CD5+ diffuse large B-cell lymphoma has heterogeneous clinical features and poor prognosis: a single-center retrospective study in China.

OBJECTIVE: De novo CD5-positive (CD5+) diffuse large B-cell lymphoma (DLBCL) has different clinical characteristics compared with CD5-negative (CD5-) DLBCL. However, few studies have been reported in Chinese cohorts. We investigated the clinical features and prognosis of patients with CD5+ DLBCL and summarized the related literature. METHODS: Data from 245 patients with newly diagnosed DLBCL were retrospectively assessed. RESULTS: Thirty-one and 214 patients were diagnosed with CD5+ DLBCL or CD5- DLBCL, respectively. In the CD5+ DLBCL group, there were significantly higher proportions of patients with older age (≥60 years), International Prognostic Index (IPI) ≥3, Eastern Cooperative Oncology Group (ECOG) scores ≥ 2, bone marrow involvement, positive B-cell lymphoma 2 expression, and positive MYC expression. Survival analysis showed that CD5+ DLBCL had a markedly poorer 2-year progression-free survival than CD5- DLBCL (18.2% vs. 56.2%). Univariate analysis indicated that age ≥60 years, ECOG score ≥ 2, IPI ≥ 3, B symptoms, and no rituximab-based treatment were poor predictive factors for overall survival (OS). Multivariate analysis revealed that B symptoms and no rituximab-based treatment, but not positive CD5 expression, were independent factors for OS. CONCLUSIONS: Patients with CD5+ DLBCL had heterogeneous clinical characteristics and poor survival. The development of more targeted and effective therapies is needed.

A new score including CD43 and CD180: Increased diagnostic value for atypical chronic lymphocytic leukemia.

Moreau score has been used to differentiate chronic lymphocytic leukemia (CLL) from other mature B-cell neoplasms. However, it showed limitations in Asian patients. Therefore, we conducted a new score system replacing CD5 and CD23 with CD43 and CD180 to evaluate its diagnostic value of CLL. 237 untreated samples diagnosed with mature B-cell neoplasms were collected and were randomly divided into an exploratory and a validation cohort by a 2:1 ratio. The expression of CD5, CD19, CD20, CD23, CD43, CD79b, CD180, CD200, FMC7, and surface immunoglobulin (SmIg) were analyzed among all the samples. A proposed score was developed based on the logistic regression model. The sensitivity and specificity of the proposed score were calculated by ROC curves. CD43/CD180, CD200, FMC7, and CD79b were included in our new CLL score, which showed a sensitivity of 91.8% and a specificity of 83.1%. These results were confirmed in a validation cohort with a sensitivity of 90.5% (p = 0.808) and a specificity of 79.5% (p = 0.639). In CD5 negative or CD23 negative CLL group, the new CLL score displayed improved sensitivity of 79.4% compared to Moreau score and CLLflow score (41.2% and 47.1%, respectively). In atypical CLL group, the new CLL score showed improved sensitivity of 84.2% compared to Moreau score and CLLflow score (61.4% and 64.9%, respectively). This proposed atypical CLL score helped to offer an accurate differentiation of CLL from non-CLL together with morphological and molecular methods, particularly in Chinese patients with atypical immunophenotype.

Biphasic Squamoid Alveolar Renal Cell Carcinoma of the Kidney Involved by Atypical CD5-Positive B-Cells.

Biphasic squamoid alveolar renal cell carcinoma (BSARCC) is a recently described kidney cancer entity with <60 published cases so far. Some unique features of BSARCC include distinct squamoid and alveolar morphology forming glomeruloid configurations and 2 types of tumor cells with different immunoprofiles. Although the mechanism is unknown, neutrophils and cellular materials engulfed by larger tumor cells (described as "emperipolesis") are observed in all reported cases including the current one. In this article, we report a case of a 70-year-old man who presented with an incidental renal mass during workup for immunoglobulin M monoclonal gammopathy of unknown significance and cold agglutinin autoimmune hemolytic anemia. A detailed pathologic evaluation and immunohistochemical studies revealed BSARCC colliding with atypical CD5+ monoclonal B-cells.

Classification of aggressive and classic mantle cell lymphomas using synchrotron Fourier Transform Infrared microspectroscopy.

