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Primary gastric follicular lymphomas (FLs) have been rarely reported, and little is known about their characteristics. In the present study, we report 5 cases of primary gastric FL and describe their clinicopathological and molecular genetic features. A total of 7 samples from 5 patients were investigated for clinicopathological characteristics and somatic mutations by the targeted sequencing of 50 lymphoma-related genes. Two cases were identified as slightly elevated submucosal tumors and 3 cases as polypoid tumors. Histologically, all cases were low-grade FLs. The immunoprofile was CD20 + /CD10 + /BCL2 + in 4 cases and CD20 + /CD10 + /BCL2 - in 1 case. The immunostaining pattern for CD21 was similar to that of classic FL. BCL2 rearrangement was not identified in fluorescence in situ hybridization studies in any of the 5 cases. Next-generation sequencing analysis showed mutations in genes involved in epigenetic modifications (KMT2D, ARID1A, EP300, and CREBBP), NK-kB pathway (CARD11), and JAK-STAT pathway as found in classic FL. All cases presented with clinical I without the involvement of regional or systemic lymph nodes. Four patients were well, whereas 1 patient who received endoscopic mucosal resection of tumor without additional chemotherapy or radiotherapy experienced 3 relapses. In conclusion, primary gastric FL is characterized by a low-grade neoplasm with infrequent BCL2 rearrangement. After resection of the lesion, additional treatment such as radiation therapy or chemotherapy is required as there is a possibility of recurrence., (Copyright © 2023 Elsevier Inc. All rights reserved.)

MYC-rearranged large B-cell lymphoma with BCL2 and/or BCL6 rearrangement, double-hit (DH) or triple-hit (TH) lymphoma, is associated with poor survival after standard treatment. To investigate the clinical impact of single-hit (SH) MYC rearrangement, we analyzed 241 cases of diffuse large B-cell lymphoma (DLBCL) for MYC, BCL2, and BCL6 rearrangement by fluorescence in situ hybridization. Fifty-five of 241 (22.8%) cases showed MYC rearrangements. Twenty-three cases were diagnosed as DLBCL; 18 as high-grade B-cell lymphoma (HGBCL)-DH; 3 as HGBCL-TH; and 11 as HGBCL, not otherwise specified. Both DH and TH lymphomas showed high-grade morphology (P = 0.002), higher stage (P = 0.022), and more frequent germinal center B-cell-like phenotype (P = 0.008). SH lymphomas displayed high-grade morphology (P = 0.002) but were not different from MYC-negative lymphomas in cell of origin, clinical stage, international prognostic index (IPI), or extranodal involvement. Patients with DH/TH lymphomas had worse overall survival (OS) (P = 0.016) and progression-free survival (PFS) (P < 0.001), while OS and PFS of SH lymphomas were not different from those of MYC-negative lymphomas. There was no survival difference between cases of BCL2 and BCL6 rearrangements. Poorer prognostic factors included higher ECOG class, higher IPI, and DH or TH translocation for OS, and higher IPI and DH or TH translocation for PFS. Higher IPI was an independent prognostic factor for OS and PFS. In conclusion, large B-cell lymphomas with single MYC rearrangement showed high-grade morphology but were otherwise not different from MYC-negative lymphomas., (Copyright © 2021. Published by Elsevier Inc.)

