Aberrant cell adhesiveness due to DNA hypermethylation of KLF11 in papillary urothelial carcinomas.

PURPOSE: The aim of this study was to clarify DNA methylation profiles determining the clinicopathological diversity of urothelial carcinomas. METHODS: Genome-wide DNA methylation analysis was performed using the Infinium HumanMethylation450 BeadChip in 46 paired samples of non-cancerous urothelium (N) and corresponding cancerous tissue (T), and 26 samples of normal control urothelium obtained from patients without urothelial carcinomas (C). For genes of interest, correlation between DNA methylation and mRNA expression was examined using the Cancer Genome Atlas database. In addition, the role of a selected target for cancer-relevant endpoints was further examined in urothelial carcinoma cell lines. RESULTS: The genes showing significant differences in DNA methylation levels between papillary carcinomas and more aggressive non-papillary (nodular) carcinomas were accumulated in signaling pathways participating in cell adhesion and cytoskeletal remodeling. Five hundred ninety-six methylation sites showed differences in DNA methylation levels between papillary and nodular carcinomas. Of those sites, that were located in CpG-islands around transcription start site, 5'-untranslated region or 1st exon, 16 genes exhibited inverse correlations between DNA methylation and mRNA expression levels. Among the latter, only the KLF11 gene showed papillary T sample-specific DNA hypermethylation in comparison to C and N samples. The DNA methylation levels of KLF11 were not significantly different between T samples and N samples or T samples and C samples for patients with papillo-nodular or nodular carcinomas. Knockdown experiments using the urothelial carcinoma cell lines HT1376 and 5637, which are considered models for papillary carcinoma, revealed that KLF11 participates in altering the adhesiveness of cells to laminin-coated dishes, although cell growth was not affected. CONCLUSION: These data indicate that DNA hypermethylation of KLF11 may participate in the generation of papillary urothelial carcinomas through induction of aberrant cancer cell adhesion to the basement membrane.

Histopathology of peritonitis due to infectious mononucleosis with background Chlamydia trachomatis infection: A case report and literature review.

Epstein-Barr virus (EBV) is a major cause of infectious mononucleosis (IM), characterized by fever, fatigue, sore throat, lymphadenopathy, atypical lymphocytosis, and elevated liver enzymes. However, ascites is a rare complication associated with IM. We present a rare case of IM with ascites and peritonitis in a patient who underwent a peritoneal biopsy. A 20-year-old woman presented with fatigue and abdominal distension. Laboratory examination revealed atypical lymphocytes in peripheral blood (54%) and elevated liver enzymes. EBV serological tests revealed a recent primary infection (EBV VCA IgM 1:160). Computed tomography revealed moderate ascites and peritonitis. Adenocarcinoma was suspected based on the ascites' cytology. Considering possible complications of IM and adenocarcinoma, a laparoscopic biopsy was performed. Histological findings of biopsy specimens from the peritoneum, omentum, and fimbria of the fallopian tube demonstrated severe inflammatory cell infiltration and focal aggregation of large EBV-encoded RNA-1 (EBER1)-positive B cells, mimicking EBV-positive polymorphous B-cell lymphoproliferative disorder. Furthermore, intracytoplasmic inclusion bodies of Chlamydia trachomatis were observed by immunohistochemistry. Real-time polymerase chain reaction detected C. trachomatis in cervical secretions. Two months after laparoscopy, ascites decreased, and the diagnosis was IM-associated peritonitis with C. trachomatis infection. IM should be considered as a differential diagnosis in young patients with ascites.

Prognostic implication of CTLA-4, PD-1, and PD-L1 expression in aggressive adult T-cell leukemia-lymphoma.

