RESUMO
Pathologic evaluation is the most crucial method for diagnosing malignant lymphomas. However, there are no established diagnostic criteria for evaluating pathologic morphology. We manually circled cell nuclei in the lesions of 10 patients with diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, and reactive lymphadenitis. Seventeen parameters related to nuclear shape, color, and other characteristics were measured. We attempted to compare the statistical differences between these subtypes and extract distinctive disease-specific populations on the basis of these parameters. Statistically significant differences were observed between the different types of lymphoma for many of the 17 parameters. Through t-distributed stochastic neighbor embedding analysis, we extracted a cluster of cells that showed distinctive features of DLBCL and were not found in follicular lymphoma or reactive lymphadenitis. We created a decision tree to identify the characteristics of the cells within that cluster. Based on a 5-fold cross-validation study, the average sensitivity, specificity, and accuracy obtained were 84.1%, 98.4%, and 97.3%, respectively. A similar result was achieved using a validation experiment. Important parameters that indicate the features of DLBCL include Area, ConcaveCount, MaxGray, and ModeGray. By quantifying pathologic morphology, it was possible to objectively represent the cell morphology specific to each lymphoma subtype using quantitative indicators. The quantified morphologic information has the potential to serve as a reproducible and flexible diagnostic tool.
Assuntos
Linfadenite , Linfoma Folicular , Linfoma Difuso de Grandes Células B , Humanos , Linfoma Folicular/diagnóstico , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Difuso de Grandes Células B/patologia , Núcleo CelularRESUMO
Intravascular large B-cell lymphoma (IVLBCL) is a unique type of extranodal lymphoma characterized by selective growth of tumor cells in small vessels without lymphadenopathy. Greater understanding of the molecular pathogenesis of IVLBCL is hampered by the paucity of lymphoma cells in biopsy specimens, creating a limitation in obtaining sufficient tumor materials. To uncover the genetic landscape of IVLBCL, we performed whole-exome sequencing (WES) of 21 patients with IVLBCL using plasma-derived cell-free DNA (cfDNA) (n = 18), patient-derived xenograft tumors (n = 4), and tumor DNA from bone marrow (BM) mononuclear cells (n = 2). The concentration of cfDNA in IVLBCL was significantly higher than that in diffuse large B-cell lymphoma (DLBCL) (P < .0001) and healthy donors (P = .0053), allowing us to perform WES; most mutations detected in BM tumor DNA were successfully captured in cfDNA and xenograft. IVLBCL showed a high frequency of genetic lesions characteristic of activated B-cell-type DLBCL, with the former showing conspicuously higher frequencies (compared with nodal DLBCL) of mutations in MYD88 (57%), CD79B (67%), SETD1B (57%), and HLA-B (57%). We also found that 8 IVLBCL (38%) harbored rearrangements of programmed cell death 1 ligand 1 and 2 (PD-L1/PD-L2) involving the 3' untranslated region; such rearrangements are implicated in immune evasion via PD-L1/PD-L2 overexpression. Our data demonstrate the utility of cfDNA and imply important roles for immune evasion in IVLBCL pathogenesis and PD-1/PD-L1/PD-L2 blockade in therapeutics for IVLBCL.
Assuntos
Linfoma Difuso de Grandes Células B/genética , Mutação , Evasão Tumoral , Neoplasias Vasculares/genética , Idoso , Idoso de 80 Anos ou mais , Animais , Antígeno B7-H1/genética , Antígeno B7-H1/imunologia , Ácidos Nucleicos Livres/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Linfoma Difuso de Grandes Células B/imunologia , Masculino , Pessoa de Meia-Idade , Proteína 2 Ligante de Morte Celular Programada 1/genética , Proteína 2 Ligante de Morte Celular Programada 1/imunologia , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/imunologia , Neoplasias Vasculares/imunologia , Sequenciamento do ExomaRESUMO
PURPOSE: Tumor sidedness (hepatic side vs. peritoneal side) reportedly predicts microvascular invasion and survival outcomes of T2 gallbladder cancer, although the actual histopathological mechanism is not fully understood. METHODS: The clinical relevance of tumor sidedness was revisited in 84 patients with gallbladder cancer using histopathological analysis of the vascular density of the gallbladder wall. RESULTS: Hepatic-side tumor location was associated with overall survival (OS) (hazard ratio [HR], 13.62; 95% confidence interval [CI], 2.09-88.93) and recurrence-free survival (RFS) (HR, 8.70; 95% CI, 1.36-55.69) in T2 tumors. The Adjusted Kaplan-Meier curve indicated a clear survival difference between T2a (peritoneal side) and T2b (hepatic side) tumors (P = 0.006). A review of 56 pathological specimens with gallbladder cancer and 20 control specimens demonstrated that subserosal vascular density was significantly higher on the hepatic side of the gallbladder, regardless of the presence of cancer (P < 0.001). Multivariate analysis also confirmed that higher subserosal vascular density was significantly associated with poor OS (HR, 1.73; 95% CI, 1.10-2.73 per 10 microscopic fields) and poor RFS (HR, 1.62; 95% CI, 1.06-2.49) in T2 gallbladder cancer. CONCLUSION: Higher subserosal vascular density may account for the higher incidence of cancer spread and the poor prognosis of T2b gallbladder cancer.
