ABSTRACT
We report a case of adult T-cell leukemia/lymphoma (ATLL) with angioimmunoblastic T-cell lymphoma (AITL/nTFHL-AI)-like feature. An 88-year-old Japanese woman with seropositive for the Human T-lymphotropic virus type 1 (HTLV-1) was incidentally diagnosed with generalized lymphadenopathy. Biopsy of the cervical lymph node demonstrated the proliferation of small- or medium-sized and large atypical lymphocytes associated with eosinophils, high endothelial venules, and clear cells. Immunohistochemical analysis revealed atypical lymphocytes were CD3- and CD4-positive. Atypical T cells bore the T-follicular helper phenotype (PD1, ICOS, and BCL6) and were positive for CD25 and chemokine receptor 4. Epstein-Barr virus encoded RNA-positive cells were scattered in the background via in situ hybridization. The histological findings were similar to those of AITL/nTFHL-AI; however, the immunohistochemical results did not exclude the possibility of ATLL. Southern blot analysis detected integration of HTLV-1 proviral DNA. The RHOA Gly 17 Val (G17V) mutation was detected by the peptide nucleic acid-locked nucleic acid clamp method. Finally, the patient was diagnosed with ATLL with AITL-like feature and exhibited a similar morphology, immunophenotype, and mutational signature to AITL/nTFHL-AI. ATLL mimics other types of T-cell lymphomas. Thus, in HTLV-1 endemic areas, routine screening for HTLV-1 serology is necessary to avoid misdiagnosis of other lymphoid malignancies.
ABSTRACT
CD28, one of the costimulatory molecules, has a pivotal role in T-cell activation, and its expression is strictly regulated in normal T cells. Gain-of-function genetic alterations involving CD28 have been frequently observed in adult T-cell leukemia/lymphoma (ATLL). These abnormalities, such as CD28 fusions and copy number variations, may not only confer continuous, prolonged, and enhanced CD28 signaling to downstream pathways but also induce overexpression of the CD28 protein. In this study, 120 ATLL cases were examined by immunohistochemistry for CD28 and its ligands CD80 and CD86, and their expression on tumor cells was semiquantitatively evaluated. CD28 was overexpressed in 55 (46%) cases, and CD80 or CD86 (CD80/CD86) was infrequently overexpressed in 12 (11%). Compared with non-overexpressers, CD28 overexpressers showed a higher frequency of CD28 genetic alterations and had an increased number of CD80/CD86-positive non-neoplastic cells infiltrating tumor microenvironment. In the entire ATLL patient cohort, CD28 overexpressers showed a significantly poorer overall survival (OS) compared with non-overexpressers (P = .001). The same was true for a subgroup who were treated with multidrug regimens with or without mogamulizumab. CD28 overexpression had no prognostic impact in the group who received allogeneic hematopoietic stem cell transplantation. In the multivariate analysis for OS, CD28 overexpression was selected as an independent risk factor. These results suggest ATLL patients with CD28 overexpression have more aggressive clinical course and are more refractory to treatment with multidrug chemotherapy. CD28 overexpression appears to be a novel unfavorable prognostic marker in ATLL patients, and further prospective studies are warranted to establish its prognostic significance.
Subject(s)
B7-1 Antigen/metabolism , B7-2 Antigen/metabolism , CD28 Antigens/genetics , CD28 Antigens/metabolism , Leukemia-Lymphoma, Adult T-Cell/mortality , Up-Regulation , Adult , Aged , Aged, 80 and over , DNA Copy Number Variations , Female , Gene Expression Regulation, Neoplastic , Humans , Leukemia-Lymphoma, Adult T-Cell/genetics , Leukemia-Lymphoma, Adult T-Cell/metabolism , Male , Middle Aged , Prognosis , Survival Analysis , Tumor MicroenvironmentABSTRACT
BACKGROUND: Other iatrogenic immunodeficiency-associated (OIIA) T- and natural killer (NK)-cell lymphoproliferative disorders (TNK-LPDs) are rare in patients with rheumatoid arthritis (RA). METHODS: We investigated the clinicopathological characteristics, Epstein-Barr virus (EBV) infection, genetic findings, therapeutic response, and prognostic factors in 21 RA patients with OIIA TNK-LPDs and compared these with those of 39 with OIIA B-cell LPDs (B-LPDs) and 22 with non-OIIA B-LPDs. RESULTS: Immunohistologically, 11 patients (52%) showed CD4+ T-LPDs, and 7 had a T follicular helper (TFH) phenotype. The other nine patients (43%) showed CD8+ T-LPDs, and the remaining one (5%) had features of CD3+ CD4- CD8- nasal type TNK-cell lymphoma. CD30+, p53+, and CMYC+ atypical lymphocytes were identified in seven (33%), eight (38%), and five (24%) patients, respectively. In situ hybridisation detected EBV-encoded RNA (EBER) + large atypical lymphocytes in five patients (24%). Nine of 17 patients (53%) showed clonal peaks of TCRγ by polymerase chain reaction. Withdrawal of MTX and biologic drugs was effective in 12 patients (57%), and 8 (38%) received chemotherapies. Two patients with TFH+ or EBV+ CD4+ CD30+ large cell peripheral T-cell lymphoma, one with CD8+ systemic anaplastic large cell lymphoma, and two with systemic EBV+ CD8+ T-cell lymphoma of childhood showed a lethal progressive clinical course within 13 months. Moreover, > 500 U/L LDH, large atypical lymphocytes, expression of CD30, p53, and CMYC, and EBER+ atypical lymphocytes were significantly poor prognostic factors for overall survival (p < 0.05). Median interval from RA onset to OIIA TNK-LPDs was 72 months, which was shorter than 166 months in OIIA B-LPDs (p = 0.003). EBV+ atypical and reactive lymphocytes were frequently found in 15 patients with OIIA TNK-LPDs (71%), in 27 with OIIA B-LPDs (69%), and only in 3 with non-OIIA B-LPDs (14%). CONCLUSIONS: OIIA TNK-LPDs occurred in early phase of RA, compared with OIIA B-LPDs, and occasionally showed a lethal progressive clinical course. Detection of OIIA TNK-LPD patients with poor prognostic factors is necessary. EBV infection in immunosuppressed patients due to persistent RA, MTX, and biologic drugs may play a role in forming the tumour microenvironment and lymphomagenesis of TNK-LPDs.
