scholarly journals Case Report: Multiple Chromosomal Translocations Including Novel CIITA-CREBBP Fusion and Mutations in a Follicular Lymphoma

2021 ◽  
Vol 11 ◽  
Author(s):  
Huan-You Wang ◽  
Ethan S. Sokol ◽  
Aaron M. Goodman ◽  
Andrew L. Feldman ◽  
Carolyn M. Mulroney
Keyword(s):  
Follicular Lymphoma ◽  
Mhc Class Ii ◽  
Fusion Gene ◽  
B Cell Lymphoma ◽  
Class Ii ◽  
Chromosomal Translocations ◽  
Proliferation Index ◽  
Low Grade ◽  
Creb Binding Protein ◽  
Ki 67

The pathogenesis of follicular lymphoma is a multi-step process, in which chromosomal translocation between immunoglobulin heavy chain (IgH) and anti-apoptotic B-cell lymphoma 2 (BCL2), namely IgH-BCL2, is an earliest step, followed by other genetic/genomic alterations including but not limited to mutation of CREB binding protein (CREBBP). MHC class II transactivator (CIITA) is a transcription regulator responsible for expression of MHC class II molecules including HLA-DR in human. We report herein a novel fusion gene involving CIITA and CREBBP in a patient with a low-grade follicular lymphoma (FL) but with high Ki-67 proliferation index. In addition, our patient also harbors CREBBP mutation. Together, we postulate that total loss of CREBBP function may contribute, in part, to the lymphoma genesis. Furthermore, this patient has addition rare (TBL1XR1-TP63) and common (IgH-BCL2) chromosomal translocations and multiple mutations including BCL2, BRAF, MUTYH, and STAT6.

scholarly journals Immune microenvironment subtypes and association with tumor cell mutations and antigen expression in follicular lymphoma

2021 ◽  
Author(s):  
Guangchun Han ◽  
Qing Deng ◽  
Enyu Dai ◽  
Minghao Dang ◽  
John Ma ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Cell ◽  
Follicular Lymphoma ◽  
Antigen Presentation ◽  
Mhc Class Ii ◽  
B Cell Lymphoma ◽  
Class Ii ◽  
T Cell Subsets ◽  
Cell Populations

AbstractFollicular lymphoma (FL) is a B-cell lymphoma with a complex tumor microenvironment that is rich in non-malignant immune cells. We applied single-cell RNA-sequencing to characterize the diverse tumor and immune cell populations of FL and identified major phenotypic subsets of FL T-cells including a novel cytotoxic CD4 T-cell population. Their relative proportions of T-cells defined four major FL subtypes, characterized by differential representation or relative depletion of distinct T-cell subsets. By integrating exome sequencing, we observed that somatic mutations are associated with, but not definitive for, reduced antigen presentation on FL cells. In turn, expression of MHC class II genes by FL cells was associated with significant differences in the proportions and targetable immunophenotypic characteristics. This provides a classification framework of the FL microenvironment, their association with FL genotypes and antigen presentation, and informs different potential immunotherapeutic strategies based upon tumor cell MHC class II expression.Statement of significanceWe have characterized the FL-infiltrating T-cells, identified cytotoxic CD4 T-cells as an important component, showed that the abundance of these T-cell populations is associated with tumor-cell-intrinsic characteristics, and identified sets of targetable immune checkpoints on T-cells that differed between FLs with normal versus low antigen presentation.

scholarly journals “Double hit” follicular lymphoma with low proliferation index: A unique case and literature review

2017 ◽  
Vol 3 (2) ◽  
Author(s):  
Pardis Vafaii ◽  
Haipeng Shao
Keyword(s):  
Follicular Lymphoma ◽  
B Cell ◽  
Clinical Course ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Proliferation Index ◽  
Low Grade ◽  
Gene Rearrangements ◽  
Double Hit ◽  
Indolent Disease

