical and genotypic studies proved the polytypic nature of the B-lymphocytes in all three lesions. The present cases indicated that benign lymphoid hyperplasia of the rectum should be included in the differential diagnosis for polypoid MALT-type lymphoma of the rectum.     

Follicular lymphoma mimicking progressive transformation of germinal centers

Three cases of a morphologically distinctive "floral" variant of follicular large cell lymphoma are presented. In each instance, the diagnosis of theoretically "florid" progressive transformation of germinal centers (PTGC) was made or considered. The features that separate this pattern of lymphoma from reactive follicular hyperplasia with PTGC include involvement of all nodules without the presence of any reactive germinal centers, a homogeneous proliferation of large transformed lymphocytes with a markedly decreased or absent population of phagocytic histiocytes, and extension by abnormal cells into the perinodal adipose tissue. If the desirability of frozen section tissue immunophenotyping is anticipated, these lymphomas would be distinguished from PTGC by monotypic staining for light chains.     

肺结节性淋巴组织增生一例

患者女,48岁。例行体检时X线发现左下肺结节2个,大小分别为0·8及1·2 cm,边界清;患者无自觉症状。于2004年3月15日入院,胸腔镜下切除病变组织。楔形切除的灰褐色肺组织2块,大小分别为2·0 cm×1·8 cm×1·6cm、5·7 cm×2·5 cm×1·5 cm,一侧面被肺膜,尚光滑;切面前者见一结节,直径约0·6 cm,结节紧邻切缘,后者肺膜下可见一结节,大小1·5 cm×1·6 cm×0·7 cm,二者切面均呈灰粉色、实性、质中。病理检查:结节由淋巴细胞构成,均与周围肺组织界限清楚,部分结节以细支气管为中心,未见累及支气管软骨,部分紧邻肺膜;小淋巴细胞位于肺间质中,…     

Dismantling the germinal center: comparing the processes of transformation, regression, and fragmentation of the lymphoid follicle

The pathologic and immunologic features of the formation of the germinal center have been extensively studied. The process of dissolution of the germinal center is not as well understood. Different patterns of germinal-center breakdown are commonly encountered in diagnostic lymph node biopsy specimens and frequently present difficulties in diagnosis. The current immunologic understanding of germinal-center dynamics is reviewed and correlated with the histologic and immunophenotypic features of three broad classes of germinal center dissolution, namely progressive transformation, regression, and follicle fragmentation. The author suggests that these different patterns represent alternate responses to antigenic stimulation. The relationships of progressive transformation to Hodgkin's disease and of follicular regression to Castleman's disease are discussed.     

Classical Hodgkin lymphoma occurring in clusters of nodal marginal zone B-lymphocytes in association with progressive transformation of germinal center. A case report

We present a case of a classical Hodgkin lymphoma occurring in clusters of marginal zone B-lymphocytes (MZBLs). Most lymphoid follicles possessed hyperplastic germinal centers, while a portion of the follicles exhibited a progressive transformation of the germinal center (PTGC). Clusters of MZBLs showed a perifollicular distribution. The classic Reed-Sternberg cells were found in clusters of MZBLs. A portion of the Reed-Sternberg cells were CD15+, CD20+, CD30+, CD79a+, fascin+, vimentin+, EMA-, and bcl-2-. Some Reed-Sternberg cells were surrounded by CD3+ CD45RO+ CD57-rosettes. In situ hybridization studies demonstrated strong expression of EBER in classic Reed-Sternberg cells and their variants. The overall morphological, immunohistological, and EBV findings confirmed that the present case is a classical Hodgkin lymphoma. The MZBLs were CD20+, CD79a+, sIgM+/-, sIgD-, CD5-, CD21-, CD43-, CD45RO-, and Bcl-2-. Some MZBLs had polytypic intracytoplasmic immunoglobulin. Problems arising in the differential diagnosis between lymphocyte-predominant Hodgkin lymphoma and PTGC have been described. An occasional association between MZBLs clusters and PTGC has been reported previously. This case suggests that classical Hodgkin lymphoma should be added to the differential diagnosis of PTGC.     