The cellular lineage of extranodal NK/T-cell lymphoma, nasal-type (ENKTL), is determined by expression of T-cell receptor (TR) or TR gene rearrangement. In ENKTL, from TR immunohistochemistry, it may often be difficult to decide whether TR-positive cells are tumor cells or not, especially when TR is expressed in a subset of tumor cells. To analyze TR expression pattern and TR rearrangement in T-lineage ENKTL, we performed double immunofluorescence staining for Epstein-Barr virus-encoded small RNAs (EBER)/T-cell receptor (TCR) βF1 and CD56/TCR βF1 in 12 cases of ENKTL that showed TCR βF1 expression in immunohistochemistry. TR gene rearrangement was analyzed using a commercial BIOMED-2 multiplex polymerase chain reaction system. Immunohistochemistry showed that all 12 cases expressed TCR βF1 in a wide range of infiltrating cells from 100% to <1%. Two of them expressed both TCR βF1 and TCR cγM1. EBER/TCR-βF1-positivity was confirmed in 10 cases by double staining. One case failed to show EBER/TCR-βF1-positive cells but showed a CD56/TCR βF1-positive result. Among 12 cases, 5 had poor-quality DNA, 3 of them showed no polymerase chain reaction product, and 2 cases showed nonspecific peak of low height. Five of 7 cases with good DNA quality demonstrated monoclonal TR gene rearrangement. Based on TR expression and TR gene rearrangement, 10 of 12 cases of ENKTL were decided as a T-lineage tumor. In conclusion, because of common TR silence and poor DNA quality, consideration of both immunohistochemistry and TR gene rearrangement is necessary to determine the lineage of ENKTL., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Gastric mucosa-associated lymphoid tissue (MALT) lymphoma is a rare extranodal marginal zone B-cell lymphoma that is often associated with plasmacytic differentiation. However, the clinicopathological characteristics of gastric MALT lymphoma with increased plasmacytic differentiation have not yet been studied. To assess the clinicopathological implications of gastric MALT lymphoma with increased plasmacytic differentiation, 36 cases with increased plasmacytic differentiation and a control group of 16 cases with minimal plasmacytic differentiation were retrospectively collected from 65 primary gastric MALT lymphomas (2010-2012). The hematoxylin and eosin slides were reviewed, and IgG, IgG4, and κ and λ immunohistochemical staining was performed. Clinicopathological differences between the 2 groups were compared using the χ 2 test and odds ratios. Logistic regression analyses were used to evaluate resistance to Helicobacter pylori eradication therapy. Increased plasmacytic differentiation is significantly correlated with the H pylori eradication response (94.4% versus 66.7%, P=.018), lower frequency of relapse (5.6% versus 35.7%, P=.014), the presence of more than one IgG4+ cell per high-power field (27.8% versus 0%, P=.022), and light-chain restriction (33.3% versus 6.2%, P=.044). Univariable logistic regression indicated that negative H pylori status (P=.016) and minimal plasmacytic differentiation (P=.019) were statistically significant predictive factors for resistance to H pylori eradication. Multivariable logistic regression analyses identified no statistically significant predictive factors. However, H pylori negativity and minimal plasmacytic differentiation showed a statistical trend toward significance (P=.078 and P=.09). Gastric MALT lymphomas with increased plasmacytic differentiation have different clinicopathological characteristics, and plasmacytic differentiation is associated with H pylori eradication response., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Nodal peripheral T-cell lymphoma, not otherwise specified, is a heterogeneous entity with variable biologic behavior. We analyze the clinicopathological features of 15 patients with Epstein-Barr virus-positive (EBV+) nodal T/NK-cell lymphoma, including 9 males and 6 females, with a median age of 64 years. All patients presented with multiple lymphadenopathy with common B symptoms (80%, 12/15) at an advanced Ann Arbor stage (III, IV) (87%, 13/15). The International Prognostic Index was high or high/intermediate in 87% (13/15) of patients, and the prognostic index for peripheral T-cell lymphoma was group 3 or 4 in 73% (11/15). Spleen and liver involvement was observed in 73% (11/15) and 60% (9/15) of patients, respectively. In contrast, extranodal involvement was infrequent, with no more than 1 site in 71% (10/15) of patients. Moreover, none had nasal lesions, and only 1 had mucocutaneous involvement. The cell lineage of EBV+ tumor cells was determined to be T cell in all except 1 patient, who was NK-cell lineage. Cytotoxic molecules were expressed in all cases, and 64% (9/14) of patients expressed the αβT-cell receptor. Moreover, most patients (67%, 10/15) showed CD8 positivity, with 2 of them being CD4CD8 double positive; the others were CD4 positive (n = 2) or CD4CD8 double negative (n = 3). The clinical course was very aggressive, with a median survival time of 3.5 months, and 10 patients died within 6 months of diagnosis. Taken together, our data demonstrate that EBV+ nodal T/NK-cell lymphoma is a distinct clinicopathological entity characterized by cytotoxic molecule expression, a frequent CD8-positive αβT-cell lineage, and a very aggressive clinical behavior., (Copyright © 2015 Elsevier Inc. All rights reserved.)

