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2.
Appl Immunohistochem Mol Morphol ; 27(8): 572-580, 2019 09.
Article in English | MEDLINE | ID: mdl-30106758

ABSTRACT

There are multiple prognostic indicators for diffuse large B-cell lymphoma (DLBCL) including the international prognostic index (IPI), and gene expression profiling (GEP) to classify the disease into germinal center B-cell and activated B-cell subtypes, the latter harboring inferior prognosis. More recently, tumor-associated macrophages (TAM) and lymphocyte-to-monocyte ratio (LMR) were found to have prognostic implications in DLBCL. However, consensus is yet to be reached in terms of the significance of each. In this study, we evaluated the prognostic value of TAM as assessed by CD163 or CD68 positivity by immunohistochemistry on tissue biopsies and LMR was calculated from peripheral blood differential, with focus on the inclusion of rituximab as a treatment modality. The number of CD68-positive cells in the tumor microenvironment did not exhibit significant prognostic value, whereas higher number of CD163-positive cells was associated with inferior overall survival in patients treated with chemotherapy alone. This effect was no longer evident in patients treated with rituximab containing chemoimmunotherapy. In contrast, the prognostic significance of LMR on survival was more persistent regardless of treatment. There was no association between LMR and the number of CD163-positive cells. Our results suggest that LMR is the more easily and widely available prognostic marker in this era of chemoimmunotherapy. Our finding supports previous literature that the effect of TAM can vary according to treatment. Interaction between rituximab and TAM warrant further scientific investigation for mechanistic insights into targeted therapeutics.


Subject(s)
Antigens, CD/metabolism , Antigens, Differentiation, Myelomonocytic/metabolism , Antineoplastic Agents, Immunological/therapeutic use , Lymphocytes/cytology , Lymphoma, Large B-Cell, Diffuse/diagnosis , Lymphoma, Large B-Cell, Diffuse/mortality , Macrophages/metabolism , Monocytes/cytology , Receptors, Cell Surface/metabolism , Rituximab/therapeutic use , Adolescent , Adult , Aged , Aged, 80 and over , Antigens, CD/genetics , Antigens, Differentiation, Myelomonocytic/genetics , Female , Humans , Immunohistochemistry , Lymphocyte Count , Lymphocytes/drug effects , Lymphocytes/metabolism , Lymphoma, Large B-Cell, Diffuse/drug therapy , Lymphoma, Large B-Cell, Diffuse/therapy , Macrophages/cytology , Macrophages/drug effects , Male , Middle Aged , Monocytes/drug effects , Monocytes/metabolism , Prognosis , Receptors, Cell Surface/genetics , Retrospective Studies , Tissue Array Analysis , Tumor Microenvironment/drug effects , Young Adult
3.
Blood Cancer J ; 8(6): 60, 2018 06 12.
Article in English | MEDLINE | ID: mdl-29895903

ABSTRACT

We sought to define the genomic landscape of diffuse large B-cell lymphoma (DLBCL) by using formalin-fixed paraffin-embedded (FFPE) biopsy specimens. We used targeted sequencing of genes altered in hematologic malignancies, including DNA coding sequence for 405 genes, noncoding sequence for 31 genes, and RNA coding sequence for 265 genes (FoundationOne-Heme). Short variants, rearrangements, and copy number alterations were determined. We studied 198 samples (114 de novo, 58 previously treated, and 26 large-cell transformation from follicular lymphoma). Median number of GAs per case was 6, with 97% of patients harboring at least one alteration. Recurrent GAs were detected in genes with established roles in DLBCL pathogenesis (e.g. MYD88, CREBBP, CD79B, EZH2), as well as notable differences compared to prior studies such as inactivating mutations in TET2 (5%). Less common GAs identified potential targets for approved or investigational therapies, including BRAF, CD274 (PD-L1), IDH2, and JAK1/2. TP53 mutations were more frequently observed in relapsed/refractory DLBCL, and predicted for lack of response to first-line chemotherapy, identifying a subset of patients that could be prioritized for novel therapies. Overall, 90% (n = 169) of the patients harbored a GA which could be explored for therapeutic intervention, with 54% (n = 107) harboring more than one putative target.


Subject(s)
Biomarkers, Tumor , Gene Expression Profiling , Genomics , Lymphoma, Large B-Cell, Diffuse/diagnosis , Lymphoma, Large B-Cell, Diffuse/genetics , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Biopsy , Computational Biology/methods , DNA Copy Number Variations , Female , Gene Expression Profiling/methods , Genomics/methods , High-Throughput Nucleotide Sequencing , Humans , Lymphoma, Large B-Cell, Diffuse/mortality , Lymphoma, Large B-Cell, Diffuse/therapy , Male , Middle Aged , Molecular Sequence Annotation , Neoplasm Grading , Neoplasm Staging , Prognosis , Transcriptome , Treatment Outcome
4.
Mod Pathol ; 31(4): 581-597, 2018 04.
Article in English | MEDLINE | ID: mdl-29192649

ABSTRACT

Erdheim-Chester disease is a rare, non-Langerhans cell histiocytosis histologically characterized by multi-systemic proliferation of mature histiocytes in a background of inflammatory stroma. The disease can involve virtually any organ system; most commonly the bones, skin, retroperitoneum, heart, orbit, lung, and brain are affected. Although a histiocytic proliferation is the histological hallmark of the disease, a wide range of morphological appearances have been described as part of case studies or small series. A comprehensive review of histopathological features in clinically and molecularly defined Erdheim-Chester disease has yet to be characterized. To address this issue and help guide clinical practice, we comprehensively analyzed the pathological spectrum of Erdheim-Chester disease in a clinically and molecularly defined cohort. We reviewed 73 biopsies from 42 patients showing involvement by histiocytosis from a variety of organ systems, including bone (16), retroperitoneum (11), skin (19), orbit (6), brain (5), lung (6), cardiac structures (2), epidural soft tissue (3), oral cavity (2), subcutaneous soft tissue (2), and testis (2). In eight patients, one or more bone marrow biopsies were performed due to clinical indication and an accompanying myeloid neoplasm was detected in six of them. Thirty-eight cases were investigated for genetic abnormalities. Somatic mutations involving BRAF (25/38), MAP2K1 (6/38), ARAF (2/38), MAP2K2 (1/38), KRAS (1/38), and NRAS (1/38) genes were detected. One of the cases with a MAP2K1 mutation also harbored a PIK3CA mutation. We have observed marked heterogeneity in histology and immunophenotype, identified site-specific features, overlap with other histiocytic and myeloid disorders and potential diagnostic pitfalls. We hope that broadening the spectrum of recognized pathologic manifestations of Erdheim-Chester disease will help practicing clinicians and pathologists to diagnose Erdheim-Chester disease early in the disease course and manage these patients effectively.


Subject(s)
Erdheim-Chester Disease/genetics , Erdheim-Chester Disease/pathology , Cohort Studies , Humans
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