The prognosis of patients with aggressive adult T cell leukemia-lymphoma (ATLL) is dismal even with intensive chemotherapy. Allogeneic hematopoietic stem cell transplantation (HSCT) is a promising option for patients with aggressive ATLL, but the posttransplant outcome remains unsatisfactory. Hence, to further improve clinical outcomes, novel therapeutic approaches are needed. The clinical significance of immune checkpoint protein expression has not been well-established in aggressive ATLL. This study aims to identify the association between the expression profile of immune checkpoint proteins on ATLL cells and clinical outcomes. This retrospective study cohort included 65 patients with aggressive ATLL diagnosed between 2001 and 2015 at the National Cancer Center Hospital, Tokyo, Japan. Formalin-fixed paraffin-embedded tissue was used to immunohistochemically determine the expression of immune checkpoint proteins and assess the impact of expression profile on the probability of overall survival from diagnosis or HSCT. The current analysis shows that cytotoxic T lymphocyte antigen-4 (CTLA-4), programmed death-1 (PD-1), and programmed death-ligand 1 (PD-L1) expressions were adverse prognostic factors in patients with aggressive ATLL. Experiments that assess the efficacy of immune checkpoint inhibitors are warranted to alleviate the adverse impacts associated with negative immune checkpoints.

Outcomes of hematopoietic cell transplantation for transformed follicular lymphoma.

This study characterized the outcomes of patients who underwent hematopoietic cell transplantation (HCT) for transformed follicular lymphoma (tFL), and clarified the association of low-dose anti-thymocyte globulin use with outcomes after allogeneic HCT. The retrospective study cohort included 74 consecutive patients who underwent autologous (n = 23) or allogeneic (n = 51) HCT at our center from 2000 to 2017. Compared with the allogeneic HCT group, the autologous HCT group underwent fewer systemic regimens before HCT (median 2 vs. 5, p < 0.001) and were more likely to have chemosensitive disease at HCT (100% vs. 82%, p = 0.05), while age, sex and HCT-specific comorbidity index were similar between the two groups. With a median follow-up of 5.8 years among survivors, the 5-year probability of progression-free survival was 64% after autologous HCT and 55% after allogeneic HCT (p = 0.21). The 5-year cumulative incidence of non-relapse mortality was 0% after autologous HCT and 9.5% after allogeneic HCT (p = 0.062). The 5-year cumulative incidence of disease progression was similar between autologous and allogeneic HCT (36% vs. 36%, respectively, p = 0.88). In the allogeneic HCT group, the use of low-dose anti-thymocyte globulin was associated with a lower incidence of severe acute GVHD but not with an increased risk of mortality or disease progression. More than half of patients with early phase chemosensitive tFL and approximately half of those with advanced-phase tFL achieved long-term progression-free survival with autologous and allogeneic HCT, respectively. Disease progression was the major cause of treatment failure after both types of HCT. Further strategies are needed to reduce the risk of disease progression.

The role of local radiotherapy following rituximab-containing chemotherapy in patients with transformed indolent B-cell lymphoma.

OBJECTIVES: This study aimed to evaluate the outcomes of local radiotherapy (LRT) in patients with histologic transformation (HT) following rituximab-containing chemotherapy. METHODS: We retrospectively analysed 92 patients with biopsy-confirmed HT undergoing rituximab-containing chemotherapy at our institution between 2003 and 2015. RESULTS: Of the 36 patients with limited-stage disease at diagnosis of HT, 29 (78%) received LRT. The estimated 5-year progression-free survival (PFS) rate was significantly better in patients who underwent LRT than in those who did not (93% and 42%, respectively; P < 0.05). Multivariate analyses employing age, sex, performance status, LRT and treatment response demonstrated that LRT was an independent prognostic factor for PFS (hazard ratio [HR]: 11.8; 95% confidence interval [CI]: 1.28-108.1; P < 0.05). Of the 32 patients who underwent LRT for HT lesion treatment, 31 (97%) did not show disease progression within radiation fields; among them, 27 patients (84%) survived without disease progression during the follow-up period. One patient developed hypothyroidism due to LRT; the others had no acute or late-onset complications of LRT. CONCLUSIONS: Our data support the recommendation of LRT for HT lesion treatment following rituximab-containing chemotherapy in select patients with localised HT, as a rational treatment approach with potentially limited toxicity.

Use of Core-Needle Biopsy for the Diagnosis of Malignant Lymphomas in Clinical Practice.

