Repeated Intravenous Methylprednisolone May Prevent Deterioration of Hypertrophic Pachymeningitis in Rosai-Dorfman Disease.

Rosai-Dorfman disease (RDD) is a rare form of non-Langerhans cell histiocytosis. Although 20% of patients with RDD have spontaneous remission, some cases with central nervous system (CNS) involvement require surgery or systemic treatment. We encountered a case of RDD in which hypertrophic pachymeningitis was diffuse, eliminating the need for surgical intervention. A 72-year-old Japanese man was diagnosed with RDD based on pathological lymph node findings. Repeated intravenous methylprednisolone (IVMP) administration resolved and stabilized the hypertrophic pachymeningitis without any sequelae. If surgery or anticancer medications are contraindicated, repeated IVMP may be a good therapeutic option for CNS-associated RDD.

Real-World Implementation of Digital Pathology: Results From an Intercontinental Survey.

The past 70 years have been characterized by rapid advancements in computer technology, and the health care system has not been immune to this trend. However, anatomical pathology has remained largely an analog discipline. In recent years, this has been changing with the growing adoption of digital pathology, partly driven by the potential of computer-aided diagnosis. As part of an international collaboration, we conducted a comprehensive survey to gain a deeper understanding of the status of digital pathology implementation in Europe and Asia. A total of 127 anatomical pathology laboratories participated in the survey, including 75 from Europe and 52 from Asia, with 72 laboratories having established digital pathology workflow and 55 without digital pathology. Laboratories using digital pathology for diagnostic (n = 29) and nondiagnostic (n = 43) purposes were thoroughly questioned about their implementation strategies and institutional experiences, including details on equipment, storage, integration with laboratory information system, computer-aided diagnosis, and the costs of going digital. The impact of the digital pathology workflow was also evaluated, focusing on turnaround time, specimen traceability, quality control, and overall satisfaction. Laboratories without access to digital pathology were asked to provide insights into their perceptions of the technology, expectations, barriers to adoption, and potential facilitators. Our findings indicate that although digital pathology is still the future for many, it is already the present for some. This decade may be a time when anatomical pathology finally embraces digital revolution on a larger scale.

Eosinophil-rich variant of nodal marginal zone lymphoma: a clinicopathological study of 11 cases.

AIMS: Tissue eosinophilia is commonly observed in T-cell and classic Hodgkin lymphomas, but rarely in B-cell lymphomas. Herein, we present the first report of a case series on nodal marginal zone lymphoma (NMZL) with tissue eosinophilia. METHODS AND RESULTS: All 11 patients in this study had nodal disease at primary presentation. The mean age at diagnosis was 64 years. The mean follow-up period was 39 months, and all patients were alive. Nine of the 11 patients (82%) showed no recurrence, but the other two patients experienced recurrence in the lymph nodes or skin. Marked eosinophilic infiltration was observed in all biopsied lymph nodes. Nine of the 11 patients had a preserved nodular architecture with expanded interfollicular areas. The other two patients showed diffuse lymphoma cell infiltration with effacement of nodal architecture. One of them was diagnosed as having diffuse large B-cell lymphoma transformed from NMZL because large cells accounted for >50% of the lymphoma cells and formed sheet-like patterns. Cells were positive for CD20 and BCL2 and negative for CD5, CD10, and BCL6. Some patients showed myeloid cell nuclear differentiation antigen (MNDA) positivity. All patients showed B-cell monoclonality via flow cytometry, southern blotting, and/or polymerase chain reaction (PCR). CONCLUSION: All patients showed distinctive morphological features and could be misdiagnosed with peripheral T-cell lymphoma due to their eosinophil-rich backgrounds. The predominance of B cells, absence of histiocytes, and high endothelial venules in the interfollicular areas are key factors for diagnosis. B-cell monoclonality is the most reliable evidence of differentiation. We designated this type of lymphoma as an eosinophil-rich variant of NMZL.

Accurate deep learning model using semi-supervised learning and Noisy Student for cervical cancer screening in low magnification images.