<p>“Double hit” lymphomas (DHLs) are aggressive B-cell lymphomas with concurrent <em>c-MYC</em> and <em>BCL2</em> and/or <em>BCL6</em> gene rearrangements. DHLs are usually classified morphologically as B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma, and less commonly as DLBCL. Follicular lymphoma (FL) is characterized genetically by the presence of <em>IGH-BCL2</em> rearrangement. A subset of DHLs arises from FL by the acquisition of <em>c-MYC</em> gene rearrangement during disease progression, but FL with concurrent <em>IGH-BCL2</em> and <em>c-MYC</em> gene initial rearrangements is rarely reported. The few reported cases had different clinical courses, including some with indolent disease. We report a case of “double hit” low grade FL with both <em>c-MYC</em> and <em>BCL2</em> gene rearrangements but at low proliferation rate. Unlike the usual DHLs with aggressive clinical course, our patient showed at least partial response to intense chemotherapy. Review of the literature shows a few similar cases with variable clinical course, including a few indolent cases. These patients appear to respond better with more intense chemotherapy for DHL.</p>

Primary Dural Lymphoma Masquerading as a Meningioma: A Rare Clinical Entity

2019 ◽  
Vol 152 (Supplement_1) ◽  
pp. S114-S114
Author(s):  
Sakshi Sakshi ◽  
Ashish Bains
Keyword(s):  
B Cell ◽  
Dura Mater ◽  
Occipital Lobe ◽  
B Cell Lymphoma ◽  
Mass Effect ◽  
Proliferation Index ◽  
Right Visual Field ◽  
Pcr Analysis ◽  
Low Grade ◽  
Ki 67

Abstract Primary dura mater–based lymphomas are extremely uncommon and when detected are often clinically and radiologically misidentified. As per literature search, they account for <0.1% of all non-Hodgkin lymphomas; however, a precise incidence is unknown since only a few cases have been described in the literature. Here we report a case of a 64-year-old female who presented for evaluation of a newly diagnosed left tentorial tumor, diagnosed as “consistent with meningioma” on imaging studies with significant mass effect on the left occipital lobe and left cerebellum with effacement of the fourth ventricle. She had been experiencing disabling headaches, balance dysfunction, and reduced vision. On examination, the patient had right visual field defect with wide-based gait. No evidence of systemic lymphoma or clinically suspicious lymphadenopathy was documented. An intraoperative consultation revealed sheets of lymphocytes, rather highly concerning for lymphoma. H&E sections showed dense fibroconnective tissue heavily infiltrated by mature small- to intermediate-sized lymphocytes with irregular nuclei and condensed chromatin without a discernible architecture. Only sparse and scattered larger lymphocytes were seen. Flow cytometry identified a subset of B cells with lambda-restricted immunophenotype expressing CD19+, CD20+, CD10+, CD5–, and CD23–. On tissue sections, Ki-67 showed an overall proliferation index of 10% to 20%. However, no residual follicular dendritic cell meshwork was detected by CD21 or CD23. PCR analysis detected clonal B-cell IgH and IgKappa gene rearrangements. A diagnosis of low-grade CD10-positive B-cell lymphoma (likely follicle center-cell origin) was made and the patient was discharged after 3 days of surgery for outpatient follow-up and treatment. In conclusion, low-grade dural-based lymphomas are extremely rare and often misdiagnosed as meningiomas clinically and radiologically. Additionally, it is important distinguish lymphomas of the dura mater, which are excluded from the definition of primary CNS lymphomas and may have a different clinical management and outcome.

scholarly journals Double-Hit and Triple-Hit Follicular Lymphoma

2020 ◽  
Vol 153 (5) ◽  
pp. 672-685 ◽  
Author(s):  
Jessica B Ziemba ◽  
Zena Wolf ◽  
Matthew Weinstock ◽  
Saja Asakrah
Keyword(s):  
Follicular Lymphoma ◽  
Small Sample Size ◽  
B Cell Lymphoma ◽  
Standard Of Care ◽  
Small Sample ◽  
Proliferation Index ◽  
Low Grade ◽  
Pathologic Features ◽  
Pubmed Search ◽  
Double Hit