INTRODUCTION: Excisional biopsy (EB) is considered the gold standard for lymphoma diagnosis. Although recent advances in interventional radiology enable sampling with core-needle biopsy (CNB), only few studies evaluated the utility of CNB compared to that of EB. METHODS: We analyzed patients with lymphoma who had a diagnostic biopsy at the National Cancer Center Hospital during 2002-2017. We investigated the clinical and pathological characteristics of CNB in 2017. RESULTS: The proportion of CNB utility in total biopsy procedures had increased from 11 to 48% during the 15 years. In 2017, CNB was opted more frequently than EB for a biopsy of superficial, abdominal, or anterior mediastinal lesions. Only one out of 72 patients who had CNB required re-biopsy with EB because of insufficiency. The incidence of complications was comparable between CNB and EB: 2 (4%) cases of minor bleeding with CNB and 1 (8%) case of minor bleeding with EB. The median time from the first visit to biopsy was significantly shorter with CNB (5.5 days) than with EB (15 days). CONCLUSION: There is an increasing trend in the utility of CNB. CNB is a less invasive method with shorter time to biopsy and can be considered an alternative to EB.

Diagnostic utility and prognostic significance of the Ki-67 labeling index in diffuse large B-cell lymphoma transformed from follicular lymphoma: a study of 76 patients.

The diagnosis of histological transformation of follicular lymphoma can be challenging and ambiguous. We investigated the distribution of the Ki-67 labeling index of histological transformation of follicular lymphoma and determined its cutoff value to predict poor outcomes. The diagnostic criteria for histological transformation were a diffuse pattern of proliferation and a proportion of large lymphoma cells ≥20%. Of the 1121 patients with follicular lymphoma, 171 (15%) showed histological transformation to diffuse large B-cell lymphoma. Of these, 76 patients, whose biopsies were obtained from the sites with the highest maximum standardized uptake values, according to the positron emission tomography findings, were included. The Ki-67 index ranged from 16.8% to 98.4% (median, 60.6%). In patients with histological transformation, the most significant differences were found in progression-free survival (p = 0.087, 58% vs. 87% at 2 years) and overall survival (p = 0.024, 53% vs. 85% at 5 years) when a 70% cutoff was used. Additionally, overall survival was significantly shorter in patients with histological transformation with maximum standardized uptake values of ≥20 (p < 0.0001) and absence of a follicular lymphoma component (p = 0.004). A Ki-67 index of ≥70% was a significant adverse factor for overall survival in patients with histological transformation of follicular lymphoma and may predict poor outcomes.

Clinical management and outcomes associated with etoposide, doxorubicin, and cisplatin plus mitotane treatment in metastatic adrenocortical carcinoma: a single institute experience.

BACKGROUND: Adrenocortical carcinoma (ACC) is a rare and aggressive disease that is often diagnosed at an advanced stage. There is no standard treatment for metastatic ACC; EDP-M (etoposide, doxorubicin, and cisplatin plus mitotane) is one treatment option. A randomized controlled trial (FIRM-ACT) evaluating the efficacy of EDP-M showed progression-free survival (PFS) was 5.0 months, overall survival (OS) was 14.8 months, the response rate was 19%, and adrenal insufficiency occurred in 3.4% of patients. However, the efficacy and safety of this regimen in Asia are not fully reported. METHODS: We retrospectively analyzed 43 patients diagnosed with metastatic ACC at the National Cancer Center Hospital between 1997 and 2020. We evaluated PFS, OS, and response in 17 patients who received EDP-M as first-line therapy. RESULTS: The median age at treatment initiation was 45 years (range 18-74). Eight patients (47%) had autonomous hormone production, including six patients with hypercortisolism. The best response of partial response and stable disease was seen in two (12%) and ten (59%) patients, respectively. The median PFS was 6.2 months [95% confidence interval (CI): 4.3-10.0]. The median OS was 15.4 months (95% CI 11.6-not reached). Three patients received only one cycle due to adverse effects associated with hypercortisolism. Grade 3/4 adverse events associated with adrenal insufficiency occurred in three (17%) cases, resulting in EDP-M discontinuation. CONCLUSIONS: The EDP-M regimen had similar PFS to that observed in FIRM-ACT. Adrenal insufficiency was more frequent in the current study, but this could be managed with supportive endocrinological care such as cortisol replacement.

