Incidence of Diffuse Large B-Cell Lymphoma of Germinal Center B-Cell Origin in Whole Diffuse Large B-Cell Lymphoma: Tissue Fluorescence In Situ Hybridization Using t(14;18) Compared with Immunohistochemistry

Diffuse large B-cell lymphoma (DLBCL) can be divided into prognostically important categories such as germinal center B (GCB)-like and non-GCB-like groups. The t(14;18)(q32;q21) translocation defines a unique subset of DLBCL cases with a GCB gene expression profile. Two-color fluorescence in situ hybridization (FISH) analysis was applied to detect t(14;18) (q32;q21) in the nuclei of paraffin-embedded tissue sections from 61 patients with de novo DLBCL. Nine (15%) of 61 cases had a positive pattern. Fifty-seven cases were subclassified in an immunohistochemical study with anti-CD10, anti-bcl-6, and anti-MUM1 antibodies. In this classification, 21 cases (37%) were placed in the GCB group, and 36 (63%) were placed in the non-GCB group. There was a discrepancy between t(14;18) occurrence and bcl-2 protein expression. Bcl-2 protein expression was positive in 40 (67%) of 60 cases. The expression of bcl-2 protein in the GCB and non-GCB groups was not significantly different: 15 (71%) of 21 cases in the GCB group and 24 (67%) of 36 cases in the non-GCB group tested positive. We found no difference between the FISH-positive and FISH-negative groups in overall survival time (P = .6019, log-rank test). The overall survival rates of GCB and non-GCB groups did not differ significantly by immunohistochemical classification (P = .5399, log-rank test). Overall survival was significantly longer in the group with a low International Prognostic Index (IPI) score than in the group with a high IPI score (P = .0002, log-rank test). Our results suggest that immunohistochemical study and cytogenetic study with t(14;18) FISH cannot predict the clinical outcomes of DLBCL patients. A study with a larger number of patients may show a difference in clinical outcomes between FISH-positive and FISH-negative groups and between GCB and non-GCB groups.     

老年起病的弥漫大B细胞淋巴瘤合并肺癌一例

目的：分析老年起病的弥漫大B细胞淋巴瘤合并肺癌的临床特点、治疗效果,提高对老年起病的恶性淋巴瘤合并或继发第二肿瘤（实体瘤）的认识水平。方法：报道1例老年起病的弥漫大B细胞淋巴瘤患者同时罹患肺癌的病例,并复习文献。结果：本例患者因肝脏活组织检查确诊弥漫大B细胞淋巴瘤,治疗过程中肺部肿块逐渐增大,肺部活组织检查确诊肺癌。结论：弥漫大B细胞淋巴瘤可与肺癌同时或相继发生,当治疗效果存疑时,应及时进行活组织检查,避免贻误病情。     

Leukemic and Meningeal Relapse of CD5+ Intravascular Large B-Cell Lymphoma with Down-Modulation of CD20 after Rituximab Therapy

Although CD20- relapses of B-cell lymphoma following rituximab therapy have increasingly been reported recently, coexistence of both the original and selected clones on relapse in a single patient have not been described. We experienced such a case with rare CD5+ intravascular lymphomatosis (IVL). A 46-year-old woman was admitted because of IVL complicated with cauda equina syndrome and pulmonary infarction. Complete remission was successfully achieved with multidrug chemotherapy in combination with rituximab. However, the disease recurred after 8 months with leukemic progression and meningeal involvement. The phenotype of the abnormal lymphocytes in the peripheral blood was fundamentally the same (CD20+CD5+CD10-CD19+CD23-sIglambda+) as that of the cells in the cerebrospinal fluid (CSF). However, CD20 expression was decreased remarkably compared with that in the CSF and that in the bone marrow before therapy. The targeting of CD20 molecules on the tumor cell surface by rituximab may have provided a selective pressure on lymphoma cells. The escape phenomenon of the lymphoma cells from rituximab was observed by simultaneously comparing the CD20 expression of cells in the peripheral blood and in a site of sanctuary from rituximab, the CSF.     

Pineal Diffuse Large B-Cell Lymphoma Concomitant With Pituitary Prolactinoma: Possible Correlation Between 2 Distinguished Pathologies: A Case Report

This is the first reported case of pineal lymphoma with concomitant prolactin-producing pituitary adenoma.A 51-year-old male experienced worsening headaches accompanied by nausea, diplopia, and memory loss for 1 month. Cranial nerve examination revealed bilateral upward gaze limitation with convergence impairment, which is known as Parinaud syndrome. Magnetic resonance images revealed a mass in the pineal gland with a coexisting mass within the enlarged sella fossa. Hormone analysis revealed hyperprolactinemia. The pineal mass was removed without injuring the hypothalamus, brain stem, or any neighboring vessels. Pathology examination confirmed the diagnosis of diffuse large B-cell lymphoma (DLBCL) involving the pineal gland. After further studies, the pineal lymphoma was determined to be a secondary tumor from a gastric primary tumor. The patient died 6 months after diagnosis due to systemic progression of DLBCL.Although the mechanistic link between hyperprolactinemia and lymphoma progression has not been clarified on a clinical basis, high prolactin levels may contribute to the rapid progression and therapeutic resistance of the lymphoma.     