Subject(s)
Arthritis, Rheumatoid , Epstein-Barr Virus Infections , Lymphoproliferative Disorders , Humans , Arthritis, Rheumatoid/complications , Arthritis, Rheumatoid/drug therapy , Arthritis, Rheumatoid/pathology , Disease Progression , Epstein-Barr Virus Infections/drug therapy , Epstein-Barr Virus Infections/pathology , Herpesvirus 4, Human , Iatrogenic Disease , Killer Cells, Natural/pathology , Lymphoproliferative Disorders/diagnosis , Lymphoproliferative Disorders/etiology , Methotrexate/therapeutic use , Prognosis , Tumor Suppressor Protein p53ABSTRACT
Adult T-cell leukemia/lymphoma (ATL) patients have a very poor prognosis. The humanized anti-CCR4 therapeutic monoclonal antibody, mogamulizumab, is a key agent for ATL treatment. Our previous integrated molecular analysis demonstrated that among all the driver genes in ATL, CCR7 gene alterations were significantly associated with clinical response to mogamulizumab. Accordingly, here we investigated the detailed clinical impact of CCR7 alterations in a larger cohort of ATL patients. These CCR7 alterations, most of which lead to C-terminus truncations, were observed in 27 of 223 patients (12%). For patients receiving mogamulizumab but not allogeneic hematopoietic stem cell transplantation (HSCT), CCR7 alterations were significantly associated with worse survival (median survival from the first dose of mogamulizumab of 0.7 years for 12 patients with CCR7 alterations vs. 1.6 years for 72 patients without, p = 0.020). On the other hand, the presence or absence of CCR7 alterations had no significant impact on survival in the entire cohort (median overall survival of 1.4 and 1.8 years, respectively, p = 0.901), or on the survival of patients receiving allogeneic HSCT (median survival from the day of transplantation of 0.9 years for 6 patients with CCR7 alterations and 1.4 years for 48 without, p = 0.543). Multivariate analysis indicated that patients with CCR4 alterations but lacking CCR7 alterations (n = 20) had significantly better survival after receiving mogamulizumab-containing treatments (hazard ratio for survival, 0.437, 95% confidence interval, 0.192-0.994). This study contributes to the establishment of precision medicine for ATL.
Subject(s)
Antibodies, Monoclonal, Humanized , Leukemia-Lymphoma, Adult T-Cell , Receptors, CCR7 , Humans , Leukemia-Lymphoma, Adult T-Cell/drug therapy , Leukemia-Lymphoma, Adult T-Cell/genetics , Receptors, CCR7/genetics , Antibodies, Monoclonal, Humanized/therapeutic useABSTRACT
Multiple oncogenic events are involved in the development of adult T-cell leukaemia/lymphoma (ATL). Because CD28 plays a pivotal role in T-cell activation, we focused on alterations of the CD28 gene in ATL. We found multiple genetic abnormalities related to CD28 among the 144 patients enrolled in the present study. These involved gene fusions with the cytotoxic T-lymphocyte-associated antigen 4 or the inducible T-cell co-stimulator in 14 patients (10%), CD28-activating mutations in 3 (2%), and CD28 copy number variations in 34 (24%). Patients with such CD28 gene alterations were significantly younger than those without. In patients not receiving allogeneic haematopoietic stem cell transplantation, those with CD28 gene alterations tended to have a worse prognosis than those without. Finally, patients with chronic or smouldering ATL subtypes with CD28 gene alterations had a significantly worse prognosis than those without. These findings indicate that ATL, especially chronic or smouldering subtypes, have a more aggressive clinical course and are more refractory to conventional chemotherapies or mogamulizumab if they harbour CD28 gene alterations, likely because of continuous, prolonged, and enhanced CD28 activatory signalling. Novel treatment strategies to overcome the effects of these CD28 gene alterations are warranted.