Assuntos
Neoplasias da Vesícula Biliar , Humanos , Prognóstico , Densidade Microvascular , Modelos de Riscos Proporcionais , Estadiamento de Neoplasias , Estudos RetrospectivosRESUMO
Follicular lymphoma (FL) is characterized by an indolent clinical course and a high relapse rate, and often exhibits a diffuse pattern beyond the follicular area. Our group previously reported that immune checkpoint (ICP) pathways, such as programmed cell death (PD-1) and programmed death ligand 1 (PD-L1), are poor prognostic factors for diffuse large B-cell lymphoma and adult T-cell leukemia/lymphoma. In this study, the association between the expression of multiple ICP molecules according to immunohistochemistry and clinicopathological features in FL was determined via immunostaining of 173 biopsy samples. Membrane and/or cytoplasm expression of CD86 (nCD86) and PD-L1 (nPD-L1) was found in tumor cells, whereas PD-1 (miPD-1), Galectin-9 (miGalectin-9), OX40 (miOX40), CTLA-4 (miCTLA-4), Tim-3 (miTim-3), OX40L (miOX40L), and LAG-3 (miLAG-3) were expressed in non-neoplastic stromal cells. MiPD-1 expression was significantly higher in the follicular area than in the diffuse area (p = 0.0450). Expression of miOX40 and miCTLA-4 was significantly higher in the diffuse area than in the follicular area (respectively, p = 0.0053 and p = 0.0092). MiTim-3 tended to be higher in the diffuse area than in the follicular area (p = 0.0616). MiTim-3 was significantly higher in relapse cases than in new-onset cases (p = 0.0440); miLAG-3 tended to be higher in relapse cases than in new-onset cases (p = 0.0622, not significant). The miOX40L-high FL group had a significantly worse overall survival than the miOX40L-low group (p = 0.0320). The expression of multiple ICP molecules on several cells reflects activated anti-tumor immunity and the unique FL microenvironment. Further studies on gene expression or genomic abnormalities will reveal the clinical and biological significance of ICP molecules in FL.
Assuntos
Linfoma Folicular , Linfoma Difuso de Grandes Células B , Adulto , Antígeno B7-H1/metabolismo , Biomarcadores Tumorais/metabolismo , Antígeno CTLA-4 , Galectinas , Receptor Celular 2 do Vírus da Hepatite A , Humanos , Proteínas de Checkpoint Imunológico , Linfoma Difuso de Grandes Células B/patologia , Prognóstico , Receptor de Morte Celular Programada 1/metabolismo , Recidiva , Microambiente TumoralRESUMO
CD37 is a tetraspanin protein expressed in various B-cell lymphomas that mediates tumor survival signaling. Follicular lymphoma (FL) is a representative B-cell neoplasm composed of germinal center B cells. In recent years, CD37 has been focused on as a therapeutic target for B-cell lymphoma. The purpose of this study was to characterize CD37 expression in FL patients to identify risk factors associated with various prognostic factors. We retrospectively reviewed 167 cases of FL and evaluated the immunohistochemical expression of CD37 and its statistical association with clinicopathological features. Immunohistochemically, CD37 was observed in the cytoplasm and/or membrane of neoplastic cells, mainly in neoplastic follicles to various extents. One hundred cases (100/167, 60.0%) were categorized as CD37-positive, and 67 cases were CD37-negative. In cases with high Follicular Lymphoma International Prognostic Index (FLIPI), CD37-negative cases had a poor overall survival compared with CD37-positive cases (P = 0.047), although no significant differences were observed in other clinicopathologic factors, including histological grade, BCL2-IGH translocation, and immunohistochemical phenotype. Therefore, CD37 protein may play a role in tumor progression and may serve as a therapeutic target. However, further studies are needed to explore its significance.
Assuntos
Linfoma de Células B , Linfoma Folicular , Antígenos de Neoplasias/genética , Linfócitos B/patologia , Centro Germinativo/patologia , Humanos , Linfoma de Células B/patologia , Estudos Retrospectivos , Tetraspaninas/genética , Tetraspaninas/metabolismoRESUMO
Histiocytic and dendritic cell (H/DC) neoplasms are heterogeneous, originating from myeloid- or stromal-derived cells. Multiple reports describe the cross-lineage transdifferentiation of neoplastic B cells into H/DC neoplasms. Most such cases are from Western countries, and rarely from Japan or East Asia. Here we report 17 cases of H/DC neoplasms in Japanese patients, with analysis of t(14;18) by fluorescence in situ hybridization, and of neoplastic programmed death-ligand 1 (PD-L1) expression by immunostaining (clones SP142, E1J2J, and 28-8). These 17 cases were diagnosed according to the 2017 World Health Organization (WHO) classification, and included two histiocytic sarcomas (HS), two interdigitating cell (IDC) sarcomas, one Langerhans cell sarcoma, two dendritic cell sarcomas, and 10 follicular dendritic cell (FDC) sarcomas. No case had any past history of follicular lymphoma (FL). Two cases of HS and one IDC sarcoma, all of which were myeloid-driven, were found to exhibit t(14;18). In the latter case, at 30 months after IDC sarcoma diagnosis, FL development was detected. Three (30%) FDC sarcoma cases exhibited neoplastic PD-L1 expression with all the three PD-L1 antibody clones. This is the first report of t(14;18) and neoplastic PD-L1 expression on H/DC neoplasms among Japanese patients, each of which appeared to be associated with HS and FDC sarcoma, respectively.