Immunohistochemical CD20-negative change in B-cell non-Hodgkin lymphomas after rituximab-containing therapy.

CD20- change after rituximab-containing therapy is considered one of the main reasons of rituximab resistance of B-cell non-Hodgkin lymphomas (B-NHLs). However, the clinicopathological characteristics of B-NHL with CD20- change are not entirely understood. In this study, 252 B-NHL patients who were CD20+ at initial diagnosis, whose diseases relapsed or were refractory after rituximab-containing therapy, and who were re-biopsied between 2000 and 2018, were included. The median number of rituximab administration was 11 (range, 1-48). Completely negative (cCD20-) and partially negative (pCD20-) change of CD20 was observed in 49 (20%) and 16 (6%) cases, respectively. Among cCD20- and pCD20- cases, 74% and 62% of the cases changed to CD20- at the second relapse or later, respectively. Overall survival was significantly shorter in cCD20- follicular lymphoma (FL) cases than in CD20+ FL cases. Seven histopathological patterns, such as CD20- change without histological change, histological transformation (HT) to CD20- diffuse large B-cell lymphoma, and proliferation of plasmablastic/plasmacytoid tumor cells, were associated with CD20- change. HT occurred more frequently in FLs with CD20- change than in FLs continuously expressing CD20 (P < 0.0001), regardless of the timing of HT. Nine out of 25 cases (36%) showed regain or heterogeneous regain of CD20 expression. In conclusion, 20% and 6% of the 252 B-NHL cases show cCD20- and pCD20- changes with 7 histological patterns after rituximab-containing therapy. Because changes in morphology and CD20 expression after rituximab-containing therapy vary, and recovery of CD20 expression is not rare, careful follow-up and re-biopsy in B-NHL patients are recommended.

Establishment of permutation for cancer risk estimation in the urothelium based on genome-wide DNA methylation analysis.

The aim of this study was to establish permutation for cancer risk estimation in the urothelium. Twenty-six samples of normal control urothelium obtained from patients without urothelial carcinomas (C), 47 samples of non-cancerous urothelium without noticeable morphological changes obtained from patients with urothelial carcinomas (N), and 46 samples of the corresponding cancerous tissue (T) in the learning cohort and 64 N samples in the validation cohort, i.e. 183 tissue samples in total, were analyzed. Genome-wide DNA methylation analysis was performed using the Infinium HumanMethylation 450K BeadChip, and DNA methylation levels were verified using pyrosequencing and MassARRAY. Amplicon sequencing was performed using the GeneRead DNAseq Targeted Panels V2. Although N samples rarely showed genetic mutations or copy number alterations, they showed DNA methylation alterations at 2502 CpG sites compared to C samples, and such alterations were inherited by or strengthened in T samples, indicating that DNA methylation alterations may participate in field cancerization in the urothelium. Receiver operating characteristic curve analysis confirmed the feasibility of cancer risk estimation to identify urothelium at the precancerous stage by DNA methylation quantification. Cancer risk estimation permutation was established using a combination of two marker CpG loci on the HOXC4, TENM3 and TLR1 genes (sensitivity and specificity 96-100%). Among them, the diagnostic impact of 10 patterns of permutation was successfully validated in the validation cohort (sensitivity and specificity 94-98%). These data suggest that cancer risk estimation using procedures such as urine tests during health checkups might become applicable for clinical use.

Mucosa-associated lymphoid tissue lymphoma with t(11;18)(q21;q21) translocation: long-term follow-up results.