Deep learning technology has been used in the medical field to produce devices for clinical practice. Deep learning methods in cytology offer the potential to enhance cancer screening while also providing quantitative, objective, and highly reproducible testing. However, constructing high-accuracy deep learning models necessitates a significant amount of manually labeled data, which takes time. To address this issue, we used the Noisy Student Training technique to create a binary classification deep learning model for cervical cytology screening, which reduces the quantity of labeled data necessary. We used 140 whole-slide images from liquid-based cytology specimens, 50 of which were low-grade squamous intraepithelial lesions, 50 were high-grade squamous intraepithelial lesions, and 40 were negative samples. We extracted 56,996 images from the slides and then used them to train and test the model. We trained the EfficientNet using 2,600 manually labeled images to generate additional pseudo labels for the unlabeled data and then self-trained it within a student-teacher framework. Based on the presence or absence of abnormal cells, the created model was used to classify the images as normal or abnormal. The Grad-CAM approach was used to visualize the image components that contributed to the classification. The model achieved an area under the curve of 0.908, accuracy of 0.873, and F1-score of 0.833 with our test data. We also explored the optimal confidence threshold score and optimal augmentation approaches for low-magnification images. Our model efficiently classified normal and abnormal images at low magnification with high reliability, making it a promising screening tool for cervical cytology.

Hodgkinoid histiocytosis: an atypical nodal CD30 and S100-positive histiocytosis with eosinophilia.

Histiocytes and dendritic cells may display cytological atypia and an aberrant immunophenotype even in reactive processes. Herein, we describe two cases of "Hodgkinoid histiocytosis" that show distinctive clinicopathological features, mimicking morphologically classic Hodgkin lymphoma (CHL), but suggesting reactive histiocytic/dendritic cell proliferation in lymph nodes. Both the patients presented with peripheral lymphadenopathy and blood eosinophilia with skin manifestations. Lymph node biopsy revealed scattered large histiocytes resembling Hodgkin cells with a round or stellate shape, abundant cytoplasm, and distinct nucleoli admixed in a predominant inflammatory background. The Hodgkinoid histiocytes occasionally showed emperipolesis. They expressed CD30, S100, and PD-L1 proteins but lacked PAX5 and CD1a expressions, Epstein-Barr association, BRAF V600E mutation, and PD-L1 gene amplification. Neither of the patients showed overt progression to malignant haematopoietic neoplasms during the disease course. An identical case series of four patients has been reported to date. Both these series highlight the potential of being interpreted as CHL due to the presence of Hodgkinoid histiocytes with CD30 positivity.

Substantial improvement of histopathological diagnosis by whole-slide image-based remote consultation.

Consultation by subspecialty experts is the most common mode of rendering diagnosis in challenging cases in pathological practice. Our study aimed to highlight the diagnostic benefits of whole-slide image (WSI)-based remote consultation. We obtained diagnostically challenging cases from two institutions from the years 2010 and 2013, with histological diagnoses that contained keywords "probable," "suggestive," "suspicious," "inconclusive," and "uncertain." A total of 270 cases were selected for remote consultation using WSIs scanned at 40 × . The consultation process consisted of three rounds: the first and second rounds each with 12 subspecialty experts and the third round with six multi-expertise senior pathologists. The first consultation yielded 44% concordance, and a change in diagnosis occurred in 56% of cases. The most frequent change was from inconclusive to definite diagnosis (30%), followed by minor discordance (14%), and major discordance (12%). Out of the 70 cases which reached the second round, 31 cases showed discrepancy between the two consultants. For these 31 cases, a consensus diagnosis was provided by six multi-expertise senior pathologists. Combining all WSI-based consultation rounds, the original inconclusive diagnosis was changed in 140 (52%) out of 266 cases. Among these cases, 80 cases (30%) upgraded the inconclusive diagnosis to a definite diagnosis, and 60 cases (22%) changed the diagnosis with major or minor discordance, accounting for 28 cases (10%) and 32 cases (12%), respectively. We observed significant improvement in the pathological diagnosis of difficult cases by remote consultation using WSIs, which can further assist in patient healthcare. A post-study survey highlighted various benefits of WSI-based consults.

Rituximab maintenance improves outcomes of transformed diffuse large B-cell lymphoma: a retrospective study of 519 cases with de novo diffuse large B-cell lymphoma and 62 cases with concurrent diffuse large B-cell lymphoma and follicular lymphoma.