Subject(s)
CD28 Antigens/genetics , Leukemia-Lymphoma, Adult T-Cell/genetics , Adult , Aged , Aged, 80 and over , DNA Copy Number Variations , Female , Hematopoietic Stem Cell Transplantation , Humans , Leukemia-Lymphoma, Adult T-Cell/diagnosis , Leukemia-Lymphoma, Adult T-Cell/therapy , Male , Middle Aged , Mutation , Oncogene Fusion , PrognosisABSTRACT
Adult T-cell leukaemia/lymphoma (ATL) patients have a poor prognosis. Here, we investigated the impact of TP53 gene mutations on prognosis of ATL treated in different ways. Among 177 patients, we identified 47 single nucleotide variants or insertion-deletions (SNVs/indels) of the TP53 gene in 37 individuals. TP53 copy number variations (CNVs) were observed in 38 patients. Altogether, 67 of 177 patients harboured TP53 SNVs/indels or TP53 CNVs, and were categorized as having TP53 mutations. In the entire cohort, median survival of patients with and without TP53 mutations was 1·0 and 6·7 years respectively (P < 0·001). After allogeneic haematopoietic stem cell transplantation (HSCT), median survival of patients with (n = 16) and without (n = 29) TP53 mutations was 0·4 years and not reached respectively (P = 0·001). For patients receiving mogamulizumab without allogeneic HSCT, the median survival from the first dose of antibody in patients with TP53 mutations (n = 27) was only 0·9 years, but 5·1 years in those without (n = 42; P < 0·001). Thus, TP53 mutations are associated with unfavourable prognosis of ATL, regardless of treatment strategy. The establishment of alternative modalities to overcome the adverse impact of TP53 mutations in patients with ATL is required.
Subject(s)
Genes, p53 , Leukemia-Lymphoma, Adult T-Cell/genetics , Mutation , Adult , Aged , Aged, 80 and over , Allografts , Antibodies, Monoclonal, Humanized/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , CD28 Antigens/genetics , Carboplatin/administration & dosage , Cyclophosphamide/administration & dosage , DNA Copy Number Variations , Doxorubicin/administration & dosage , Etoposide/administration & dosage , Female , Hematopoietic Stem Cell Transplantation , Humans , INDEL Mutation , Kaplan-Meier Estimate , Lenalidomide/administration & dosage , Leukemia-Lymphoma, Adult T-Cell/drug therapy , Leukemia-Lymphoma, Adult T-Cell/mortality , Leukemia-Lymphoma, Adult T-Cell/therapy , Male , Middle Aged , Nitrosourea Compounds/administration & dosage , Polymorphism, Single Nucleotide , Prednisolone/administration & dosage , Prednisone/administration & dosage , Prognosis , Receptors, CCR4/genetics , Vincristine/administration & dosage , Vindesine/administration & dosageABSTRACT
Recently, the use of targeted synthetic or biological disease-modifying anti-rheumatic drugs (ts/bDMARDs) in addition to conventional synthetic (cs)DMARDs including methotrexate (MTX) for rheumatoid arthritis (RA) has increased. However, whether ts/bDMARDs are associated with the development and clinicopathological features of MTX-associated lymphoproliferative disorder (MTX-LPD) in patients with RA remains unknown. Therefore, we evaluated the clinical outcomes of 121 patients with MTX-LPD. Results showed that prior use of ts/bDMARDs was not associated with the different histopathological subtypes of MTX-LPD. Patients with polymorphic-type LPD had a better event-free survival than those with diffuse large B-cell lymphoma (DLBCL), classical Hodgkin lymphoma and peripheral T-cell lymphoma. The pathological subtype of lymphoma could predict the clinical outcome of MTX-LPD. In patients with DLBCL, the use of tumour necrosis factor-alpha (TNF-α) inhibitors prior to MTX-LPD onset was associated with a higher non-relapse mortality. Further, patients with RA previously treated with Janus kinase (JAK) inhibitors more commonly required chemotherapy than those treated with csDMARDs alone, indicating disease aggressiveness. Hence, special caution should be observed when managing patients with MTX-LPD previously treated with JAK or TNF-α inhibitors for RA.