Translocation (11;18)(q21;q21) is found in mucosa-associated lymphoid tissue (MALT) lymphoma, resulting in API2/MALT1 gene fusion. It is known that t(11;18)-positive MALT lymphoma shows a tendency to disseminate and be resistant to Helicobacter pylori eradication by antibiotics. However, the prognostic features including recurrence and histological transformation (HT) remain unknown. We conducted a single-institute retrospective analysis of 464 patients with newly diagnosed MALT lymphoma, evaluating the impact of t(11;18) on clinical outcomes. One hundred and six patients were screened for the translocation by fluorescence in situ hybridization and/or reverse transcriptase-polymerase chain reaction. Of these patients, 26 patients (25%) were diagnosed as MALT lymphoma with t(11;18). The patients had a significantly shortened progression-free survival (PFS at 10 years; 26% v 57%; P = 0.004) compared to those without t(11;18). However, this did not translate into overall survival or incidence of HT. We confirmed previous reports stating that t(11;18)-positive MALT lymphoma showed disseminated disease and refractoriness to H. pylori eradication therapy. Patients with t(11;18) had more frequent monoclonal gammopathy, especially of IgM subtype (31% v 8%; P = 0.008), some of which developed class switch. These findings characterize the features of t(11;18)-positive MALT lymphoma, suggesting that it comprises a distinct clinical entity of MALT lymphoma.

Association of CD204+ macrophages with poor outcomes of malignant lymphomas not in remission treated by allogeneic HCT.

OBJECTIVE: CD204+ tumor-associated macrophages are associated with adverse outcomes of various malignancies. We performed a study to elucidate the role of CD204+ macrophages in allogeneic hematopoietic cell transplantation (allogeneic HCT). METHODS: In a total of 81 patients who received allogeneic HCT for non-remission malignant lymphoma, immunohistochemical staining of CD204 using specimens preserved before allogeneic HCT was performed. According to the average number of CD204+ macrophages in a high-power field, patients were categorized into three groups: low (<25th percentile), intermediate (≥25th percentile and <50th percentile), and high (≥50th percentile). RESULTS: The B-cell lymphoma proportion was higher in the low group, while T-cell lymphoma and adult T-cell leukemia proportions were higher in the high group. The 3-year overall survival (OS) was poorest in the high group; low vs intermediate vs high = 83.3% vs 43.7% vs 20.2% (P < .01). The 3-year cumulative incidences of relapse were significantly higher in the high group than the intermediate and low groups: 67.0% vs 38.1% vs 18.2% (P < .01). In multivariate analyses, the numbers of CD204+ macrophages were independent risk factors of poorer OS and cumulative incidences of relapse. CONCLUSIONS: CD204+ macrophages might be associated with poorer prognosis in allogeneic HCT for malignant lymphomas.

Biomarker discordance between primary breast cancer and bone or bone marrow metastases.

BACKGROUND: Discordance in biomarker expression between primary and metastatic tumor sites has been reported in several studies; yet, few have examined this feature in bone lesions. METHODS: We retrospectively enrolled patients with breast cancer metastasis to the bone or bone marrow, excluding cases where samples from both the primary and metastatic lesions were not available. Expression patterns of the estrogen receptor (ER), progesterone receptor (PgR), human epidermal growth factor receptor 2 (HER2) and Ki67 were compared in primary tumors and bone or bone marrow lesions. RESULTS: Forty-six patients with a median age of 52 years (range, 34-72 years) were included in the study. Discordant rates of ER, PgR and HER2 were 20%, 46% and 0%, respectively. Physicians usually determined treatment options considering the results of biomarker re-evaluation. It is unlikely that biomarker discordance was related to prior treatment. CONCLUSIONS: Biomarker discordance in bone or bone marrow lesions is common in patients with breast cancer. An accurate and thorough analysis of biomarkers and metastatic tumor properties is important for clinical decision-making.

EBV-encoded RNA1-positive cells in the bone marrow specimens of patients with EBV-negative lymphomas and sarcomas.