Mantle cell lymphoma (MCL) is regarded as an incurable neoplasm, even to the novel drug strategies. It is known MCL has two morphological variants- classic and aggressive. Aggressive MCL is characterized by a higher mitotic index and proliferation rate, and poor overall survival in comparison to classic subtype. The insight into the detailed biochemical composition of MCL is crucial in the further development of diagnostic and treatment guidelines for MCL patients; therefore Synchrotron radiation Fourier Transform Infrared (S-FTIR) microspectroscopy combined with Principal Component Analysis (PCA) was used. The major spectral differences were observed in proteins and nucleic acids content, revealing a classification scheme of classic and aggressive MCLs. The results obtained suggest that FTIR microspectroscopy has reflected the histopathological discrimination of both MCL subtypes.

CD5 expression correlates with inferior survival and enhances the negative effect of p53 overexpression in diffuse large B-cell lymphoma.

De novo CD5-positive diffuse large B-cell lymphoma (CD5+ DLBCL) is increasingly recognized as a distinct pathologic phenomenon with a specific clinical picture. However, CD5+ DLBCL has not been studied on a large scale in China. In this study, we show that CD5+ DLBCL occurs at a low frequency (9.2%). Comparison of clinical characteristics of CD5+ vs CD5- DLBCL showed that CD5+ DLBCL was more frequently elderly (>60 years) and had B symptoms, high-performance status, stage III-IV, an IPI score >2 and bone marrow involvement. Patients with CD5+ DLBCL had tumours with a higher prevalence of BCL-2 and p53 overexpression than CD5- DLBCL. Patients with CD5+ DLBCL had inferior progression-free survival (PFS) and overall survival (OS) than did patients with CD5- DLBCL. For CD5+ DLBCL, the patients who were treated with rituximab showed significantly better PFS and OS than those treated without rituximab. However, patients treated with RCHOP showed similar PFS and OS when compared with the group treated with intensive therapy. In addition, patients with p53 and CD5 co-expression had the worst PFS and OS. In conclusion, CD5+ DLBCL was associated with unfavorable clinicopathologic variables and with inferior survival. CD5+ DLBCL has a high frequency of p53 overexpression, and CD5 augments the negative effect of p53 overexpression in DLBCL.

Respiratory Bordetella bronchiseptica Carriage is Associated with Broad Phenotypic Alterations of Peripheral CD4⁺CD25⁺ T Cells and Differentially Affects Immune Responses to Secondary Non-Infectious and Infectious Stimuli in Mice.

The respiratory tract is constantly exposed to the environment and displays a favorable niche for colonizing microorganisms. However, the effects of respiratory bacterial carriage on the immune system and its implications for secondary responses remain largely unclear. We have employed respiratory carriage with Bordetella bronchiseptica as the underlying model to comprehensively address effects on subsequent immune responses. Carriage was associated with the stimulation of Bordetella-specific CD4⁺, CD8⁺, and CD4⁺CD25⁺Foxp3⁺ T cell responses, and broad transcriptional activation was observed in CD4⁺CD25⁺ T cells. Importantly, transfer of leukocytes from carriers to acutely B. bronchiseptica infected mice, resulted in a significantly increased bacterial burden in the recipient's upper respiratory tract. In contrast, we found that respiratory B. bronchiseptica carriage resulted in a significant benefit for the host in systemic infection with Listeria monocytogenes. Adaptive responses to vaccination and influenza A virus infection, were unaffected by B. bronchiseptica carriage. These data showed that there were significant immune modulatory processes triggered by B. bronchiseptica carriage, that differentially affect subsequent immune responses. Therefore, our results demonstrated the complexity of immune regulation induced by respiratory bacterial carriage, which can be beneficial or detrimental to the host, depending on the pathogen and the considered compartment.

Pure intravascular recurrence of CD5-positive diffuse large B-cell lymphoma primarily arising from the nasal cavities.