Subject(s)
Antirheumatic Agents/therapeutic use , Arthritis, Rheumatoid/drug therapy , Lymphoproliferative Disorders/drug therapy , Methotrexate/adverse effects , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Bleomycin/administration & dosage , Cyclophosphamide/administration & dosage , Dacarbazine/administration & dosage , Doxorubicin/administration & dosage , Female , Follow-Up Studies , Humans , Janus Kinases/antagonists & inhibitors , Kaplan-Meier Estimate , Lymphoma, Non-Hodgkin/mortality , Lymphoproliferative Disorders/chemically induced , Lymphoproliferative Disorders/mortality , Male , Methotrexate/therapeutic use , Middle Aged , Prednisone/administration & dosage , Progression-Free Survival , Proportional Hazards Models , Rituximab/administration & dosage , Treatment Outcome , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Vinblastine/administration & dosage , Vincristine/administration & dosageABSTRACT
OBJECTIVE: Acute and lymphoma type adult T-cell leukaemia/lymphoma (ATLL) patients show an aggressive clinical course. While some clinical signs indicate good prognosis, definitive cytohistological prognostic factors have yet to be described. METHODS: We classified 65 ATLL patients into three groups by tumour cell size and nuclear pleomorphism on fine-needle aspiration and tumour touch smear samples. Semi-quantitative analysis of background small lymphocytes, reactive CD20-positive B cells and CD8-positive T cells was performed. RESULTS: Thirty-one patients had pleomorphic lymphoma with predominantly medium-sized cells and coarse granular nuclei. Another 24 patients showed pleomorphic large cell lymphoma with stippled chromatin. The remaining 10 demonstrated monomorphic large lymphoma cells with fine granular chromatin. Patients with pleomorphic lymphoma with medium-sized cells showed significantly higher serum lactate dehydrogenase and lower CD30 and C-MYC expression in lymphoma cells than the other two groups (P = .0216, P < 0.01, respectively). Patients with pleomorphic medium-sized ATLL had few usual small lymphocytes observed on routine morphological examination and showed less concurrent detection of CD20-positive B cells and CD8-positive T cells, both of which were lower than in the other two groups (P = .006, P = .019, respectively). Furthermore, ATLL patients with predominantly medium-sized lymphocytes exhibited a worse prognosis than patients with pleomorphic large cells (P = .0197). Background small lymphocytes and concurrent detection of CD20-positive B cells and CD8-positive T cells may thus be good prognostic factors (P = .011, P = .021, respectively). CONCLUSIONS: Morphological features, size of neoplastic cells and background non-neoplastic lymphocyte (B cells and CD8-positive T cells) volume appear to influence the prognosis of patients with aggressive-type ATLL.
Subject(s)
B-Lymphocytes/pathology , Leukemia-Lymphoma, Adult T-Cell/pathology , Lymphocytes/pathology , Lymphoma, Non-Hodgkin/pathology , Acute Disease , Aged , Aged, 80 and over , Biomarkers, Tumor/analysis , Female , Humans , Leukemia-Lymphoma, Adult T-Cell/diagnosis , Lymphoma, Non-Hodgkin/diagnosis , Male , Middle Aged , PrognosisABSTRACT
A 65-year-old woman presented to our emergency room because of sudden onset of right hemiparesis with severe fatigue. Neurological examination revealed right hemiparesis with right facial numbness and an extensor planter response on the right side.Magnetic resonance imaging with diffusion-weighted imaging revealed multiple highintensity areas in both cerebral hemispheres and the right cerebellum. A diagnosis of acute stage of multiple brain infarctions caused by emboli was made. An abdominal computed tomography showed a pancreatic tumor with multiple liver metastases. High D-dimer and serum carbohydrate antigen 19-9 concentration strongly suggested Trousseau syndrome associated with pancreatic cancer. The patient had another large embolic stroke and died on day 47. Autopsy was performed. There were large thrombi in the left ventricular apex and in the left atrial appendage There was also a papillary-shaped vegetation on the aortic valve that consisted mainly of fibrin without any inflammatory cells or destruction of the valve, these findings being characteristic of NBTE. This case is remarkable in that the patient had 3 different types of cardiac thrombi in her heart associated with Trousseau syndrome.
Subject(s)
Blood Coagulation , Carcinoma/complications , Endocarditis, Non-Infective/etiology , Heart Diseases/etiology , Pancreatic Neoplasms/complications , Thrombophilia/complications , Thrombosis/etiology , Aged , Autopsy , Brain Infarction/diagnostic imaging , Brain Infarction/etiology , CA-19-9 Antigen/blood , Carcinoma/blood , Carcinoma/diagnostic imaging , Carcinoma/secondary , Diffusion Magnetic Resonance Imaging , Endocarditis, Non-Infective/blood , Endocarditis, Non-Infective/diagnostic imaging , Fatal Outcome , Female , Fibrin Fibrinogen Degradation Products/analysis , Heart Diseases/blood , Heart Diseases/diagnostic imaging , Humans , Intracranial Embolism/diagnostic imaging , Intracranial Embolism/etiology , Liver Neoplasms/secondary , Pancreatic Neoplasms/blood , Pancreatic Neoplasms/diagnostic imaging , Pancreatic Neoplasms/pathology , Syndrome , Thrombophilia/blood , Thrombophilia/diagnosis , Thrombosis/blood , Thrombosis/diagnostic imaging , Tomography, X-Ray ComputedABSTRACT
AIMS: The objective of this study was to investigate the incidence and clinical significance of lymphoma-associated chromosomal translocations, particularly those involving the immunoglobulin heavy chain gene (IGH) locus, in patients with small-bowel diffuse large B-cell lymphoma (DLBCL). METHODS AND RESULTS: Translocations involving IGH, bcl-6, MYC and bcl-2 were investigated with interphase fluorescence in-situ hybridization on paraffin-embedded tissues in 35 patients with primary small-bowel DLBCL, and the overall survival (OS) and progression-free survival (PFS) rates were evaluated with the Kaplan-Meier method. Translocations involving IGH, bcl-6, MYC and bcl-2 were detected in 23 (70%), 12 (36%), eight (24%) and six (18%) of 33 cases, respectively. The patients with IGH translocations showed less frequent relapse or progression of lymphoma (17%) than those without (60%, P = 0.034). Univariate analyses demonstrated that young age, a low international prognostic index, translocations involving IGH, extra copies of MALT1/bcl-2 and bcl-6 immunoexpression were significantly associated with better OS and PFS. Cox multivariate analysis revealed translocations involving IGH to constitute an independent prognostic factor for better PFS, but not better OS. CONCLUSIONS: Translocations involving IGH are frequent in cases of small-bowel DLBCL. These translocations may be predictive of a favourable clinical course.