Epstein-Barr virus (EBV) infection is associated with pathogenesis of various cancers, including extranodal natural killer/T-cell lymphoma, nasal type (ENKL). ENKL tumor cells are positive for EBV-encoded RNA1 (EBER1), which is the most useful marker to identify ENKL tumor cells in histopathology. Currently, EBER1 in situ hybridization (ISH) is recommended to evaluate bone marrow (BM) involvement of ENKL. However, the actual burden of EBER1-positive cells in normal BM specimens remains unclear. In the present study, we performed EBER1 ISH on 111 BM specimens, which were obtained during an initial staging procedure in patients with EBV-negative cancers and were also negative for BM involvement. One or more EBER1-positive cells per whole specimen were observed in 38 specimens (34%). The number of EBER1-positive cells was distributed as follows: single positive cell, n = 17; two positive cells, n = 13; three positive cells, n = 3; and four positive cells, n = 5. These findings suggest that four or fewer EBER1-positive cells can be observed in BM specimens of patients with non-EBV-related cancers. The clinical implications of a small number of EBER1-positive cells in BM specimens of patients with ENKL should be evaluated in further studies.

Double-Expressor Lymphoma Is Associated with Poor Outcomes after Allogeneic Hematopoietic Cell Transplantation.

Double-expressor lymphoma (DEL) is a diffuse large B cell lymphoma that exhibits co-expression of MYC and BCL2 proteins by immunohistochemistry. Patients with double-expressor lymphoma have a poor prognosis after standard chemoimmunotherapy or after high-dose chemotherapy with autologous transplantation, but the prognostic impact of DEL after allogeneic hematopoietic cell transplantation has not been well characterized. We retrospectively analyzed 60 consecutive patients with de novo diffuse large B cell lymphoma or transformed follicular lymphoma who underwent allogeneic transplantation at our center and had available immunohistochemistry data. Thirty-seven patients (62%) had DEL. The 2-year progression-free and overall survival rates were lower in patients with DEL than in those without DEL (20% versus 78%; overall P <.001 and 46% versus 77%; overall P = .016, respectively). The cumulative incidence of disease progression at 2 years was higher in patients with DEL (60% versus 13%; overall P = .005). The cumulative incidence of nonrelapse mortality did not differ statistically in the 2 groups. Even in patients with DEL and chemosensitive disease at transplantation, the 2-year progression-free survival rate was only 27% due to early disease progression. Multivariate analysis showed associations between DEL and increased risks of progression-free survival events (hazard ratio [HR], 4.58; 95% confidence interval [CI], 2.07-10.2; P <.001), overall mortality (HR, 2.29; 95% CI, 1.03-5.09; P = .042) and disease progression (HR, 3.60; 95% CI, 1.38-9.44; P = .009). Patients with DEL had poor outcomes after allogeneic transplantation. Innovative strategies are needed to improve outcomes in this population.

Expression pattern of PD-L1 and PD-L2 in classical Hodgkin lymphoma, primary mediastinal large B-cell lymphoma, and gray zone lymphoma.

OBJECTIVES: We aimed at investigating the relationship between classical Hodgkin lymphoma (cHL), primary mediastinal large B-cell lymphoma (PMBL), and gray zone lymphoma (GZL) with intermediate characteristics between cHL and PMBL, from the perspective of the aberration in programed cell death 1 and the programed death ligands (PDLs) network. METHODS: We explored the expression levels of PDLs and chromosomal anomalies in 67 cases: 34 cases with cHL, 20 with PMBL, and 13 with GZL, using immunohistochemical analyses and Fluorescence In Situ Hybridization (FISH). RESULTS: Twenty-one cHL (62%), 3 PMBL (15%), and 6 GZL (46%) cases showed staining to PD-L1 antibodies in more than 70% of tumor cells. Two cHL (6%), 10 PMBL (50%), and 3 GZL (23%) cases were not stained by PD-L1 antibodies. Patients over 40 years old manifest more frequent expression of PD-L1 in cHL. Proportion of tumors stained by PD-L2 antibody was increased in PMBL. FISH analyses with a PD-L1/PD-L2 probe detected 5 amplification, 1 gain, and 7 polysomy cases in cHL, 1 amplification and 1 polysomy case in GZL, and amplification in 1 PMBL case. CONCLUSION: We identified increased staining of PD-L1 in cHL and that of PD-L2 in PMBL. GZL had a pattern similar to that of cHL.