Assuntos
Antígeno B7-H1/metabolismo , Sarcoma de Células Dendríticas Foliculares , Sarcoma Histiocítico , Adolescente , Adulto , Idoso , Biomarcadores Tumorais/análise , Sarcoma de Células Dendríticas Foliculares/imunologia , Sarcoma de Células Dendríticas Foliculares/metabolismo , Sarcoma de Células Dendríticas Foliculares/patologia , Células Dendríticas/metabolismo , Células Dendríticas/patologia , Feminino , Histiócitos/metabolismo , Histiócitos/patologia , Sarcoma Histiocítico/imunologia , Sarcoma Histiocítico/metabolismo , Sarcoma Histiocítico/patologia , Humanos , Imuno-Histoquímica , Imunofenotipagem , Hibridização in Situ Fluorescente , Japão , Sarcoma de Células de Langerhans/imunologia , Sarcoma de Células de Langerhans/metabolismo , Sarcoma de Células de Langerhans/patologia , Linfoma Folicular/imunologia , Linfoma Folicular/metabolismo , Linfoma Folicular/patologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Linfócitos T/metabolismoRESUMO
Primary diffuse large B-cell lymphoma (DLBCL) of the central nervous system (PCNS-DLBCL) is rare. Thirty-nine patients consecutively diagnosed as having PCNS-DLBCL were analyzed to highlight the prognostic value of the expression of programmed cell death ligand-1 (PD-L1) by neoplastic cells and immune cells in the microenvironment. They were positive for CD20 in all (100%), CD5 in two (5%), CD10 in nine (23%), BCL-2 in 27 (69%), BCL-6 in 34 (87%), and MUM-1 in 37 (95%). Only one case was positive for neoplastic PD-L1, with an unexpectedly long clinical course of 92 months. The remaining 38 cases were further divided into three groups based on the percentage of PD-L1+ cells among microenvironmental immune cells. Cutoffs of < 5%, 5-40%, and ≥ 40% successfully stratified mean prognoses with three-year overall survival (OS) of 21%, 63%, and 100% (P = 0.009), respectively. Progression-free survival (PFS) and OS were different between the groups with and without methotrexate (MTX)-containing chemotherapy (P = 0.007 and P < 0.001, respectively). Multivariate analysis identified three independent adverse factors of OS: PD-L1 negativity (< 5%) on microenvironmental immune cells (P = 0.027), deep structure involvement (P = 0.034), and performance status (PS) 2-4 (P = 0.009). The study showed that PD-L1 expression on immune cells in the microenvironment was associated with prognosis among patients with PCNS-DLBCL.
Assuntos
Antígeno B7-H1/metabolismo , Sistema Nervoso Central/patologia , Linfoma Difuso de Grandes Células B/metabolismo , Microambiente Tumoral/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígeno B7-H1/imunologia , Biomarcadores Tumorais/metabolismo , Sistema Nervoso Central/imunologia , Sistema Nervoso Central/metabolismo , Feminino , Humanos , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Linfoma Difuso de Grandes Células B/imunologia , Masculino , Pessoa de Meia-Idade , Microambiente Tumoral/fisiologiaRESUMO
BACKGROUND: This study aimed to reveal long-term outcomes, such as incidence of metachronous esophageal and head and neck squamous cell carcinomas and overall survival rate, through long-term observation of patients with esophageal carcinoma post-endoscopic submucosal dissection. METHODS: Risk of metachronous carcinogenesis was evaluated in 88 patients with intramucosal esophageal carcinoma (without history of metachronous esophageal or head and neck squamous cell carcinomas) who underwent endoscopic submucosal dissection from 2007 to 2008 and were endoscopically observed for > 3 years. Histologically, the papillary vessel is defined as the clock gear-like structure composed of capillaries directly penetrating the epithelium (starting from the lamina propria) and covering at least two-thirds of it, around which the tumor cells are arranged in a spiral pattern. RESULTS: Median endoscopic follow-up period was 11.0 years. Cumulative 2-, 5-, and 10-year metachronous esophageal carcinoma rates were 11.4%, 20.6%, and 39.3%, respectively. Stepwise multivariate Cox proportional hazard regression analysis identified multiple Lugol-voiding lesions (LVLs) as the single significant independent predictor. Cumulative 2-, 5-, and 10-year metachronous head and neck squamous cell carcinoma rates were 6.9%, 10.4%, and 19.6%, respectively. Stepwise multivariate Cox proportional hazard regression analysis identified multiple LVLs, Brinkman index, papillary vessel, and younger age as significant predictive factors. Overall post-endoscopic submucosal dissection survival rates were 98.8% and 87.5% at 5 and 10 years, respectively. CONCLUSION: Patients with a history of esophageal carcinoma remain at risk for metachronous carcinogenesis even > 5 years after endoscopic submucosal dissection. Thus, long-term follow-up is important.