Subject(s)
Genes, Immunoglobulin Heavy Chain/genetics , Intestinal Neoplasms/diagnosis , Lymphoma, Large B-Cell, Diffuse/diagnosis , Translocation, Genetic , Adult , Aged , Aged, 80 and over , Disease-Free Survival , Female , Humans , In Situ Hybridization, Fluorescence , Incidence , Interphase , Intestinal Neoplasms/genetics , Intestinal Neoplasms/pathology , Intestine, Small/pathology , Lymphoma, Large B-Cell, Diffuse/genetics , Male , Middle Aged , Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein/genetics , Prognosis , Proto-Oncogene Proteins c-bcl-2/genetics , Proto-Oncogene Proteins c-bcl-6/geneticsABSTRACT
AIMS: To analyse the clinicopathological characteristics and prognosis of 40 rheumatoid arthritis (RA) patients with methotrexate (MTX)-associated large B cell lymphoproliferative disorders (MTX-BLPD). METHODS AND RESULTS: Soluble interleukin 2 receptor titres (median 1500 U/ml) in 40 patients with MTX-BLPD were lower than those of 24 RA patients with non-MTX- associated (non-MTX) BLPD (5731 U/ml) and 15 with control diffuse large B cell lymphoma (DLBCL, 5918 U/ml) (P < 0.01). Using in-situ hybridization, Epstein-Barr virus (EBV) was detected in tumour cells of 25 of 40 RA patients with MTX-BLPD (63%). Immunohistologically, BCL2 expression was detected in 35% of patients with MTX-BLPD, which was lower than 93% of control DLBCL patients (P < 0.01). Eleven patients with EBV(+) MTX-BLPD (44%) showed remission after MTX withdrawal. In RA patients with clinical stage III/IV BLPD, 15 with rituximab (R)+ cytotoxic therapies pursued better prognosis than 10 with R- cytotoxic therapies (P < 0.05). Among the 15 patients, seven with MTX-BLPD showed better overall survival than nine control DLBCL patients (P < 0.01). CONCLUSIONS: In RA patients with MTX-BLPD, immunosuppression by MTX, EBV infection and low BCL2 expression in tumour cells may play roles in tumorigenesis and tumour regression. R+ cytotoxic therapies as well as MTX withdrawal were highly effective in these patients.
Subject(s)
Antirheumatic Agents/adverse effects , Arthritis, Rheumatoid/drug therapy , Lymphoma, Large B-Cell, Diffuse/chemically induced , Lymphoma, Large B-Cell, Diffuse/pathology , Methotrexate/adverse effects , Rituximab/therapeutic use , Adult , Aged , Aged, 80 and over , Antirheumatic Agents/therapeutic use , Arthritis, Rheumatoid/pathology , Arthritis, Rheumatoid/virology , Epstein-Barr Virus Infections/diagnosis , Female , Herpesvirus 4, Human/genetics , Herpesvirus 4, Human/isolation & purification , Humans , In Situ Hybridization , Lymphoma, Large B-Cell, Diffuse/blood , Lymphoma, Large B-Cell, Diffuse/virology , Male , Middle Aged , Proto-Oncogene Proteins c-bcl-2/blood , RNA, Viral/genetics , Receptors, Interleukin-2/bloodABSTRACT
The uridine diphosphate glucuronosyltransferase (UGT) gene 1A1*6 polymorphism, which affects irinotecan metabolism, has been associated with improved survival in lymphoma patients treated with of carboplatin, dexamethasone, etoposide and irinotecan (CDE-11). This study assessed the efficacy of CDE-11 relative to the UGT1A1*6 polymorphism in 27 elderly patients with relapsed or refractory diffuse large B-cell lymphoma who were ineligible for high-dose chemotherapy plus autologous stem cell transplantation. The 2-year survival rate after initial CDE-11 treatment was significantly higher in patients with than without UGT1A1*6 (57% vs. 5%). The most common grade 4 adverse event in patients with the UGT1A1*6 genotypes was neutropenia (88.9%), but there were no gastrointestinal adverse events or treatment-related deaths. Disease progression was the most frequent cause of death. CDE-11 was well tolerated and provided clinical benefit to elderly patients with relapsed or refractory diffuse large B-cell lymphoma. The response to CDE-11 likely correlated with UGT1A1*6 polymorphisms, but further prospective studies are warranted to optimize irinotecan-based chemotherapies relative to UGT1A1 polymorphism.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Glucuronosyltransferase/genetics , Lymphoma, Large B-Cell, Diffuse/drug therapy , Lymphoma, Large B-Cell, Diffuse/genetics , Polymorphism, Genetic/genetics , Aged , Aged, 80 and over , Camptothecin/administration & dosage , Camptothecin/analogs & derivatives , Carboplatin/administration & dosage , Dexamethasone/administration & dosage , Etoposide/administration & dosage , Female , Follow-Up Studies , Humans , Irinotecan , Lymphoma, Large B-Cell, Diffuse/diagnosis , Male , Middle Aged , Prospective Studies , Recurrence , Treatment OutcomeABSTRACT