Abstract Objectives To better characterize the clinicopathologic presentation and outcomes of follicular lymphoma with MYC and BCL2 and/or BCL6 rearrangements (double-hit and triple-hit follicular lymphoma), we present three cases from our institution and perform a literature review of 37 published cases. Methods Cases were identified using institutional SoftPath software and the MEDLINE database via the PubMed search engine. Clinical and pathologic data were collected with subsequent stratification by histologic grade and treatment for comparison. Results Similar to classic follicular lymphoma, patients presented most often with low-grade (1-2) but high-stage (III-IV) disease with absence of B symptoms; however, overall survival was worse than that of traditional follicular lymphoma. In a small sample size, etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (EPOCH-R) achieved better outcomes than a regimen of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Specific pathologic features that might prompt testing for MYC rearrangement include elevated proliferation index out of proportion to cytology and aggressive features such as angioinvasion. Conclusions Double-hit and triple-hit follicular lymphoma may be better classified as a distinct entity from classical follicular lymphoma with a worse prognosis. Aggressive therapy with a treatment regimen used for high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements might be beneficial, but more evidence is needed to justify aggressive treatment as standard of care.

scholarly journals Primitive myxoid mesenchymal tumor of infancy in scrotum: A case report and literature review

2021 ◽  
Author(s):  
Chunsen Li ◽  
Mengqiao Wang ◽  
Hongwei Dang ◽  
Yan Pan ◽  
Yi Liu ◽  
...  
Keyword(s):  
Good Condition ◽  
B Cell Lymphoma ◽  
Mesenchymal Tumor ◽  
Proliferation Index ◽  
Pathological Examination ◽  
Low Grade ◽  
Ki 67 ◽  
Grade Malignancy ◽  
One Year ◽  
The Right

Abstract BackgroundPrimitive myxoid mesenchymal tumor of infancy (PMMTI) is a rare tumor and its molecular mechanism and prognosis remain unclear. We here report a case of PMMTI, and review the reported literature of PMMTI.Case presentationA one-year-old boy found a lump in his right groin. The size of the mass was 1 cm×1 cm. Computed tomography showed a round, slightly dense shadow of 38 mm×32 mm in the right groin. The tumor was removed for pathological examination, and the size of the tumor was 6.0 cm×5.0 cm×3.0 cm. Tumor cells are diffusely distributed, mainly spindle cells. The blood vessels were abundant, many adipocytes can be observed in some areas, and focal lymphocyte infiltration can be seen in a few areas. Immunophenotype was as follows: histone H3 at lysine 27 (H3K27me3), B-cell lymphoma 6 corepressor (BCOR) and Bcl-2 were positive, cluster of differentiation 99 (CD99) showed diffuse reactivity, BCL6 was scattered positive, Ki-67 proliferation index was 20%. Dual-color fluorescence in situ hybridization (FISH) showed red and green signal nuclei caused by the deletion of ETV6 gene rearrangement. The patient underwent extensive surgical resection during the recurrence period and was in good condition 7 months later.ConclusionsPMMTI is at least a low-grade malignancy. BCOR, BCL2, BCL6, and CD99 can be used as special IHC markers, and most PMMTI cases exhibit BCOR ITD change. H3K27me3 may be used as a new IHC marker for PMMTI.