BACKGROUND: CD5-positive diffuse large B-cell lymphoma (DLBCL) and intravascular large B-cell lymphoma (IVL) are recognized as rare subsets of large B-cell lymphoma with poor prognosis. These two categories have similar clinicopathological features suggesting that they might overlap. CASE PRESENTATION: We present a case of a 72-year-old man with submental tumors. Positron emission tomography/computed tomography (PET/CT) showed tumors in the nasal and paranasal region and multiple submental and jugular swollen lymph nodes with abnormal uptake of 18F-fluorodeoxyglucose (FDG). Histology of biopsy from nasal tumors showed diffuse infiltration of large lymphoid cells, which showed positive expressions for CD20, CD79a, CD5 and negative for CD3 on immunohistochemistry. Thus, a CD5-positive DLBCL was diagnosed. After administration of 8 cycles of R-THPCOP (rituximab, pirarubicin, cyclophosphamide, vincristine and prednisolone), complete remission was achieved. Eight months after the first chemotherapy dose, local recurrence occurred. After salvage chemotherapy, nasal and paranasal tumors and lymph node swelling disappeared on PET/CT images, although the patient suffered from respiratory disturbance. A random skin biopsy revealed IVL, which was consistent with intravascular recurrence of CD5-positive DLBCL. Bone marrow smears showed hemophagocytosis. CONCLUSION: We present a rare case of primary CD5-positive DLBCL that relapsed as pure IVL after chemotherapy. Our case suggests that CD5-positive DLBCL is closely related to IVL.

Lymphoma-like monoclonal B cell lymphocytosis in a patient population: biology, natural evolution, and differences from CLL-like clones.

High-count monoclonal B cell lymphocytosis (MBL) with a chronic lymphocytic leukemia (CLL) phenotype is a well-known entity, featuring 1-4% annual risk of progression towards CLL requiring treatment. Lymphoma-like MBL (L-MBL), on the other hand, remains poorly defined and data regarding outcome are lacking. We retrospectively evaluated 33 L-MBL cases within our hospital population and compared them to 95 subjects with CLL-like MBL (C-MBL). Diagnoses of L-MBL were based on asymptomatic B cell clones with Matutes score < 3, B cells < 5.0 × 103/µl, and negative computerized tomography scans. We found that median B cell counts were considerably lower compared to C-MBL (0.6 vs 2.3 × 103/µl) and remained stable over time. Based on immunophenotyping and immunogenetic profiling, most L-MBL clones did not correspond to known lymphoma entities. A strikingly high occurrence of paraproteinemia (48%), hypogammaglobulinemia (45%), and biclonality (21%) was seen; these incidences being significantly higher than in C-MBL (17, 21, and 5%, respectively). Unrelated monoclonal gammopathy of undetermined significance was a frequent feature, as the light chain type of 5/12 paraproteins detected was different from the clonal surface immunoglobulin. After 46-month median follow-up, 2/24 patients (8%) had progressed towards indolent lymphoma requiring no treatment. In contrast, 41% of C-MBL cases evolved to CLL and 17% required treatment. We conclude that clinical L-MBL is characterized by pronounced immune dysregulation and very slow or absent progression, clearly separating it from its CLL-like counterpart.

[Clinicopathologic characteristics and prognositic indicators of tonsillar mantle cell lymphoma].

Objective: To investigate clinicopathological features and prognosis of tonsillar mantle cell lymphoma(TMCL). Methods: Clinical data of 25 patients with TMCL at Beijing Friendship Hospital, Capital Medical University from 2002 to 2016 were included. All the cases were reviewed microscopically. Various immunohistochemical stains were performed using the MaxVision two-step method. IgH/CCND1 gene fusion was detected by fluorescent in situ hybridization(FISH). Additionally, randomly selected 40 cases of non-tonsil MCL of the same period were compared. Results: Among all mantle cell lymphomas (MCL), TMCL accounted for 5.6%(25/449). The median age of the patients was 60 years(range: 44-82 years) with a M∶F ratio of 5.3 to 1.0. The main symptoms were sore throat and foreign body sensation and patients usually presented with enlargement or mass of tonsil. At the early stage of the disease, 18 cases(72.0%) were clinically misdiagnosed as tonsillitis. Lymph node involvement was present in 76.0%(19/25) of the patients. There were 4 cases(16.0%)with current splenic involvement, 11 cases(44.0%) with pharyngeal focal recidivism, and 3 cases(12.0%) with involvement of other non-lymphoid organs. Morphologically, tonsillar architectures were effaced at various degrees. Eighteen MCL cases showed classical type and 7 cases were blastoid variant. All tumors were positive for CD20 and cyclin D1. 92.0%(23/25) tumors showed weakly positive or positive expression for CD5. FISH test that IgH/CCND1 gene fusion was positive in two CD5 negative classical cases. 18 patients(72.0%) had a median follow-up time of 26 months(range: 6-81 months). The difference of survival rate between stage Ⅰ-Ⅱ and stage Ⅲ-Ⅳ patients was not statistically significant(P>0.05). Compared with NTMCL, TMCL was found to have higher proportion of stage Ⅰ-Ⅱ disease (χ(2)=12.789, P<0.01), lower the proportion of non-lymphatic organ involvement (χ(2)=8.125, P<0.01), and better prognosis (χ(2)=4.351, P=0.037). Conclusion: The incidence of TMCL is low and prone to be misdiagnosed as tonsillitis. Patients with TMCL are more likely at stage Ⅰ-Ⅱ at presentation and the prognosis is better than that of NTMCL.