Prognosis of patients with peripheral T cell lymphoma who achieve complete response after CHOP/CHOP-like chemotherapy without autologous stem cell transplantation as an initial treatment.

Cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP)/CHOP-like chemotherapy has been mostly applied to patients with untreated peripheral T cell lymphoma (PTCL). Because the long-term outcome of patients with PTCL, especially those achieving complete response (CR), has not been fully elucidated, we retrospectively analyzed 78 consecutive patients initially treated with CHOP/CHOP-like chemotherapy, without high-dose chemotherapy followed by autologous stem cell transplantation (HDC/auto-SCT). Median overall and progression-free survivals in all 78 patients were 44 and 17 months, respectively, with a median follow-up of 62 months. In the 53 patients achieving CR, the median relapse-free survival (RFS) was 21 months, and 2-, 3-, and 5-year RFSs were 46, 45, and 36%, respectively. Although our results showed an unfavorable outcome for PTCL as a whole, those who achieved CR following CHOP/CHOP-like chemotherapy did not always have a poor outcome without the consolidation of HDC/auto-SCT; in particular, 45% of the 65 years or younger patients were alive without disease at 5 years.

Clinicopathological features of histological transformation from extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue to diffuse large B-cell lymphoma: an analysis of 467 patients.

This study analysed incidence, patient outcome, immunophenotype and prognostic factors of histological transformation (HT) from extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) to diffuse large B-cell lymphoma (DLBCL) in 467 patients (median age, 61 years). The primary sites of MALT lymphoma were the stomach (43%), ocular adnexa (25%), lung (8%), systemic (8%) and other tissues (16%). HT occurred in 8% of MALT lymphomas. Risk of HT by 15 years was 5%: 4% in limited-stage diseases (n = 385) and 16% in advanced-stage diseases (n = 56) (P = 0·02). The median time to HT was 48 months (range, 4-139). Five-year progression-free survival (PFS) and overall survival (OS) rates after HT were 80% and 94%, respectively. Immunohistochemical results of DLBCL were as follows: germinal centre B-cell (GCB)/non-GCB, 37%/63%; CD10, 9%; BCL6, 59%; MUM1, 38%; MYC, 42%; BCL2, 35%; Ki67 ≥ 90%, 23%; and CD5, 3%. The majority (75%, 9/12) of GCB-type DLBCLs exhibited CD10(-) , BCL6(+) and MUM1(-) immunophenotypes; the remainder had CD10(+) immunophenotypes. Multivariate analysis revealed that only advanced stage at HT was a significant adverse factor for PFS (P = 0·037). Thus, overall risk of HT was low and prognosis after HT was favourable; however, in advanced-stage cases, risk of HT was relatively high and prognosis was unfavourable.

Prognostic significance of HLA class I and II expression in patients with diffuse large B cell lymphoma treated with standard chemoimmunotherapy.

Loss of tumor cell human leukocyte antigen (HLA) is an immune escape mechanism for malignancies. However, the effect of low HLA class I or class II expression in diffuse large B cell lymphoma (DLBCL) treated with chemoimmunotherapy with the monoclonal antibody rituximab is largely unknown. We retrospectively analyzed samples and other data from 144 patients with DLBCL who were newly diagnosed in our institution and treated with standard R-CHOP therapy. We used antibodies against pan-HLA class I and pan-HLA class II molecules to assess HLA expression and its effect on prognosis. In a multivariate analysis, loss of HLA class II expression was a significantly independent adverse factor for progression-free survival (PFS; hazard ratio 2.3; 95 % confidence interval 1.2-4.6; P = 0.01). Although HLA class I loss of expression did not correlate with prognosis, the combination of HLA class I(+) with either low peripheral lymphocyte count or CD3(+) lymphocyte count was an adverse prognostic factor for PFS. Loss of HLA class II is an International Prognostic Index (IPI)-independent adverse factor for PFS in patients with DLBCL treated with standard therapy. However, in contrast to other solid cancers, HLA class I loss was not solely a prognostic factor in DLBCL.