Umbrella Cells Mimicking Focal High-Grade Urothelial Carcinoma in Low-Grade Papillary Urothelial Carcinoma

2019 ◽  
Vol 152 (Supplement_1) ◽  
pp. S121-S121
Author(s):  
Muhammad Masood Hassan ◽  
Tammey Naab ◽  
Ali Afsari
Keyword(s):  
Urothelial Carcinoma ◽  
Proliferation Index ◽  
Low Grade ◽  
High Grade ◽  
Ki 67 ◽  
Prostate Hyperplasia ◽  
History Of ◽  
Papillary Urothelial Carcinoma ◽  
Artery Disease ◽  
Umbrella Cells

Abstract Objectives Low-grade papillary urothelial carcinoma (LGUC) has overall a preserved orderly appearance, minimal variability in architecture, and lack of significant cytologic atypia and mitotic activity without pleomorphism. A total of 53.8% of LGUC cases recur with 18.3% progression to high-grade UC. Even focal HGUC in LGUC can be a harbinger of progression. Accurate pathological interpretation is paramount in predicting recurrence and determining treatment. Methods A 63-year-old male with a past medical history of coronary artery disease, benign prostate hyperplasia, and obesity was referred to urology with a chief complaint of chronic hematuria. Cystoscopy with transurethral resection of bladder tumor was performed, which revealed mainly LGUC with focal high-grade-appearing UC. Results Histologic sections revealed papillary architecture with fused fronds, low-grade nuclear atypia, and scattered mitoses comprising 95% of the tissue submitted. No muscular wall invasion by carcinoma was seen. However, in one section, collections of large cells with well-defined cytoplasmic borders, multinucleation, and rare nuclear grooves were identified. The morphology raised the suspicion of a focal HGUC. Diffuse expression of CK20 and low Ki-67 proliferation index (1%) favored umbrella cells. Conclusion Our case reinforces the fact that sectioning can reveal foci, suspicious for HGUC, especially in urothelium. However, proper interpretation of morphology combined with the help of immunohistochemistry aids in accurate diagnosis, which is critical in determining proper clinical management of the patient.

HLA-DR Protein Status Predicts Survival in Patients with Diffuse Large B Cell Lymphoma (DLBCL) Treated with the MACOP-B Chemotherapy Regimen.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3273-3273
Author(s):  
Lisa M. Rimsza ◽  
Pedro Farinha ◽  
Deborah A. Fuchs ◽  
Hamid Masoudi ◽  
Joseph M. Connors ◽  
...  
Keyword(s):  
B Cell ◽  
Mhc Class Ii ◽  
Chemotherapy Regimen ◽  
Detection System ◽  
Cell Lineage ◽  
B Cell Lymphoma ◽  
Class Ii ◽  
Response To Treatment ◽  
Hla Dr ◽  
Antigen Presenting

Abstract Background: HLA-DR is one of the MHC Class II antigen presenting molecules. Loss of HLA-DR expression on DLBCL tumor cells has been associated with poor survival in patients on Southwest Oncology Group (SWOG) studies as well as the recent Leukemia and Lymphoma Molecular Profiling project (Rosenwald et al, NEJM 2002). This study was conceived to examine the effect of HLA-DR status on a completely different cohort of patients from a single institution treated uniformly with a single chemotherapy regimen, MACOP-B, in an attempt to validate HLA-DR as an important biomarker in DLBCL. Methods: HLA-DR immunostaining was performed using a tissue microarray block containing two 0.6mm cores of paraffin embedded tissues from 97 patients treated on the MACOP-B regimen (1981–86) at the BC Cancer Agency in Vancouver, Canada (Semin Hematol 1988, suppl 2: 41–6). Only cases of B cell lineage were used. We used the HLA-DR antibody Class II DR, (IgG2b) at a 1:50 dilution (Novocastra, UK) with epitope recovery, on an automated immunostainer (Ventana Benchmark System) using a biotin-avidin-diaminobenzidine-based detection system. Two pathologists (LR and DF) scored all slides for positive or negative results. Results: All patients had advanced-stage disease and were treated uniformly with the MACOP-B chemotherapy regimen. The median follow-up of living patients is 17 years. The IPI was predictive of overall survival (OS) in the study group (p = 0.023). Of the 97 B cell cases, 82 had interpretable staining. The other cases were eliminated for lack of tumor (2), necrotic tissue (1), or lack of internal positive control cells in the tissue core (12). Of the remaining 82 cases, 52 were positive for HLA-DR protein with a median OS of 16.2 years while 30 were negative with a median OS of 4.2 years, (p=0.037, figure below). A Cox multivariate model established both IPI (p = 0.031) and HLA-DR status (p = 0.04) as independent predictors of OS. Discussion: The importance of loss of antigen presenting molecules on cells of DLBCL was a key finding of the previous LLMPP work, and is now further confirmed as impacting OS in a separate set of patients treated uniformly with a different chemotherapy regimen. These findings lend credence to the hypothesis that loss of immunogenicity is of key importance in patient response to treatment and OS and suggest that specific therapies focused on this pathway may benefit patients with DLBCL regardless of their treatment regimen. Figure Figure