Assuntos
Ressecção Endoscópica de Mucosa , Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Carcinogênese , Ressecção Endoscópica de Mucosa/efeitos adversos , Neoplasias Esofágicas/epidemiologia , Neoplasias Esofágicas/etiologia , Neoplasias Esofágicas/cirurgia , Carcinoma de Células Escamosas do Esôfago/complicações , Carcinoma de Células Escamosas do Esôfago/epidemiologia , Carcinoma de Células Escamosas do Esôfago/cirurgia , Humanos , Incidência , Medição de RiscoRESUMO
A pathological evaluation is one of the most important methods for the diagnosis of malignant lymphoma. A standardized diagnosis is occasionally difficult to achieve even by experienced hematopathologists. Therefore, established procedures including a computer-aided diagnosis are desired. This study aims to classify histopathological images of malignant lymphomas through deep learning, which is a computer algorithm and type of artificial intelligence (AI) technology. We prepared hematoxylin and eosin (H&E) slides of a lesion area from 388 sections, namely, 259 with diffuse large B-cell lymphoma, 89 with follicular lymphoma, and 40 with reactive lymphoid hyperplasia, and created whole slide images (WSIs) using a whole slide system. WSI was annotated in the lesion area by experienced hematopathologists. Image patches were cropped from the WSI to train and evaluate the classifiers. Image patches at magnifications of ×5, ×20, and ×40 were randomly divided into a test set and a training and evaluation set. The classifier was assessed using the test set through a cross-validation after training. The classifier achieved the highest levels of accuracy of 94.0%, 93.0%, and 92.0% for image patches with magnifications of ×5, ×20, and ×40, respectively, in comparison to diffuse large B-cell lymphoma, follicular lymphoma, and reactive lymphoid hyperplasia. Comparing the diagnostic accuracies between the proposed classifier and seven pathologists, including experienced hematopathologists, using the test set made up of image patches with magnifications of ×5, ×20, and ×40, the best accuracy demonstrated by the classifier was 97.0%, whereas the average accuracy achieved by the pathologists using WSIs was 76.0%, with the highest accuracy reaching 83.3%. In conclusion, the neural classifier can outperform pathologists in a morphological evaluation. These results suggest that the AI system can potentially support the diagnosis of malignant lymphoma.
Assuntos
Aprendizado Profundo , Diagnóstico por Computador/métodos , Linfoma/diagnóstico , Algoritmos , Diagnóstico por Computador/estatística & dados numéricos , Técnicas Histológicas , Humanos , Interpretação de Imagem Assistida por Computador/métodos , Interpretação de Imagem Assistida por Computador/estatística & dados numéricos , Linfoma/diagnóstico por imagem , Linfoma/patologia , Linfoma Folicular/diagnóstico , Linfoma Folicular/diagnóstico por imagem , Linfoma Folicular/patologia , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Difuso de Grandes Células B/diagnóstico por imagem , Linfoma Difuso de Grandes Células B/patologia , Redes Neurais de Computação , Variações Dependentes do Observador , Patologistas , Pseudolinfoma/diagnóstico , Pseudolinfoma/diagnóstico por imagem , Pseudolinfoma/patologiaRESUMO
Although cases with metachronous or synchronous co-occurrence of classic Hodgkin lymphoma (CHL) and B-cell non-Hodgkin lymphoma (B-NHL) have been reported, few reports have analyzed the clonal relationship between both lesions in detail, especially in Epstein-Barr virus (EBV)-positive settings. Here, we report a case of a 38-year-old male with CHL, followed by the recurrence of EBV-positive mucocutaneous ulcers of the large intestine and EBV-positive diffuse large B-cell lymphoma in the liver. Surprisingly, polymerase chain reaction analysis for immunoglobulin heavy chain gene rearrangement revealed that all lesions were clonally distinct. We further reviewed the literature on synchronous and metachronous co-occurrence of CHL and B-NHL in EBV-positive settings. In contrast to EBV-negative settings, all evaluable cases showed clonally distinct multiple lesions. These findings suggest that histologically and clonally distinct B-cells could simultaneously proliferate in EBV-associated settings, providing a new insight into the pathogenesis of EBV-associated lymphoproliferative disorders.