OBJECTIVES: Our study aimed to clarify the immunological characteristics and the mechanism of interstitial fibrosis in immunoglobulin G4-related kidney disease (IgG4-RKD) by the immunohistological analysis. METHODS: Immunohistological study was performed in the biopsied renal tissues of 16 IgG4-RKD, 16 Sjögren syndrome (SJS), and 17 idiopathic tubulointerstitial nephritis (ITIN) patients using antibodies against IgG; IgG1; IgG4; CD38; CD3; C-X-C chemokine receptor type 3 (CXCR3); chemokine (C-C motif) receptor 4 (CCR4); forkhead box 3 (Foxp3); Type I, Type III, Type IV, and Type VI collagens; and transforming growth factor (TGF)-ß1. RESULTS: Interstitial lymphoplasmacytic and eosinophilic infiltration and the severity of interstitial fibrosis were greater in IgG4-RKD than SJS and ITIN. The ratio of CXCR3+/CD3 + cells was greater in SJS as compared with that in IgG4-RKD and ITIN. The ratio of CCR4+/CD3 + cells was not different among the three diseases. The ratio of interstitial IgG4+/IgG+ plasma cells, Foxp3+/CD3 + cells, and TGF-ß1 + cells/total infiltrating cells was higher in IgG4-RKD than SJS and ITIN. There was a positive correlation between the ratio of Foxp3+/CD3 + cells and that of IgG4+/IgG+ plasma cells in IgG4-RKD. Significant correlation was found between the ratio of Foxp3+/CD3 + cells and that of TGF-ß1 + cells/total infiltrating cells in IgG4-RKD. Foxp3 + cells and TGF-ß1 + cells were colocalized in the interstitium in IgG4-RKD. The significant correlation between the ratio of TGF-ß1 + cells/total infiltrating cells and the severity of fibrosis was noticed in IgG4-RKD. The interstitial distribution of type III collagen and type IV collagen was higher in IgG4-RKD than in SJS. CONCLUSIONS: Our results suggest that regulatory T-cells (Tregs) may play a central role in IgG4 production in the interstitium and TGF-ß1 induced by Tregs may play a pivotal role in the interstitial fibrosis including type III and type IV collagens in IgG4-RKD.
Subject(s)
Chemokines/metabolism , Immunoglobulin G/immunology , Nephritis, Interstitial/immunology , T-Lymphocytes, Regulatory/immunology , Aged , Aged, 80 and over , Female , Humans , Immunoglobulin G/metabolism , Immunohistochemistry , Kidney/immunology , Kidney/pathology , Male , Middle Aged , Nephritis, Interstitial/metabolism , Nephritis, Interstitial/pathology , T-Lymphocytes, Regulatory/pathologyABSTRACT
OBJECTIVE: The prognosis for gastric carcinoma patients with liver metastasis is very poor. This retrospective study investigated the prognostic significance of MK-1 expression in gastric carcinoma patients with liver metastasis. METHODS: Immunohistochemical staining using monoclonal antibody FU-MK-1 against MK-1 antigen was performed on paraffin-embedded tissues from 64 gastric carcinoma patients with liver metastasis. We attempted to determine the presence of any relationship between pathological prognostic factors and the expression of MK-1 in 64 gastric carcinoma patients with liver metastasis. RESULTS: MK-1 expression was found in 43 (67%) of 64 tumor samples. MK-1 expression was significantly higher in the intestinal type (73%) than in the diffuse type carcinoma (33%, P = 0.049). Multivariate analysis showed that MK-1 expression and lymph node metastasis were significant factors for overall survival. The difference between overall survival rates with positive or negative MK-1 expression was statistically significant as shown by Kaplan-Meier survival analysis (P < 0.0001; log-rank). In addition, the difference between cumulative disease-free survival rates with positive or negative MK-1 expression in gastric carcinoma patients with metachronous liver metastasis was statistically significant as well, as shown by Kaplan-Meier survival analysis (P = 0.0006; log-rank). CONCLUSIONS: The prognostic significance of MK-1 expression as a biological tumor marker was demonstrated in a series of gastric carcinoma patients with liver metastasis. MK-1 positivity may be a reliable marker for predicting and taking measures to control liver metastasis after curative gastrectomy for gastric carcinoma.