Association of Increased Thymidine Uptake Relative to Tumor Cell Proliferation in Low-Grade Follicular Lymphoma and DNA Repair.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3236-3236
Author(s):  
Malik E. Juweid ◽  
Sergei I. Syrbu ◽  
Michelle Bleile ◽  
Andreas Buck ◽  
Marielle Wondergem ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Dna Repair ◽  
Dna Replication ◽  
Follicular Lymphoma ◽  
Germinal Center ◽  
Staining Pattern ◽  
Low Grade ◽  
Ki 67 ◽  
High Contribution ◽  
Thymidine Analogs

Abstract Abstract 3236 Poster Board III-173 We have observed that the uptake of the thymidine analog 18F-fluorothymidine (FLT) is highly disproportional to cellular proliferation in untreated low-grade follicular lymphoma (FL). Since the uptake of thymidine/thymidine analogs is also increased with enhanced DNA repair synthesis, we investigated whether the “excess” uptake of FLT in FL may be related to DNA repair. We stained tumor samples from 20 patients each with grade 1 FL and DLBCL for Ki-67, a marker of cell proliferation and DNA replication but not DNA repair and 2 DNA replication and repair biomarkers: proliferating cell nuclear antigen (PCNA) and replication protein A (RPA). Median %Ki-67-positive cells (Ki-67 index) was 10% (range; 5-20%) in FL compared to 80% (range 60-90%) in DLBCL (P<4×10-20). In contrast, median %positive cells for PCNA and RPA were 90% and 100% in FL and 100% and 100% in DLBCL. In both FL and DLBCL, PCNA showed a characteristic staining pattern with 3+ or 4+ staining of the proliferating Ki-67-positive cells vs. 1+ to 2+ staining of quiescent cells. Similar results were obtained when staining for thymidine kinase I (TK1). Interestingly, similar staining pattern to that seen in lymphoma samples was seen in germinal center but not mantle zone cells of normal tonsils and reactive lymph nodes indicating that the DNA repair seen in both FL and DLBCL is likely related to somatic hypermutations (SHM) generated by error-prone DNA repair known to occur in FL, most DLBCLs and normal germinal center cells. Comparison of FLT uptake in FL and DLBCL indicated that > 70% of FLT uptake in FLs with a Ki-67 index of ≤10% was due to DNA repair. In contrast, contribution of DNA repair to overall FLT uptake in DLBCL with a Ki-67 index of ≥ 80% was <10% presumably due to the 4-fold lower fraction of quiescent compared with proliferating cells with high replicative DNA synthesis. This is the first demonstration of a high contribution of SHM/DNA repair to overall uptake of thymidine/thymidine analogs in low-grade FL. Our data further suggest that FLT use for assessing response to cytostatic therapy in low-grade FL will be confounded by this high contribution and highlights the pitfalls associated with the use of PCNA or RPA to assess proliferative activity in FL and DLBCL. Disclosures No relevant conflicts of interest to declare.

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