We present the first case of peripheral T-cell lymphoma, not otherwise specified expressing follicular helper T-cell markers with different histologic features simultaneously involving the common bile duct and pericholedochal lymph nodes in a 72-year-old woman patient. Abdominal computed tomography revealed a localized wall thickening in the common bile duct. With the impression of cholangiocarcinoma, pancreaticoduodenectomy was done. Microscopically, dense small lymphoid cells with only minimal cytologic atypia were observed with occasional lymphoepithelial-like lesions, whereas many atypical large cells infiltrated the pericholedochal lymph nodes. Immunohistochemically, most small cells in the bile duct and the large atypical cells in the lymph nodes were all reactive for follicular helper T-cell markers including CD4, PD-1, and CXCL-13. BIOMED-2 based polymerase chain reaction using the DNA template from either the bile duct lesion or the lymph node revealed identical but different dominant clonal peaks, indicating these 2 lesions represent a spectrum of the same disease., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Mutations in 2 upstream components of the nuclear factor κB (NF-κB) pathway, CD79B and MYD88, are important information for new target therapy in malignant lymphoma. We examined the prevalence and clinicopathologic characteristics of CD79B and MYD88 mutation in a cohort of Asian diffuse large B cell lymphoma (DLBCL) patients. CD79B and MYD88 mutations were analyzed by Sanger sequencing in 187 DLBCL tissue samples. CD79B immunoreceptor tyrosine-based activation motif spanning exon 5 and 6 and MYD88 TIR domain spanning exons 3, 4 and 5 were amplified and sequenced. The cell-of-origin was determined based on immunohistochemical stains for CD10, BCL-6 and MUM-1 by Hans' algorithm. CD79B was mutated in 16 cases (8.5%), mostly involving the first tyrosine (Y196) of immunoreceptor tyrosine-based activation motif. For MYD88, L265P mutation was found in 31 cases (out of 161, 19.3%). In 11 of these, a CD79B mutation coexisted, which constituted 69% of CD79B mutants and 36% of MYD88 L265P cases. Clinicopathologic comparison between the mutant and the wild-type group showed that the mean age was older for both CD79B (66 versus 58 years) and MYD88 L265P mutant groups (64 versus 58 years). Survival analyses showed that neither CD79B mutation nor MYD88 L265P was a significant prognostic indicator. In conclusion, CD79B and MYD88 mutations are associated with an older age at onset in DLBCL with a significant overlap, which did not affect the outcome of the disease., (Copyright © 2014 Elsevier Inc. All rights reserved.)

According to the new World Health Organization classification system, there are 2 types of enteropathy-associated T-cell lymphoma. Type 1 is associated with celiac disease and accounts for the majority of cases in Western countries, whereas type 2 is not associated with celiac disease. To characterize enteropathy-associated T-cell lymphoma types in Korea, we carried out clinicopathologic and immunophenotypic analyses of 8 Koreans with enteropathy-associated T-cell lymphoma and investigated genomic profile using array comparative genomic hybridization. The tumors involved the small intestine in 5 patients and the colorectum in 3 patients. Two patients carried an HLA DQB10302 allele that corresponds to HLA DQ8. None of the patients had gluten-sensitive malabsorption syndrome. Intraepithelial lymphocytosis was observed in all patients. The sizes of the tumor cells were small or small-to-medium in 7 cases and medium-to-large in 1 case. The immunophenotypes of the tumor cells were CD4-CD8+CD56+ in 4 cases, CD4-CD8+CD56- in 1 case, CD4-CD8-CD56+ in 2 cases, and CD4-CD8-CD56- in 1 case. Array comparative genomic hybridization analysis showed that chromosome 9q33-q34.1 gain was present in 4 (80%) of the 5 cases examined. Other recurrent genomic alterations were gain of 6p21.1-21.31 (3/5, 60%), gain of 19q (2/5), and the loss of 3p12.1-p12.2 (2/5) and 3q26.31 (2/5). These results suggest that the most prevalent type of enteropathy-associated T-cell lymphoma in this geographic region is type 2, and the genetic changes associated with it are similar to those in Western countries., (Copyright 2010 Elsevier Inc. All rights reserved.)