Subject(s)
Antigens, Neoplasm/analysis , Biomarkers, Tumor/analysis , Cell Adhesion Molecules/analysis , Liver Neoplasms/secondary , Stomach Neoplasms/chemistry , Stomach Neoplasms/pathology , Adult , Aged , Aged, 80 and over , Disease-Free Survival , Epithelial Cell Adhesion Molecule , Female , Humans , Immunohistochemistry , Lymphatic Metastasis , Male , Middle Aged , Prognosis , Retrospective Studies , Stomach Neoplasms/mortalityABSTRACT
Crystal-storing histiocytosis (CSH) is a rare non-neoplastic histiocytic lesion with abnormal accumulation of immunoglobulin (Ig) light chain. CSH is associated with Ig overproduction by B-lymphoproliferative disorders (B-LPDs) or by persistent inflammatory diseases. Eighteen cases of pulmonary CSH have been reported. However, no case reports of tracheal CSH have been published. In this patient, we found a solitary tracheal tumor in an asymptomatic 60-year-old man on chest computed tomography scan. Histologically, the tumor comprised two different lesions. One lesion showed diffuse proliferation of spindle-shaped histiocytes with abundant eosinophilic granular cytoplasm. With immunohistochemistry, the histiocytic cells were positive for CD68, CD163 and Ig kappa light chain, and the cytoplasm was weakly positive for anaplastic lymphoma kinase (ALK) protein. Fluorescence in situ hybridization indicated no split signals for the ALK gene. Electron microscopy demonstrated many elongated or rhomboid-shaped dense crystals in the cytoplasm of histiocytes. The second lesion showed proliferation of CD20-positive small atypical lymphocytes mixed with Ig kappa chain-positive plasma cells. A diagnosis of CSH and concomitant mucosa-associated lymphoid tissue lymphoma was made. In this patient, unexpected ALK protein was detected in infiltrating histiocytes. Therefore, careful assessment of the ALK protein and gene was necessary to differentiate from other histiocytic disorders.
Subject(s)
Histiocytosis , Lymphoma, B-Cell, Marginal Zone , Histiocytes/pathology , Histiocytosis/complications , Humans , In Situ Hybridization, Fluorescence , Lymphoma, B-Cell, Marginal Zone/complications , Lymphoma, B-Cell, Marginal Zone/diagnosis , Male , Middle Aged , Receptor Protein-Tyrosine KinasesABSTRACT
Epstein-Barr virus (EBV)+ diffuse large B-cell lymphoma (DLBCL) has specific tumour cell characteristics, and these patients have worse outcomes than EBV-negative DLBCL patients. We compared 38 EBV+ DLBCL patients with 43 methotrexate-associated EBV+ B-cell lymphoproliferative disorders (MTX+/EBV+ BLPDs) and 30 non-germinal centre (GC) subtype DLBCL. Lymphoma cells of the EBV+ DLBCL group were positive for BCL2 in 17 patients (44.7%), CMYC in 23 patients (60.5%), and p53 in 33 patients (86.8%), which was significantly higher than in the MTX+/EBV+ BLPD group (P < 0.05), and were positive for CD30 in 29 patients (76.3%), compared with two in non-GC subtype DLBCL (6.7%) (P < 0.0001). Significantly more EBV+ DLBCL patients (n = 16, 42.1%) had programmed cell death-ligand 1 (PD-L1)+ tumour cells than patients with non-GC subtype DLBCL (n = 5, 16.7%; P = 0.024), and PD-L1+ tumour cells were more common in advanced stages than in early stages (P = 0.048). Twenty-five EBV+ DLBCL patients (69.4%) had few reactive PD1+ tumour-infiltrating lymphocytes (TILs), compared with 12 patients with MTX+/EBV+ BLPDs (37.5%) (P = 0.008). In the EBV+ DLBCL group, CD30, BCL2, CMYC, and p53 expression was not related to patient prognosis. Poor outcomes were associated with PD-L1+ tumour cells (P = 0.001) and low-reacting PD1+ TILs (P = 0.02), while their combination conferred a worse outcome (P < 0.0001). Immune evasion by PD-L1+ tumour cells and exhaustion of PD1+ TILs may occur in EBV+ DLBCL patients, and PD-L1/PD1 interactions may influence tumour progression and poor prognosis.
Subject(s)
Epstein-Barr Virus Infections , Lymphoma, Large B-Cell, Diffuse , Apoptosis , B7-H1 Antigen/metabolism , Herpesvirus 4, Human , Humans , Lymphocytes, Tumor-Infiltrating/metabolism , Lymphocytes, Tumor-Infiltrating/pathology , Lymphoma, Large B-Cell, Diffuse/pathology , Methotrexate , Prognosis , Proto-Oncogene Proteins c-bcl-2/metabolism , Tumor Suppressor Protein p53/metabolismABSTRACT
A 67-year-old man, hospitalized with fever and pancytopenia, experienced cardiogenic shock on the 3rd day of hospitalization. He complained of chest pain and exhibited cardiac dysfunction, upregulated serum troponin levels, and an ST elevation on electrocardiogram. Severe fever with thrombocytopenia syndrome (SFTS) was suspected based on the symptom course after a tick bite and was definitively diagnosed using the serum polymerase chain reaction (PCR) test. An endomyocardial biopsy performed in the convalescent phase revealed a sign of myocardial inflammation with increases in CD3- and CD68-positive cells. We herein report the first case of acute myocarditis complicated with SFTS.