Assuntos
Infecções por Vírus Epstein-Barr/patologia , Doença de Hodgkin/patologia , Linfoma Difuso de Grandes Células B/patologia , Transtornos Linfoproliferativos/virologia , Adulto , Infecções por Vírus Epstein-Barr/diagnóstico , Herpesvirus Humano 4/metabolismo , Doença de Hodgkin/diagnóstico , Humanos , Linfoma Difuso de Grandes Células B/diagnóstico , Transtornos Linfoproliferativos/diagnóstico , Transtornos Linfoproliferativos/patologia , Masculino , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/patologiaRESUMO
Inhibitors of programmed cell-death 1 (PD-1) and programmed cell-death ligand 1 (PD-L1) have revolutionized cancer therapy. Nodal cytotoxic T-cell lymphoma (CTL) is characterized by a poorer prognosis compared to nodal non-CTLs. Here we investigated PD-L1 expression in 50 nodal CTL patients, with and without EBV association (25 of each). We identified seven patients (14%) with neoplastic PD-L1 (nPD-L1) expression on tumor cells, including three males and four females, with a median age of 66 years. One of the seven cases was TCRαß type, three were TCRγδ type and three were TCR-silent type. Six of the seven cases exhibited a lethal clinical course despite multi-agent chemotherapy, of whom four patients died within one year of diagnosis. Morphological findings were uniform, with six cases showing centroblastoid appearance. Among nPD-L1+ cases, two of three examined had structural variations of PD-L1 disrupting 3'-UTR region. Notably, all of the TCRγδ-type nodal CTL cases showed nPD-L1 or miPD-L1 positivity (3 and 10 cases, respectively). TCRγδ-type cases comprised 42% of nPD-L1+ cases (P = 0.043 vs. PD-L1- ), and 35% of miPD-L1+ cases (P = 0.037 vs. PD-L1- ). The results indicate that PD-L1+ nodal CTL cases, especially of the TCRγδ type, are potential candidates for anti-PD-1/PD-L1 therapies.
Assuntos
Antígeno B7-H1/metabolismo , Linfoma de Células T Periférico , Adulto , Idoso , Biomarcadores Tumorais/metabolismo , Infecções por Vírus Epstein-Barr/diagnóstico , Infecções por Vírus Epstein-Barr/patologia , Feminino , Humanos , Linfoma de Células T/diagnóstico , Linfoma de Células T/metabolismo , Linfoma de Células T/patologia , Linfoma de Células T Periférico/diagnóstico , Linfoma de Células T Periférico/metabolismo , Linfoma de Células T Periférico/patologia , Masculino , Pessoa de Meia-Idade , PrognósticoRESUMO
Composite lymphoma is a well-known diagnostic entity exhibiting the synchronous occurrence of two or more distinct types of lymphomas in the same specimen. Here we report two patients, a 14-year-old female (Case 1) and a 45-year-old male (Case 2), with mediastinal composite lymphoma, comprising nodular sclerosis classic Hodgkin lymphoma (NSCHL) and primary mediastinal large B-cell lymphoma (PMBL). Both patients had a mediastinal mass, and manifested two different histologic components in the same biopsy, one characteristic of NSCHL and the other PMBL. The NSCHL areas included Hodgkin and Reed-Sternberg (HRS) cells with typical immunophenotypic features (CD30-positive and CD20-negative), whereas the sheets of large tumor cells characteristic of PMBL were strongly and uniformly CD20-positive. Interestingly, although both cases showed neoplastic PD-L1 (nPD-L1) positivity on the HRS cells of NSCHL, they differed regarding nPD-L1 expression on the PMBL tumor cells. In Case 1, the nPD-L1-negative PMBL component was anatomically situated outside the NSCHL lesion. On the other hand, in Case 2, the nPD-L1-positive PMBL component was characterized by transitional or continuous areas with the NSCHL component. These findings suggested that nPD-L1 expression may define two subtypes of PMBL that are more similar to or distinct from classic Hodgkin lymphoma.
Assuntos
Antígeno B7-H1/metabolismo , Linfoma Composto/diagnóstico , Doença de Hodgkin/diagnóstico , Linfoma Difuso de Grandes Células B/diagnóstico , Neoplasias do Mediastino/diagnóstico , Adolescente , Biomarcadores Tumorais/metabolismo , Feminino , Doença de Hodgkin/metabolismo , Humanos , Linfoma Difuso de Grandes Células B/metabolismo , Masculino , Pessoa de Meia-IdadeRESUMO
Although several reports have highlighted neoplastic PD-L1 (nPD-L1) expression in classic Hodgkin lymphoma (CHL), some have addressed associations between its expression and detailed histopathologic features. Here we describe four cases of syncytial variant of CHL (SV-CHL), with and without Epstein-Barr virus (EBV) association, and highlight the diagnostic utility of PD-L1 (clone SP142) immunohistochemistry. The patients were a 61-year-old male, 45-year-old male, 85-year-old female, and 89-year-old female. All presented with cervical or axillary lymphadenopathy, which on biopsy had the established histopathologic features of SV-CHL with a biphasic pattern of cohesive sheets of large tumor cells and typically scattered distribution of Hodgkin and Reed-Stenberg (HRS) cells. These tumor cells showed identical immunophenotypic findings for CD15, CD30, Fascin, PAX5, OCT2, BOB1 and EBV harboring, regardless of location. The exception was absent or decreased expression of nPD-L1 from tumor cells in the confluent sheets, contrasting with HRS cell positivity in typical areas of CHL. These findings offer the first suggestion of possible downregulation of nPD-L1 expression in association with the histopathologic progression of CHL. The results may be relevant for recognizing 'confluent' sheets in the diagnostic workup for SV-CHL.