Although outcomes of transformed diffuse large B-cell lymphoma (DLBCL) from follicular lymphoma (FL) were improved using rituximab-combined immunochemotherapy, the efficacy of subsequent rituximab maintenance (RM) remains unclear. We retrospectively analyzed the prognoses of 519 patients with de novo DLBCL and 62 patients with concurrent DLBCL and FL (concurrent-DLBCL/FL). Progression-free survival (PFS) was shorter in patients with concurrent-DLBCL/FL than in de novo DLBCL (p=.030). Twenty-four patients with concurrent-DLBCL/FL received RM after induction therapy, and they achieved better OS and PFS (p=.010 and p<.001, respectively) with lower risk of relapse (p<.001) than the non-RM group. Moreover, concurrent-DLBCL/FL showed better subsequent OS and PFS after recurrence than de novo DLBCL (p=.0083 and p=.0044, respectively). Our study indicates that in the face of a high relapse rate, concurrent-DLBCL/FL is manageable and benefits from RM.

Progression-free survival at 24 months as a predictor of survival outcomes after CHOP treatment in patients with peripheral T-cell lymphoma: a single-center validation study in a Japanese population.

Peripheral T-cell lymphoma (PTCL) is a group of aggressive lymphomas commonly treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). Progression-free survival at 24 months (PFS24) constitutes a survival predictor for some lymphomas but has not been examined in Asian populations. We retrospectively investigated whether PFS24 was predictive of survival outcomes after CHOP treatment in 73 Japanese patients with PTCL. Patients without PFS24 had shorter median subsequent overall survival (OS) (20.2 vs. 121.0 months, p < 0.001) and shorter median subsequent progression-free survival (5.0 vs. 17.1 months, p = 0.03). Patients without PFS24 had worse overall (62.5% vs. 100%) and complete response rates (45.8% vs. 96.0%) (both p < 0.001). PFS24 absence (hazard ratio: 3.34, p = 0.004) and poor performance status (hazard ratio: 3.17, p = 0.04) were independently predictive of shorter OS. These findings suggest that PFS24 is predictive of survival after CHOP treatment in Japanese patients with PTCL.

Impact of Omission/Reduction of Vincristine From R-CHOP in Treatment of DLBCL.

BACKGROUND: The R-CHOP regimen (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) is the standard therapy for patients with diffuse large B-cell lymphoma (DLBCL). However, vincristine is sometimes omitted or reduced owing to side effects. MATERIALS AND METHODS: We retrospectively reviewed newly diagnosed patients with DLBCL with R-CHOP-like chemotherapy in our institute from January 2005 to February 2018 to investigate whether the omission/reduction of vincristine reduced the efficacy of the treatment. We compared the overall survival (OS) with and without the omission/reduction of vincristine from the R-CHOP regimen. RESULTS: A total of 576 cases were reviewed, and vincristine was omitted/reduced in 50 (9%) patients. The 4-year OS with and without vincristine omission/reduction for relative dose intensity < 80%, 50%, and 25% was 70% versus 82% (P = .035), 70% versus 82% (P = .085), and 53% versus 82% (P = .0007). In a multivariate analysis, adjusting for international prognostic index risk factors, a statistically significant, poor OS was indicated in the patients with relative dose intensity < 25%. CONCLUSIONS: Excessive dose omission/reduction of vincristine might lead to a substantial loss of efficacy of R-CHOP therapy.

Primary human herpesvirus 8-negative effusion-based lymphoma: a large B-cell lymphoma with favorable prognosis.