Subject(s)
Leukopenia , Myocarditis , Phlebovirus , Severe Fever with Thrombocytopenia Syndrome , Thrombocytopenia , Aged , Fever/etiology , Humans , Male , Myocarditis/complications , Myocarditis/diagnosis , Thrombocytopenia/complications , Thrombocytopenia/diagnosisABSTRACT
A 57-year-old man was referred to our hospital for further management of a subepithelial lesion noted on colonoscopy. He underwent endoscopic treatment of unroofing technique, in which the protruding portion of the tumor was partially resected. Due to a small amount of hematochezia, colonoscopy was performed to re-evaluate the lesion post-treatment. This enabled the observation of the drainage process of the residual lipoma. Remission was achieved and confirmed 8 months after the treatment. Endoscopic unroofing technique has been reported as a safe and effective method of treating lipomas, particularly large ones. To the best of our knowledge, this is the first endoscopic unroofing case in which the drainage process of the residual lipoma was observed and the remission of the lesion was confirmed.
Subject(s)
Colonic Neoplasms , Lipoma , Colonic Neoplasms/complications , Colonic Neoplasms/pathology , Colonic Neoplasms/surgery , Colonoscopes , Colonoscopy/adverse effects , Colonoscopy/methods , Drainage , Gastrointestinal Hemorrhage/etiology , Gastrointestinal Hemorrhage/surgery , Humans , Lipoma/complications , Lipoma/diagnostic imaging , Lipoma/surgery , Male , Middle AgedABSTRACT
A 60-year-old Japanese woman was diagnosed with celiac disease (CeD) and treated with a gluten-free diet. For five years, she had a good clinical course. However, she complained of inappetence and nausea. Colonoscopy revealed ulcerative tumors in the terminal ileum. A histological examination of biopsy specimens from the ulcerative tumor showed diffuse infiltration of large atypical lymphocytes. Immunohistologically, the atypical lymphoid cells were positive for cluster of differentiation (CD) 10 and CD20. Many Epstein-Barr virus-encoded small RNA (EBER)-positive atypical lymphocytes were detected by in situ hybridization. This represents the first reported case of Epstein-Barr virus-positive intestinal diffuse large B-cell lymphoma complicated with CeD.
Subject(s)
Celiac Disease , Epstein-Barr Virus Infections , Lymphoma, Large B-Cell, Diffuse , Celiac Disease/complications , Celiac Disease/diagnosis , Epstein-Barr Virus Infections/complications , Epstein-Barr Virus Infections/diagnosis , Female , Herpesvirus 4, Human , Humans , Japan , Lymphoma, Large B-Cell, Diffuse/complications , Lymphoma, Large B-Cell, Diffuse/diagnosis , Middle AgedABSTRACT
BACKGROUND: Chromosomal translocation t(14;18)(q32;q21) involving the immunoglobulin heavy chain gene (IGH) and the BCL2 gene (t[14;18][q32;q21]/IGH-BCL2) is present in 60% to 90% of nodal follicular lymphomas. To the authors' knowledge, the prevalence and clinical significance of this translocation have not been examined previously in gastrointestinal follicular lymphomas. METHODS: Clinicopathologic and molecular features were investigated in 48 patients who had gastrointestinal follicular lymphoma. The site of involvement was the duodenum in 54% of patients, the jejunum in 52%, the ileum in 52%, the stomach in 29%, and the colorectum in 15%. The presence of the t(14;18)/IGH-BCL2 translocation was detected by interphase fluorescence in situ hybridization. RESULTS: Treatment modalities included surgical resection (n = 16), rituximab plus chemotherapy (n = 13), rituximab alone (n = 6), antibiotics (n = 5), and watchful waiting (n = 8). Complete remission (CR) of lymphoma was achieved in 31 patients (65%). The overall survival and event-free survival rates after 5 years were 93% and 68%, respectively. The t(14;18)/IGH-BCL2 was detected in 39 patients (81%). The involvement of multiple sites (69% vs 0%), manifestation of the lymphomatous polyposis type (72% vs 22%), and histologic grade 1 or 2 tumors (92% vs 56%) were more frequent in the t(14;18)-positive group than in the negative group. In addition, the CR rate was lower in the t(14;18)-positive group than in the negative group (56% vs 100%; P = .0179), and a trend was observed toward poorer event-free survival in the positive group (P = .089). CONCLUSIONS: The t(14;18)/IGH-BCL2 chromosomal translocation occurred frequently in gastrointestinal follicular lymphomas. The current results indicated that this translocation may be a predictor of an adverse clinical course.