Assuntos
Antígeno B7-H1/biossíntese , Biomarcadores Tumorais/metabolismo , Doença de Hodgkin/diagnóstico , Doença de Hodgkin/patologia , Idoso de 80 Anos ou mais , Antígeno B7-H1/análise , Biomarcadores Tumorais/análise , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-IdadeRESUMO
Epstein-Barr virus (EBV) is prevalent among healthy individuals, and is implicated in numerous reactive and neoplastic processes in the immune system. The authors originally identified a series of senile or age-related EBV-associated B-cell lymphoproliferative disorders (LPD) bearing a resemblance to immunodeficiency-associated ones. These LPDs may be associated with immune senescence and are now incorporated into the revised 4th edition of 2017 WHO lymphoma classification as EBV-positive (EBV+) diffuse large B-cell lymphoma (DLBCL), not otherwise specified (NOS). These EBV+ B-cells often have a Hodgkin/Reed-Sternberg (HRS)-like appearance and are shared beyond the diagnostic categories of mature B-cell neoplasms, mature T-cell neoplasms, classic Hodgkin lymphoma, and immunodeficiency-associated LPD. In addition, peculiar new diseases, such as EBV+ mucocutaneous ulcer and EBV+ DLBCL affecting the young, were recognized. On the other hand, lymphoma classification is now evolving in accord with deeper understanding of the biology of programmed death ligand 1 (PD-L1). Assessing PD-L1 positivity by staining with the anti-PD-L1 monoclonal antibody SP142 provides new insight by discriminating between immune evasion and senescence or immunodeficiency. The aim of the present review is to briefly summarize the diagnostic use of immunostaining with SP142 in malignant lymphomas and/or LPDs that feature tumor and nonmalignant large B-cells harboring EBV.
Assuntos
Linfócitos B , Antígeno B7-H1/imunologia , Infecções por Vírus Epstein-Barr , Transtornos Linfoproliferativos , Envelhecimento , Anticorpos/sangue , Linfócitos B/patologia , Linfócitos B/virologia , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/imunologia , Doença de Hodgkin/diagnóstico , Humanos , Evasão da Resposta Imune , Linfoma/diagnóstico , Transtornos Linfoproliferativos/diagnóstico , Transtornos Linfoproliferativos/imunologia , Transtornos Linfoproliferativos/patologiaRESUMO
Methotrexate-associated lymphoproliferative disorders are categorized as "other immunodeficiency-associated lymphoproliferative disorders in the WHO classification. Methotrexate-associated lymphoproliferative disorder is mainly a B-cell lymphoproliferative disorders or Hodgkin lymphoma type, whereas T-cell lymphoproliferative disorders are relatively rare (4-8%). Only a small number of methotrexate-associated T-cell lymphoproliferative disorders have been detailed thus far. Because of the rarity, methotrexate-associated T-cell lymphoproliferative disorder has not been well studied and its clinicopathological characteristics are unknown. A total of 28 cases of methotrexate-associated T-cell lymphoproliferative disorders were retrospectively analyzed. Histologically and immunohistochemically, they were divided into three main types: angioimmunoblastic T-cell lymphoma (n = 19), peripheral T-cell lymphoma, NOS (n = 6), and CD8+ cytotoxic T-cell lymphoma (n = 3). Among the 28 cases, only one CD8+ cytotoxic T-cell lymphoma case was Epstein-Barr virus-positive. The other 27 cases were negative for Epstein-Barr virus on tumor cells, but scattered Epstein-Barr virus-infected B-cells were detected in 24 cases (89%), implying the reactivation of Epstein-Barr virus caused by immunodeficient status of the patients. After the diagnosis of methotrexate-associated T-cell lymphoproliferative disorder, methotrexate was immediately withdrawn in 26 cases. Twenty (77%) cases presented with spontaneous regression. Compared to methotrexate-associated B-cell lymphoproliferative disorder, patients with methotrexate-associated T-cell lymphoproliferative disorder had a significantly higher proportion of males (p = 0.035) and presence of B-symptoms (p = 0.036), and lower proportion of Epstein-Barr virus+ tumor cells (p < 0.001). Although the difference was not significant, the methotrexate-associated T-cell lymphoproliferative disorder also had more frequent spontaneous regression (p = 0.061). In conclusion, methotrexate-associated T-cell lymphoproliferative disorder was divided into three main types: angioimmunoblastic T-cell lymphoma, peripheral T-cell lymphoma, NOS, and CD8+ cytotoxic T-cell lymphoma. Angioimmunoblastic T-cell lymphoma was the most common type. Methotrexate-associated T-cell lymphoproliferative disorder was characterized by a high rate of spontaneous regression after methotrexate cessation. Epstein-Barr virus positivity was relatively rare in methotrexate-associated T-cell lymphoproliferative disorder, significantly less frequent than methotrexate-associated B-cell lymphoproliferative disorder, suggesting different pathogenesis.