Quantitative assessment of informative immunophenotypic markers increases the diagnostic value of immunophenotyping in mature CD5-positive B-cell neoplasms.

BACKGROUND: The data on the clinical utility of the quantitative assessment of immunophenotypes in distinguishing mature CD5-positive B-cell neoplasms is limited. The study aim was to assess the diagnostic value of the quantitative assessment of a panel of 18 markers and to identify the most informative ones. METHODS: The immunophenotype of the neoplastic population was determined in diagnostic specimens from 188 patients. BD FACSCanto II flow cytometer and FACSDiva software were used to analyze the positivity/negativity and mean fluorescence intensity (MFI) of the surface expression of 18 markers. Advanced data mining methods were used to define the key differential diagnostic features of CLL/SLL (chronic lymphocytic leukemia/small lymphocytic lymphoma), MCL (mantle cell lymphoma), and CD5+ MZL (marginal zone lymphoma). RESULTS: The most informative markers for the distinction of CLL/SLL, MCL, CD5+ MZL, including atypical cases, were the MFI values of CD79b, CD20, CD23, CD43, CD38, CD11c, FMC7, CD200, kappa light chain, and their combinations. CD23 and CD200 were the most discriminant between CLL/SLL and MCL and CD23 plus CD79b between CLL/SLL and CD5+ MZL. The quantitative analysis of the most informative markers failed to accurately distinguish MCL and CD5+ MZL. The study highlights the data mining methods for the analysis and selection of the most informative immunophenotypic markers and for the design of a predictive model (diagnostic classifier), minimizing the subjectivity of expert-based assessment. CONCLUSIONS: Our data confirmed that the quantification of the expression of informative markers increases the diagnostic value of immunophenotyping in mature CD5+ B-cell neoplasms. © 2017 International Clinical Cytometry Society.

Outcome of Thyroid Carcinoma Showing Thymus-Like Differentiation in Patients Undergoing Radical Resection.

BACKGROUND: Carcinoma showing thymus-like differentiation (CASTLE) is a rare malignant tumor of the thyroid. It is difficult to diagnose, and there is no universally recognized therapeutic regimen. This study aims to define the clinicopathological features and discuss the optimal management of CASTLE. METHODS: We retrospectively analyzed six patients with CASTLE who accepted surgery at the First Hospital of China Medical University between January 2010 and December 2015. RESULTS: The six patients (three women and three men) had median age of 53 years (range 47-61 years). All patients presented with a slow-growing, painless neck mass; three patients also had hoarseness. All tumors were located in middle-lower or lower lobe, and two tumors extended to the substernal region. All patients underwent radical surgery without postoperative radiotherapy or chemotherapy. Five patients had extrathyroidal extension and two had lymph node metastasis. All six tumors were positive for CD5 and negative for thyroglobulin (Tg) and thyroid transcription factor (TTF)-1. Median follow-up was 32 months (range 23-81 months). Lateral cervical lymph node metastasis occurred in one patient at 26 months after initial treatment. CONCLUSIONS: CASTLE is a rare, aggressive malignant tumor of the thyroid. Ultrasound, computed tomography, and fine-needle aspiration biopsy may not be sufficient to establish the diagnosis preoperatively; pathological examination and immunohistochemistry, particularly positive CD5 staining, are necessary to establish the diagnosis. Patients with CASTLE can yield a favorable outcome after radical surgery.