Expression of Bcl-6 and CD10, markers for the tumor of the germinal center (GC) B-cell derivation, has been studied in primary diffuse large B-cell lymphomas (DLBCLs) of the lymph node, gastrointestinal tract, and mediastinum. In these studies, the coexpression rate of CD10 and Bcl-6 was relatively constant at 30% approximately 40%, but the frequency of Bcl-6+ tumors varied from 55% to 100%, raising doubts about the usefulness of Bcl-6 expression in identifying the tumor of GC B-cell derivation. Because the expression of Bcl-6 in tumors of non-GC B-cell origin has recently been reported, we critically evaluated the expression of Bcl-6 and CD10 in primary DLBCLs of the tonsil, a relatively common tumor in Japan and Korea. The cases (n = 51) represented a consecutive series for any recent 2-year period at several teaching hospitals in Korea and Japan. Formalin-fixed, paraffin-embedded specimens were used for immunostaining. Staining for Bcl-6 and CD10 was positive in 44 (86%) and 22 cases (45%), respectively. However, among those positive for Bcl-6 (>10% Bcl-6+ tumor cells), 2 basic patterns were recognized: uniform and nonuniform. The uniform pattern was characterized by a dense population (>75%) and a consistent density in any given area, resembling the staining pattern observed in GC or follicular lymphoma (FL) (the "GC/FL" pattern). In contrast, the nonuniform pattern exhibited a varying density from area to area, as well as a less-dense population (<75%). The uniform pattern was observed in 26 cases (51%). All but 1 (95%) of the CD10+ tumors coexpressed Bcl-6, with most (82%) displaying the uniform pattern. We conclude that tumors showing a uniform pattern of Bcl-6 expression should be distinguished from those showing a nonuniform pattern, because the former most likely represent tumors of GC B-cell derivation and the latter most likely represent tumors of non-GC derivation. GC B-cell lymphoma thus defined accounted for 51% of tonsillar DLBCL, a proportion comparable to that of the nodal DLBCL. CD10 expression correlated with the "GC/FL" pattern, but appeared to be not essential for the identification of GC B-cell lymphoma. This study suggests that a significant proportion of tonsillar DLBCLs in Asia is of GC B-cell origin rather than of mucosa-associated lymphoid tissue origin. This finding may have significance for clinical management of these lymphomas.

Focal follicular features in diffuse large B-cell lymphomas (DLBCLs) are bound to raise the question of follicular lymphoma (FL) with diffuse areas, because the diagnosis of FL is based on the presence of follicular areas, even though focal. We report 7 cases of primary tonsillar DLBCLs with focal follicular features that presented with morphologic, immunohistochemical, and biological features distinct from those of FL. Histologically, these tumors were characterized by involvement of pericryptal follicles with adjacent dominant diffuse areas. Monomorphous large tumor cells were evenly spaced with abundant, often clear cytoplasm, and blastoid nuclei often with a delicate nuclear membrane. Importantly, residual germinal centers (GCs) were present in the form of either an intrafollicular GC remnant or an isolated GC in the midst of diffuse tumor. An extrafollicular and/or parafollicular growth pattern was also observed. Bcl-6 staining revealed a predominantly sporadic occurrence of Bcl-6(+) cells, comprising <50% of tumor cells, and none displayed diffusely dense collections (>75%) of Bcl-6(+) tumor cells characteristic of the GC or FL. Staining for CD10 was negative in 6 cases. Five of 7 patients were younger than 60, the median age of other patients with primary tonsillar DLBCL. No extratonsillar involvement was seen at 18 months after diagnosis. After chemotherapy or radiotherapy, complete remission was achieved with ease in all patients, but 2 patients who were treated with chemotherapy alone relapsed at 24 and 30 months. In conclusion, tonsillar DLBCL includes a small (10%) but distinct subgroup that warrants distinction from FL with predominant diffuse areas or de novo DLBCL. It appears that the focal follicular features in tonsillar DLBCL likely represent follicular colonization of marginal zone B-cell lymphoma, probably high-grade, if the possibility of FL is excluded., (Copyright 2002, Elsevier Science (USA). All rights reserved.)