Predictive Significance of a New Prognostic Score for Patients With Diffuse Large B-Cell Lymphoma in the Interim-Positron Emission Tomography Findings

We hypothesized that the objective treatment response of patients with diffuse large B-cell lymphoma (DLBCL) was affected by many factors such as pathophysiological, biological, and pharmaceutical mechanisms. This retrospective study aimed to evaluate the predictive significance of clinical prognostic factors and interim fluorine-18-fluorodeoxyglucose (¹⁸F-FDG) positron emission tomography/computed tomography (PET/CT), and to find a new prognostic predictor significantly associated with DLBCL patients’ outcome. A total of 105 adult patients with DLBCL were reviewed. Each patient underwent an interim ¹⁸F-FDG PET/CT scan after the second chemotherapy cycle. The visual method based on the Deauville 5-point scale was used to evaluate the interim-PET/CT scans. The relationships among the prognostic factors, the 3-year progression-free survival (PFS) rate and overall survival (OS) rate were analyzed with Kaplan–Meier plots. The predictive value of the newly constructed prognostic score was analyzed with multivariate analysis (Cox proportional hazard regression model). The visual analysis showed statistically significant differences in both PFS and OS between the patients with a negative interim-PET/CT and those with a positive interim-PET/CT. Advanced age, advanced stage, and DLBCL subtype were also significantly associated with outcome. A new prognostic score that composed of the above 4 factors was obtained. New prognostic score stratified patients into 4 risk groups with 3-year PFS of 98.5%, 73.9%, 11.1%, and 0%, and 3-year OS of 100%, 91.3%, 55.6%, and 0% (P < 0.001 for PFS and OS). Multivariate analysis showed that the new prognostic score had the greatest ability to predict relapse (P < 0.001) and death (P < 0.001). In DLBCL patients, interim ¹⁸F-FDG PET/CT can provide significant independent prognostic information. Our work illustrates that the new prognostic score has the strongest potential for accurately prognostication, for stratification in clinical trials, and for design of novel strategies for DLBCL patients in the high-risk group.     

CD5+ Diffuse Large B-Cell Lymphoma Consists of Germline Cases and Hypermutated Cases in the Immunoglobulin Heavy Chain Gene Variable Region

CD5+ diffuse large B-cell lymphoma (DLBCL) has recently been identified as a subgroup with different clinical characteristics from CD5- DLBCL and as having a poorer outcome than CD5- DLBCL. Data regarding differences in gene alteration between CD5+ and CD5- DLBCL have accumulated. In this article, we report an analysis of the immunoglobulin heavy-chain gene variable region (VH) gene in 35 cases of CD5+ DLBCL and compare these cases with those with the germline of the VH gene (GL-VH) and those with a somatically hypermutated VH gene (HM-VH). When the CD5+ DLBCL cases were subdivided with a cutoff value of 98% homology in the VH gene, there were 7 cases (20%) of GL-VH and 28 cases (80%) of HM-VH. The proportion of GL-VH cases in CD5+ DLBCL was more than that in CD5 DLBCL. Although we found no significant difference in pretreatment clinical parameters between the GL-VH and HM-VH subgroups, there was a tendency for the GL-VH subgroup to show lower incidences of elevation of lactate dehydrogenase and >1 site of extranodal involvement compared to the HM-VH subgroup. The overall survival curve of the HM-VH subgroup showed a rapid decline followed by a plateau, whereas that of the GL-VH subgroup declined constantly after 5 years, suggesting that GL-VH disease may not be curable by standard therapies. These findings suggest that CD5+ DLBCL with GL-VH shares clinical features with mantle cell lymphoma, the cellular origin of which has been considered to be pre-germinal center B-cells. We therefore propose that analysis of the VH gene is important for predicting the clinical course of CD5+ DLBCL.     

t(6;14)(q15;q32) in a Patient with CD5+CD10+ Diffuse Large B-Cell Lymphoma

A 68-year-old man presented with systemic lymph node swelling. A biopsy specimen taken from the right cervical lymph node showed that the normal architecture was replaced by a diffuse proliferation of large lymphoid cells with large atypical nuclei. Immunohistochemical analysis showed that the atypical lymphoid cells were positive for CD5, CD10, CD20, CD79a, and Bcl2, and negative for CD3 and cyclin D1. A diagnosis of diffuse large B-cell lymphoma was made. Karyotypic findings included add(5)(q13), del(6)(q13), add(17)(p11), add(19)(p11), add(19)(p13), and t(6;14)(q15;q32). The serum lactate dehydrogenase level and indirect bilirubin level were slightly elevated. Elliptocytosis was observed in the peripheral blood, and a diagnosis of hereditary spherocytosis was made from the family history. Regarding CD5+CD10+ diffuse large B-cell lymphoma with a non-random chromosomal translocation of t(6;14)(q15;q32), studies on the mechanism of lymphomagenesis are needed.     