Human Blood CD1c+ Dendritic Cells Encompass CD5high and CD5low Subsets That Differ Significantly in Phenotype, Gene Expression, and Functions.

There are three major dendritic cell (DC) subsets in both humans and mice, that is, plasmacytoid DCs and two types of conventional DCs (cDCs), cDC1s and cDC2s. cDC2s are important for polarizing CD4+ naive T cells into different subsets, including Th1, Th2, Th17, Th22, and regulatory T cells. In mice, cDC2s can be further divided into phenotypically and functionally distinct subgroups. However, subsets of human cDC2s have not been reported. In the present study, we showed that human blood CD1c+ cDCs (cDC2s) can be further separated into two subpopulations according to their CD5 expression status. Comparative transcriptome analyses showed that the CD5high DCs expressed higher levels of cDC2-specific genes, including IFN regulatory factor 4, which is essential for the cDC2 development and its migration to lymph nodes. In contrast, CD5low DCs preferentially expressed monocyte-related genes, including the lineage-specific transcription factor MAFB. Furthermore, compared with the CD5low subpopulation, the CD5high subpopulation showed stronger migration toward CCL21 and overrepresentation among migratory DCs in lymph nodes. Additionally, the CD5high DCs induced naive T cell proliferation more potently than did the CD5low DCs. Moreover, CD5high DCs induced higher levels of IL-10-, IL-22-, and IL-4-producing T cell formation, whereas CD5low DCs induced higher levels of IFN-γ-producing T cell formation. Thus, we show that human blood CD1c+ cDC2s encompass two subsets that differ significantly in phenotype, that is, gene expression and functions. We propose that these two subsets of human cDC2s could potentially play contrasting roles in immunity or tolerance.

EBI2 overexpression in mice leads to B1 B-cell expansion and chronic lymphocytic leukemia-like B-cell malignancies.

Human and mouse chronic lymphocytic leukemia (CLL) develops from CD5+ B cells that in mice and macaques are known to define the distinct B1a B-cell lineage. B1a cells are characterized by lack of germinal center (GC) development, and the B1a cell population is increased in mice with reduced GC formation. As a major mediator of follicular B-cell migration, the G protein-coupled receptor Epstein-Barr virus-induced gene 2 (EBI2 or GPR183) directs B-cell migration in the lymphoid follicles in response to its endogenous ligands, oxysterols. Thus, upregulation of EBI2 drives the B cells toward the extrafollicular area, whereas downregulation is essential for GC formation. We therefore speculated whether increased expression of EBI2 would lead to an expanded B1 cell subset and, ultimately, progression to CLL. Here, we demonstrate that B-cell-targeted expression of human EBI2 (hEBI2) in mice reduces GC-dependent immune responses, reduces total immunoglobulin M (IgM) and IgG levels, and leads to increased proliferation and upregulation of cellular oncogenes. Furthermore, hEBI2 overexpression leads to an abnormally expanded CD5+ B1a B-cell subset (present as early as 4 days after birth), late-onset lymphoid cancer development, and premature death. These findings are highly similar to those observed in CLL patients and identify EBI2 as a promoter of B-cell malignancies.

Composite Follicular Lymphoma and CD5-Positive Nodal Marginal Zone Lymphoma.

Composite CD10-positive low-grade B-cell and CD5-positive low-grade B-cell lymphoma is extremely rare. We report a case of a composite follicular lymphoma (FL) and CD5-positive nodal marginal zone lymphoma (NMZL) in a resected inguinal lymph node of a 72-year-old Japanese male. Histologically, multiple follicles had reactive-germinal centers with tingible body macrophages, a thin mantle zone and a wide marginal zone. The wide marginal zone consisted of medium-sized cells having slightly indented nuclei and clear cytoplasm, indicating monocytoid cells with CD5-positive B-cells. Several follicles had germinal centers filled with many centrocytes, with CD10-positive B-cells. Polymerase chain reaction/sequence analysis of the immunoglobulin heavy chain gene obtained from microdissected regions of CD5-positive NMZL and FL showed different sequences within the CDR3 region. To our knowledge, this is the first report of FL and CD5-positive NMZL.

Development tuberculous meningitis during chemotherapy for CD5-positive diffuse large B-cell lymphoma.