Most follicular lymphomas (FLs) transform to diffuse lymphoma eventually, comprising a significant proportion of diffuse large B-cell lymphoma (DLBCL). Judging by bcl-2 rearrangement (bcl-2R), one third of DLBCLs are believed to be of FL derivation in the Western population. However, bcl-2R is not specific and is not detectable in every case of FL. In East Asia, FL is uncommon but DLBCL is not. The proportion of tumors of FL origin in DLBCL is not known in this region. The coexpression of Bcl-6 and CD10 proteins, a reliable marker to identify germinal center (GC) B-cell lymphoma including FL, was analyzed in primary nodal DLBCLs (n = 104) diagnosed at major hospitals in Seoul during a recent 2-year period, along with well-defined cases (n = 17) of nodal FL as controls. Bcl-2 protein expression (n = 77) was also studied along with bcl-2R (n = 64), by polymerase chain reaction. Formalin-fixed archival specimens were used in all these assays. The Bcl-6/CD10 coexpression was observed in 35 DLBCLs (34%) and 14 FLs (82%), and most of them showed a pattern of Bcl-6 expression similar to that of the GC. Bcl-2 expression or bcl-2R did not correlate with Bcl-6/CD10 coexpression. Histologically, compartmentalizing sclerosis was associated with a high rate of the coexpression (8 of 10). In conclusion, to detect GC B-cell lymphoma in routine biopsy specimens, a pattern of Bcl-6 staining similar to the GC must be identified. Bcl-6+/CD10+ GC B-cell lymphomas thus defined comprised one third of primary nodal DLBCLs in Korea. The incidence rate is similar to that in the West. The reasons for the discrepancy between the incidence of GC B-cell lymphoma and the paucity of the follicular pattern in East Asian subjects warrant further studies., (Copyright 2001 by W.B. Saunders Company)

Background: The Bcl-6 gene product, a nuclear phosphoprotein, is expressed independently of Bcl-6 gene rearrangement. In lymph nodes, expression of Bcl-6 protein is restricted to germinal center (GC) B-cells and 10% to 15% of CD3/CD4+ intrafollicular T cells. Interfollicular cells are negative for Bcl-6 protein, except for rare CD3+/CD4+ T cells. Recently, we reported cases of angioimmunoblastic T-cell lymphoma (AITL) with hyperplastic GCs (AITL/GC), and observed that borders of enlarged GCs were ill defined, with features suggestive of an outward migration of GC cells to surrounding interfollicular zones. This prompted a study of follicular borders with Bcl-6 staining in reactive follicular hyperplasias and follicular lymphomas to compare with AITL/GC., Materials and Methods: Formalin-fixed paraffin sections were used for immunostaining of Bcl-6. Six cases of AITL/GC, 12 nonspecific reactive follicular hyperplasia (FH), 7 HIV adenopathy, 10 follicular lymphoma (FL), and 8 typical AITL (ie, AITL without GC) were studied. Double staining for Bcl-6/CD20, Bcl-6/CD3, and Bcl-6/CD57 was performed in selected cases., Results: In FH and HIV adenopathy, staining for Bcl-6 revealed densely populated GCs with well-defined and regular GC borders, whereas Bcl-6+ cells were rare in the interfollicular areas. An occasional GC with an ill-defined border was invariably surrounded by a broad mantle zone; those with indistinct mantle zones had well-defined, regular borders. In FL, follicles were densely populated, and their borders were irregular, with some Bcl-6+ cells in the interfollicular zones. In AITL/GC, GCs were less dense, GC borders were ill defined and irregular, and the number of interfollicular Bcl-6+ cells was markedly increased. Double staining revealed that these interfollicular Bcl-6+ cells in AITL/GC were Bcl6+/CD3+/CD20-/CD57- T cells. Moreover, CD3+ intrafollicular T cells were depleted in AITL/GC, whereas they were abundant in FH. Intrafollicular CD57+ cells did not stain for Bcl-6, and were also depleted in AITL/GC. In typical AITL, some neoplastic cells were positive for Bcl-6, showing variable degrees of staining., Conclusions: (1) GCs of AITL/GC differed from those of other reactive follicular hyperplasias and follicular lymphomas, and staining for Bcl-6 was useful to discern them. (2) Intrafollicular CD3+ T cells, many of which were also positive for Bcl-6, were markedly depleted in AITL/GC, with increased interfollicular Bcl-6+/CD3+ cells, suggesting an outward migration of intrafollicular T cells in this condition. (3) Interfollicular Bcl-6+/CD3+ cells in AITL/GC were too numerous to be accounted for by migration alone, suggesting local proliferation. (4) Intrafollicular CD57+ cells were negative for Bcl-6, indicating heterogeneity of the intrafollicular T-cell population. (5) Some neoplastic cells in AITL stained for Bcl-6, suggesting up-regulation of Bcl-6 expression in this tumor.