CXCR4 and CCR7 Expression in Primary Nodal Diffuse Large B-Cell Lymphoma—A Clinical and Immunohistochemical Study

Background

A few studies have evaluated the expression of chemokine receptors CXCR4 and CCR7 in diffuse large B-cell lymphoma (DLBCL); however, the association between CXCR4 and CCR7 with bone marrow (BM) involvement and their synergistic effect on prognosis is still unclear. Our study investigated this aspect.

ALK5- and TGFBR2-independent role of ALK1 in the pathogenesis of hereditary hemorrhagic telangiectasia type 2

ALK1 belongs to the type I receptor family for transforming growth factor-beta family ligands. Heterozygous ALK1 mutations cause hereditary hemorrhagic telangiectasia type 2 (HHT2), a multisystemic vascular disorder. Based largely on in vitro studies, TGF-beta1 has been considered as the most likely ALK1 ligand related to HHT, yet the identity of the physiologic ALK1 ligand remains controversial. In cultured endothelial cells, ALK1 and another TGF-beta type I receptor, ALK5, regulate angiogenesis by controlling TGF-beta signal transduction, and ALK5 is required for ALK1 signaling. However, the extent to which such interactions between these 2 receptors play a role in pathogenesis of HHT is unknown. We directly addressed these issues in vivo by comparing the phenotypes of mice in which the Alk1, Alk5, or Tgfbr2 gene was conditionally deleted in restricted vascular endothelia using a novel endothelial Cre transgenic line. Alk1-conditional deletion resulted in severe vascular malformations mimicking all pathologic features of HHT. Yet Alk5- or Tgfbr2-conditional deletion in mice, or Alk5 inhibition in zebrafish, did not affect vessel morphogenesis. These data indicate that neither ALK5 nor TGFBR2 is required for ALK1 signaling pertinent to the pathogenesis of HHT and suggest that HHT might not be a TGF-beta subfamily disease.     

Primary Hepatic Low-Grade B-Cell Lymphoma of the Mucosa-Associated Lymphoid Tissue Type: A Case Report and Review of the Literature

Primary hepatic lymphoma, mostly diffuse large B-cell lymphoma, is a rare disease. We describe an extremely rare case of low-grade B-cell lymphoma of the mucosa-associated lymphoid tissue (MALT) type occurring in the liver. A 61-year-old man with a history of hepatitis A presented with early gastric cancer and a liver mass. Needle biopsy of the liver tumor suggested low-grade B-cell lymphoma by histology and polymerase chain reaction of the immunoglobulin heavy chain gene. The tumor (3.4 x 2.8 x 2.4 cm) was completely resected from the anterior segment of the right lobe of the liver. Atypical lymphoid cells of small to intermediate size proliferated in the tumor, and lymphoepithelial lesions were recognized. Immunohistochemically, lymphoma cells were positive for CD20 and negative for CD5, CD10, and cyclin D1. Staging procedures showed no lymphoma lesion other than the liver tumor. Thus, the patient was diagnosed with low-grade hepatic marginal zone B-cell lymphoma of the MALT type. The patient has been followed up for 1.5 years since surgical resection with no recurrence. The clinicopathologic characteristics and management of this rare disease are discussed.     

Prediction of Central Nervous System Relapse of Diffuse Large B-Cell Lymphoma Using Pretherapeutic [18F]2-Fluoro-2-Deoxyglucose (FDG) Positron Emission Tomography/Computed Tomography

Central nervous system (CNS) relapse of diffuse large B-cell lymphoma (DLBCL) is a rare complication, but has a poor prognosis with unknown pathophysiology. Recent trials of CNS prophylaxis have shown to be ineffective, despite patient''s selection using several known clinical risk factors. In this study, the authors evaluated the value of pretreatment [¹⁸F]2-Fluoro-2-deoxyglucose positron emission tomography in predicting CNS relapse in DLBCL patients.The authors analyzed 180 pathologically confirmed DLBCL patients, retrospectively. Patients underwent [¹⁸F]2-Fluoro-2-deoxyglucose positron emission tomography/computed tomography before first line rituximab to cyclophosphamide, doxorubicin, vincristine, and prednisone therapy. Clinical characteristics were evaluated and total lesion glycolysis (TLG) with a threshold margin of 50% was calculated.Among age, sex, Ann Arbor stage, International Prognostic Index, revised International Prognostic Index, high serum lactate dehydrogenase level, presence of B symptoms, bulky disease (≥10 cm), extranodal lesion involvement, bone marrow involvement, high metabolic tumor volume ( >450 mL), and high TLG50 (>2000), the high TLG50 was the only significant prognostic factor for predicting CNS relapse in a multivariate analysis (P = 0.04). Kaplan–Meir survival analysis between high TLG50 (>2000) and low TLG50 (≤2000) groups revealed significantly different mean progression free survival (PFS) of 1317.2 ± 134.3 days and 1968.6 ± 18.3 days, respectively (P < 0.001).High TLG50 on [¹⁸F]2-Fluoro-2-deoxyglucose positron emission tomography/computed tomography is the most significant predictor of CNS relapse in un-treated DLBCL patients.