The patient was a 62-year-old woman with CD5(+) diffuse large B-cell lymphoma. Treatment with the R-CHOP regimen (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) was started. On the eleventh day of the third cycle, headache and low grade fever developed. Her consciousness gradually deteriorated. Seven days after symptom onset, she was brought to the emergency department of our hospital. Cerebrospinal fluid (CSF) analysis revealed a white blood cell count of 25/µl, and a protein level of 188 mg/dl. Antibacterial and antiviral agents were administered based on a diagnosis of acute meningitis. She showed no improvement. We performed another lumbar puncture and intrathecal chemotherapy, a combination of methotrexate and dexamethasone, was administered because we suspected central nervous system involvement of lymphoma. She showed transient improvement. On day 12, we started the R-MPV regimen (rituximab, methotrexate, procarbazine, and vincristine). However, fever and disturbance of consciousness persisted. On day 20, we empirically started anti-tuberculosis treatment. Four days later, tubercle bacilli were confirmed by CSF culture after a 23-day incubation. We ultimately confirmed a diagnosis of tuberculous meningitis. Impaired cellular immunity in lymphoma patients increases the risk of tuberculosis. It is important to consider tuberculous meningitis in the differential diagnosis of a lymphoma patient presenting with meningitis.

Expression of activated molecules on CD5(+)B lymphocytes in autoimmune hemolytic anemia.

To investigate the expression of activation molecules on CD5(+)B lymphocytes in peripheral blood of autoimmune hemolytic anemia (AIHA)/Evans patients. The expression of CD80, CD86, and CD69 on CD5(+)B lymphocytes was detected using flow cytometry in 30 AIHA/Evans patients, 18 normal controls (NC) and nine chronic lymphocytic leukemia (CLL) patients. CD80 on CD5(+)B lymphocytes in untreated patients was higher than that in remission patients (P < 0.05), NC (P < 0.01) and CLL patients (P < 0.01). CD80 on CD5(+)B lymphocytes was higher than that on CD5(-)B lymphocytes in untreated patients (P > 0.05), but lower than those of CD5(-)B lymphocytes in remission patients and NC (P < 0.05). CD86 on CD5(+)B lymphocytes of untreated patients was higher than that of remission patients (P < 0.05), NC (P < 0.01). CD86 on CD5(+)B lymphocytes of CLL was higher than that of NC, remission (P < 0.05), and untreated patients (P > 0.05). CD80 and CD86 on CD5(+)B lymphocytes was negatively correlated with hemoglobin (HB), C3, C4 (P < 0.05) and positively correlated with reticulocyte (Ret) (P < 0.05). CD69 on CD5(+) and CD5(-)B lymphocytes of CLL was higher than those of AIHA/Evans patients and NC (P < 0.05). The active molecules on CD5(+)B lymphocytes in peripheral blood of AIHA/Evans patients differ from those on CD5(-) and clonal CD5(+)B lymphocytes.

Decreased Frequency of Intestinal Regulatory CD5+ B Cells in Colonic Inflammation.

BACKGROUND: CD5+ B cells are a type of regulatory immune cells, though the involvement of this B cell subset in intestinal inflammation and immune regulation is not fully understood. METHODS: We examined the distribution of CD5+ B cells in various mouse organs. Expression levels of CD11b, IgM, and toll-like receptor (TLR)-4 and -9 in B cells were evaluated. In vitro, TLR-stimulated IL-10 production by colonic lamina propria (LP) CD5+ and CD5- B cells was measured. In vivo, mice with acute or chronic dextran sulfate sodium (DSS)-induced colonic injury were examined, and the frequency of colonic LP CD5+ B cells in those was assessed by flow cytometry. RESULTS: The expression level of TLR9 was higher in colonic LP CD5+ B cells as compared to CD5- B cells. Colonic LP CD5+ B cells produced greater amounts of IL-10 following stimulation with TLR ligands, especially TLR9, as compared with the LP CD5- B cells. Acute intestinal inflammation transiently decreased the frequency of colonic LP CD5+ B cells, while chronic inflammation induced a persistent decrease in colonic LP CD5+ B cells and led to a CD5- B cell-dominant condition. CONCLUSION: A persistent altered mucosal B cell population caused by chronic gut inflammation may be involved in the pathogenesis of inflammatory bowel diseases.