Assuntos
Proliferação de Células/efeitos dos fármacos , Imunossupressores/efeitos adversos , Transtornos Linfoproliferativos/induzido quimicamente , Metotrexato/efeitos adversos , Subpopulações de Linfócitos T/efeitos dos fármacos , Idoso , Idoso de 80 Anos ou mais , Feminino , Herpesvirus Humano 4/isolamento & purificação , Humanos , Linfadenopatia Imunoblástica/induzido quimicamente , Linfadenopatia Imunoblástica/imunologia , Linfadenopatia Imunoblástica/patologia , Linfoma de Células T Periférico/induzido quimicamente , Linfoma de Células T Periférico/imunologia , Linfoma de Células T Periférico/patologia , Transtornos Linfoproliferativos/imunologia , Transtornos Linfoproliferativos/patologia , Transtornos Linfoproliferativos/virologia , Masculino , Pessoa de Meia-Idade , Fenótipo , Prognóstico , Estudos Retrospectivos , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/patologia , Subpopulações de Linfócitos T/virologia , Linfócitos T Citotóxicos/efeitos dos fármacos , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/patologiaRESUMO
Elderly patients with Epstein-Barr virus (EBV) infection are at increased risk for developing B-cell lymphoproliferative disorder (B-LPD) due to immunosenescence. Here, we describe a case of a 75-year-old man who developed an EBV-positive (EBV+) mucocutaneous ulcer (EBVMCU) in the gingiva with spontaneous regression. Eighteen months after regression, he had a cervical lymph node enlargement that was diagnosed as EBV+ nodal polymorphous B-LPD, Ann Arbor stage IA. Clinicians decided to observe his clinical course without any treatment. Fourteen months later, the patient developed EBV-positive diffuse large B-cell lymphoma (DLBCL), Ann Arbor stage IIA, and received six courses of age-adjusted dose chemotherapy and achieved a complete remission. No evidence of a clonal relationship was found among these three lesions by standard polymerase chain reaction (PCR) analysis for immunoglobulin heavy chain. However, they all had expression of PD-L1 in the EBV+ large B-cells and Hodgkin Reed-Sternberg-like cells. This is the first case report of a PD-L1-positive (PD-L1+) EBVMCU and the development of multiple EBV-driven B-LPDs in the setting of immunosenescence within a 32-month period.
Assuntos
Antígeno B7-H1/metabolismo , Infecções por Vírus Epstein-Barr/patologia , Herpesvirus Humano 4/isolamento & purificação , Linfoma Difuso de Grandes Células B/etiologia , Transtornos Linfoproliferativos/etiologia , Úlcera/etiologia , Idoso , Linfócitos B/patologia , Linfócitos B/virologia , Infecções por Vírus Epstein-Barr/virologia , Gengiva/patologia , Gengiva/virologia , Humanos , Imunossenescência , Linfonodos/metabolismo , Linfonodos/patologia , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/patologia , Linfoma Difuso de Grandes Células B/virologia , Transtornos Linfoproliferativos/patologia , Transtornos Linfoproliferativos/virologia , Masculino , Mucosa Bucal/patologia , Mucosa Bucal/virologia , Indução de Remissão , Úlcera/patologia , Úlcera/virologiaRESUMO
Intravascular large B-cell lymphoma (IVLBCL) is a distinct disease, but the neoplastic PD-L1 expression on tumor cells may vary among cases. We evaluated 10 IVLBCL autopsy cases for neoplastic PD-L1 expression, and had positive results in two cases. In one case, neoplastic PD-L1 expression (SP142, 28-8, and E1J2J clones) was dependent on the organ and anatomical site (capillaries vs. vessels) of the tumor tissue. Neoplastic PD-L1 expression was found in tumor cells located in capillaries in the central nervous system, pituitary gland, kidneys, lung, and gastrointestinal tract; sinuses/sinusoids of the spleen, liver, bone marrow, and lymph nodes; and an extravascular location. However, this expression was not detected in tumor cells located in the adrenal gland, thyroid gland, pancreas, ovaries, uterus, pleura, and small or larger-sized vessels of the lung. The other case showed constant neoplastic PD-L1 expression on the tumor cells, and in addition to the affected organs, capillaries, and vessels with two anti-PD-L1 antibodies (28-8 and E1J2J, but not SP142). The divergence and heterogeneity of neoplastic PD-L1 expression were clearly demonstrated in our cases. To the best of our knowledge, this is the first description of divergent neoplastic PD-L1 expression among the affected organs and anatomical sites in IVLBCL.