F18 fluorodeoxyglucose uptake in progressive transformation of germinal centres

FDG-PET/CT is a widely established imaging modality for staging, restaging and monitoring therapy response in lymphoma patients. Progressive transformation of germinal centres (PTGC) is a benign condition presenting characteristically as asymptomatic lymphadenopathy. This paper presents a case of a 53-year-old man with a history of Hodgkin's disease (HD) whose F(18) FDG-PET/CT scan showed high uptake in left axillary lymph nodes (SUV 3.8). A subsequent, left axillary lymph node biopsy revealed PTGC. PTGC can present as a false positive finding on FDG-PET/CT in lymphoma patients and biopsy should be done in HD patients in clinical remission but have a positive FDG-PET/CT scan.     

BCL2 translocation defines a unique tumor subset within the germinal center B-cell-like diffuse large B-cell lymphoma

Gene expression profiling of diffuse large B-cell lymphoma (DLBCL) has revealed prognostically important subgroups: germinal center B-cell-like (GCB) DLBCL, activated B cell-like (ABC) DLBCL, and primary mediastinal large B-cell lymphoma. The t(14;18)(q32;q21) has been reported previously to define a unique subset within the GCB-DLBCL. We evaluated for the translocation in 141 cases of DLBCL that were successfully gene expression profiled. Using a dual-probe fluorescence in situ hybridization assay, we detected the t(14;18) in 17% of DLBCLs and in 34% of the GCB subgroup which contained the vast majority of positive cases. In addition, 12 t(14;18)-positive cases detected by polymerase chain reaction assays on additional samples were added to the fluorescence in situ hybridization-positive cases for subsequent analysis. Immunohistochemical data indicated that BCL2, BCL6, and CD10 protein were preferentially expressed in the t(14;18)-positive cases as compared to t(14;18)-negative cases. Within the GCB subgroup, the expression of BCL2 and CD10, but not BCL6, differed significantly between cases with or without the t(14;18): 88% versus 24% for BCL2 and 72% versus 32% for CD10, respectively. In the GCB-DLBCL subgroup, a heterogeneous group of genes is overexpressed in the t(14;18)-positive subset, among which BCL2 is a significant discriminator. Interestingly, the t(14;18)-negative subset is dominated by overexpression of cell cycle-associated genes, indicating that these tumors are significantly more proliferative, suggesting distinctive pathogenetic mechanisms. However, despite this higher proliferative activity, there was no significant difference in overall or failure-free survival between the t(14;18)-positive and -negative subsets within the GCB subgroup.     

IL-2: fine-tuning the germinal center reaction

T follicular cells help B cells to drive germinal center formation. In this issue of Immunity, Ballesteros-Tato et?al. (2012) demonstrate that high amounts of interleukin-2 inhibit production of this critical T effector subset.     

The spectrum of micronodular thymic epithelial tumours with lymphoid B-cell hyperplasia

AIMS: A rare type of thymoma, micronodular thymoma with lymphoid B-cell hyperplasia, was recently reported by Suster and Moran. Thymic epithelial tumours with a similar pattern but with varied cytological features of the tumour cells are analysed. METHODS AND RESULTS: A total of 11 cases of thymic epithelial tumours characterized by micronodular proliferation of tumour cells separated by abundant lymphoid stroma with prominent germinal centres were reviewed clinicopathologically and examined immunohistochemically. The presence of Epstein-Barr virus (EBV) genome was also examined by in-situ hybridization. Based on the morphology of tumour epithelial cells, cases were subdivided into four groups: group 1 (two cases) having spindle epithelial cells; group 2 (two cases) showing an admixture of spindle and polygonal epithelial cells; group 3 (five cases) having polygonal epithelial cells, with mild to moderate cytological atypia in four cases, and group 4 (two cases) representing lymphoepithelioma-like carcinoma. The degree of cytological atypia and the number of tumour cells positive for MIB-1 and p53 gradually increased towards group 4. The abundant lymphoid stroma in all cases contained many CD20-positive B-cells and CD3 and CD45RO-positive T-cells. CD99-positive immature T-cells were present in all cases of groups 1 and 2 and in most cases of group 3, but not in both cases of group 4 tumours. IgG, IgM and IgD-positive plasma cells and lymphocytes were also present in all cases, more prominent in those of groups 3 and 4. The EBV genome was detected in only a few lymphocytes in five cases. CONCLUSIONS: The tumours in this series belong to a distinct category of thymic epithelial tumours and each of the above groups may constitute a spectrum in the continuum of cytological atypia. The aetiological relationship of EBV with these tumours could not be proved. The lymphoid B-cell hyperplasia may result from a host immune response and may suggest a favourable clinical course of this type of tumour.