Assuntos
Antígeno B7-H1/metabolismo , Biomarcadores Tumorais/imunologia , Neoplasias Pulmonares/patologia , Linfoma Difuso de Grandes Células B/patologia , Autopsia/métodos , Feminino , Humanos , Imuno-Histoquímica/métodos , Neoplasias Pulmonares/imunologia , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Difuso de Grandes Células B/imunologia , Masculino , Pessoa de Meia-IdadeRESUMO
We identified six patients with Epstein-Barr virus (EBV)-negative extranodal diffuse large B-cell lymphoma (DLBCL) and immunohistochemical expression of PD-L1 on their tumor cells by examining 283 DLBCL cases with the PD-L1 SP142 clone between 2015 and 2017. They consisted of two men and four women with a median age of 71 years, and were examined in an autopsy (n = 1) and biopsies from the adrenal gland (n = 2), skin (n = 1), pelvic cavity (n = 1), and kidney (n = 1). All showed a monomorphic population of large transformed B-cells leading to diagnoses of DLBCL with two intravascular large B-cell lymphoma (IVLBCL) and one de novo CD5+ type and were featured by an invariable immunephenotype: CD3-, CD20+, BCL-2+, and MUM1+. In addition, CD5 and CD10 were each detected in one case. All cases expressed PD-L1 on >10% to >90% of tumor cells, which was confirmed with two other PD-L1 antibodies (E1J2J and 28-8). Three untreated patients had a rapid, lethal clinical course within 7 months after diagnosis; while, the remaining three achieved complete remission after treatment and were alive at the last follow-up. We suggest immune evasion-related extranodal large B-cell lymphoma should be recognized beyond the currently identified entities of IVLBCL and de novo CD5+ DLBCL.
Assuntos
Antígeno B7-H1/metabolismo , Biomarcadores Tumorais/metabolismo , Linfoma Difuso de Grandes Células B/patologia , Idoso , Antígenos CD5/metabolismo , Feminino , Humanos , Imuno-Histoquímica , Linfoma Difuso de Grandes Células B/metabolismo , Masculino , Pessoa de Meia-Idade , Neprilisina/metabolismo , Evasão TumoralRESUMO
Anaplastic variant (av) of diffuse large B-cell lymphoma (DLBCL) is morphologically defined in the 2017 World Health Organization classification, but still an enigmatic disease in its clinicopathologic distinctiveness, posing the differential diagnostic problem from gray zone lymphoma (GZL) and classic Hodgkin lymphoma (cHL). Thirty-one cases previously diagnosed as avDLBCL were reassessed. Of these, 27 (87%) and 4 (13%) were node-based and extranodal diseases, respectively. They were further reclassified into nodal avDLBCL (n = 18), nodal CD30+ DLBCL with T-cell/histiocyte-rich large B-cell lymphoma-like features (CD30+ DLBCL-THRLBCL) (n = 6), GZL with features intermediate between DLBCL and cHL (n = 3) and CD30+ extranodal DLBCL, NOS (n = 4). The nodal avDLBCL cases had a sheet-like proliferation of large cells and/or Hodgkin/Reed-Sternberg (HRS)-like cells in 12 (67%) notably with a sinusoidal pattern in 16 (89%). They showed an expression of CD20 and/or CD79a in all and CD30 in 15 of 18. All of them were negative for PD-L1 on tumor cells, although HRS-like cells showed negativity or partial loss of other B-cell markers to varying degrees. The present study highlighted the distinctiveness of the nodal avDLBCL with sinusoidal pattern, but without neoplastic PD-L1 expression, which provide refined diagnostic criteria for a more precise pathologic and clinical characterization of this disease.
Assuntos
Biomarcadores Tumorais/metabolismo , Doença de Hodgkin/patologia , Linfoma Difuso de Grandes Células B/patologia , Idoso , Idoso de 80 Anos ou mais , Antígenos CD20/metabolismo , Antígenos CD79/metabolismo , Capilares/metabolismo , Capilares/patologia , Feminino , Doença de Hodgkin/diagnóstico , Doença de Hodgkin/metabolismo , Humanos , Antígeno Ki-1/metabolismo , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Difuso de Grandes Células B/metabolismo , Masculino , Pessoa de Meia-IdadeRESUMO
Nodal cytotoxic molecule (CM)-positive peripheral T-cell lymphoma (CTL) has recently been recognized as a clinicopathologically distinct disease. To further characterize this disease, here we compared 58 patients with Epstein-Barr virus (EBV)-negative CTL to 48 patients with EBV-positive CTL. The two groups did not differ in histopathology, T-cell receptor (TCR) expression or rearrangement incidences, or survival curves. However, patients with EBV-negative CTL less frequently showed hepatic involvement (P = .007), B symptoms (P = .020), hemophagocytosis (P = .024), and detectable CD4 (P = .002) and CD5 (P = .009). Univariate and multivariate analyses identified three factors that independently predicted favorable survival, onset age <60 years (P = .002), CD5 expression (P = .002), and mixed morphology (P = .013), TCRαß was not an independent predictor (P = .30), but was strongly linked with long survivorship among patients younger than 60 years old. A prognostic model incorporating these factors worked well for prognostic delineation, independently of the International Prognostic Index (P = .007 vs P = .082) and Prognostic Index for PTCL (P = .020 vs P = .15). Moreover, this constellation of findings indicated two nodal indolent diseases: CD5+ TCRαß (n = 13), and CD5+ NK-cell type lacking TCR expression or clonal TCRγ rearrangement (n = 4). The survival curves for these two groups were significantly superior to others (n = 29, P < .001). These diseases appear to be unique in their indolent clinical behavior, and should be managed differently from other diseases.