Primary effusion-based lymphoma (EBL) presents as a malignant effusion in a body cavity. The clinicopathologic features and prognosis of primary human herpesvirus 8 (HHV8)-negative EBL remain unclear. We therefore conducted a retrospective study of 95 patients with EBL, regardless of HHV8 status, in Japan. Of 69 patients with EBL tested for HHV8, a total of 64 were negative. The median age of patients with primary HHV8-negative EBL at diagnosis was 77 years (range, 57-98 years); all 58 tested patients were negative for HIV. Primary HHV8-negative EBL was most commonly diagnosed in pleural effusion (77%). Expression of at least 1 pan B-cell antigen (CD19, CD20, or CD79a) was observed in all cases. According to the Hans algorithm, 30 of the 38 evaluated patients had nongerminal center B-cell (non-GCB) tumors. Epstein-Barr virus-encoded small RNA was positive in 6 of 45 patients. In 56 of 64 HHV8-negative patients, systemic therapy was initiated within 3 months after diagnosis. Cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) or CHOP-like regimens with or without rituximab (n = 48) were the most common primary treatments. The overall response and complete response rates were 95% and 73%, respectively. Three patients did not progress without systemic treatment for a median of 24 months. With a median 25-month follow-up, the 2-year overall survival and progression-free survival rates were 84.7% and 73.8%. Sixteen patients died; 12 were lymphoma-related deaths. Thus, most EBL cases in Japan are HHV8-negative and affect elderly patients. The non-GCB subtype is predominant. Overall, primary HHV8-negative EBL exhibits a favorable prognosis after anthracycline-based chemotherapy.

Insignificance of surveillance imaging in patients with diffuse large B-cell lymphoma who achieved first complete remission: a retrospective cohort study.

The aim of this study was to evaluate the value of scheduled imaging for patients who achieved first complete remission after CHOP-like chemotherapy plus rituximab. In this retrospective cohort study, we included 759 patients newly diagnosed with de novo diffuse large B-cell lymphoma (DLBCL) at the Cancer Institute, Japanese Foundation for Cancer Research. Relapsed patients were divided into two groups based on method of diagnosis: clinical symptoms (symptom group, n = 57) or scheduled imaging (imaging group, n = 27). Our primary goal was to compare overall survival and relapse-free survival between the two groups. No significant difference in outcomes was found between the symptom and imaging groups. Median overall survival [7.5 years; 95% confidence interval (CI) 4.0-9.7 vs. 9.1 years; 95% CI 2.7 to not reached; P = 0.747), and median relapse-free survival (1.8 years; 95% CI 1.4-2.5 vs. 2.4 years; 95% CI 1.2-4.4; P = 0.108). Surveillance imaging in patients with DLBCL who achieved first complete remission did not demonstrate an advantage in terms of overall survival or relapse-free survival.

Recurrent 8q24 rearrangement in blastic plasmacytoid dendritic cell neoplasm: association with immunoblastoid cytomorphology, MYC expression, and drug response.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare skin-tropic hematological malignancy of uncertain pathogenesis and poor prognosis. We examined 118 BPDCN cases for cytomorphology, MYC locus rearrangement, and MYC expression. Sixty-two (53%) and 41 (35%) cases showed the classic and immunoblastoid cytomorphology, respectively. Forty-one (38%) MYC+BPDCN (positive for rearrangement and expression) and 59 (54%) MYC-BPDCN (both negative) cases were identified. Immunoblastoid cytomorphology was significantly associated with MYC+BPDCN. All examined MYC+BPDCNs were negative for MYB/MYBL1 rearrangement (0/36). Clinically, MYC+BPDCN showed older onset, poorer outcome, and localized skin tumors more commonly than MYC-BPDCN. MYC was demonstrated by expression profiling as one of the clearest discriminators between CAL-1 (MYC+BPDCN) and PMDC05 (MYC-BPDCN) cell lines, and its shRNA knockdown suppressed CAL-1 viability. Inhibitors for bromodomain and extra-terminal protein (BETis), and aurora kinases (AKis) inhibited CAL-1 growth more effectively than PMDC05. We further showed that a BCL2 inhibitor was effective in both CAL-1 and PMDC05, indicating that this inhibitor can be used to treat MYC-BPDCN, to which BETis and AKis are probably less effective. Our data will provide a rationale for the development of new treatment strategies for patients with BPDCN, in accordance with precision medicine.

TP53 and OSBPL10 alterations in diffuse large B-cell lymphoma: prognostic markers identified via exome analysis of cases with extreme prognosis.

Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma subtype characterized by both biological and clinical heterogeneity. In refractory cases, complete response/complete response unconfirmed rates in salvage therapy remain low. We performed whole-exome sequencing of DLBCL in a discovery cohort comprising 26 good and nine poor prognosis cases. After candidate genes were identified, prognoses were examined in 85 individuals in the DLBCL validation cohort. In the discovery cohort, five patients in the poor prognosis group harbored both a TP53 mutation and 17p deletion. Sixteen mutations were identified in OSBPL10 in nine patients in the good prognosis group, but none in the poor prognosis group. In the validation cohort, TP53 mutations and TP53 deletions were confirmed to be poor prognostic factors for overall survival (OS) (P = 0.016) and progression-free survival (PFS) (P = 0.023) only when both aberrations co-existed. OSBPL10 mutations were validated as prognostic markers for excellent OS (P = 0.037) and PFS (P = 0.041). Significant differences in OS and PFS were observed when patients were stratified into three groups-OSBPL10 mutation (best prognosis), the coexistence of both TP53 mutation and TP53 deletion (poorest prognosis), and others. In this study, the presence of both TP53 mutation and 17p/TP53 deletion, but not the individual variants, was associated with poor prognosis in DLBCL patients after treatment with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) or similar regimens. We also identified OSBPL10 mutation as a marker for patients with excellent prognosis in the R-CHOP era.

Epstein-Barr virus-negative extranodal "true" natural killer-cell lymphoma harbouring a KDM6A mutation.

Extranodal natural killer (NK)/T-cell lymphoma, nasal type (ENKTL) is an extranodal aggressive T or NK-cell lymphoma that is characteristically associated with Epstein-Barr virus (EBV) infection and cytotoxic tissue-destructive features. Although ENKTL is described as a distinct entity according to the 2008 WHO classification, a considerable complexity is associated with the differential diagnosis of other T-cell lymphomas with respect to tumour cell origins, locations, and the presence of EBV infection, as well as molecular and cytogenetic abnormalities. Here, we report a rare case of EBV-negative ENKTL, where the absence of EBV in the true NK-lineage cells was confirmed by extensive phenotypic and genotypic analyses. Furthermore, using the next-generation sequencing approach, we identified mutations in the tumour suppressor genes KDM6A and TP53. The clinicopathological characteristics were almost similar to those of EBV-positive ENKTL, except for the absence of EBV and histologically apparent angioinvasiveness. This is the first reported ENKTL case with mutations in the KDM6A gene. KDM6A is one of the histone-modifying genes that are mutated in many human diseases including haematological cancers. Epigenetic regulation of gene expression has recently been demonstrated in ENKTL, and a similar pathway is thought to play an oncogenic role in EBV-negative ENKTL. Our report shows the extent of comprehensive examination required before making a definitive diagnosis for NK- and T-cell neoplasms and broadens the therapeutic options for potential targets.

Delayed recovery of serum immunoglobulin G is a poor prognostic marker in patients with follicular lymphoma treated with rituximab maintenance.

Clinical trials involving various treatment schedules for rituximab maintenance have been conducted for patients with follicular lymphoma (FL) and have not confirmed their impact on serum immunoglobulin (sIg) levels until the completion of maintenance. However, the long-term use of rituximab is a concern because of circulating plasma cell-depletion risk, suggesting that the mechanism of change in sIg levels after RM has not been determined. Additionally, the relationship between host humoral immunity and the prognosis of patients with B cell malignancies has not been determined. We retrospectively investigated data from 213 patients with FL from a single institute who achieved at least a partial response with rituximab, cyclophosphamide, vincristine, and prednisolone with or without doxorubicin. Of these, 166 patients underwent RM with a median period of 1.6 years. A significantly delayed recovery of sIgG levels was observed in the maintenance group until 3 years after RM in comparison to the observation group. A multivariate analysis showed that a sIgG level of < 718 mg/dl 1 year after RM was an independent predictor for poor progression-free survival (PFS) (hazard ratio, 2.3; P = 0.04). Therefore, the sIgG levels scarcely recovered and were significantly delayed after RM, leading to shorter PFS in patients with FL.

Anaplastic large cell lymphoma: pathology, genetics, and clinical aspects.

Anaplastic large cell lymphoma (ALCL) was first described in 1985 as a large-cell neoplasm with anaplastic morphology immunostained by the Ki-1 antibody, which recognizes CD30. In 1994, the nucleophosmin (NPM)-anaplastic lymphoma kinase (ALK) fusion receptor tyrosine kinase was identified in a subset of patients, leading to subdivision of this disease into ALK-positive and -negative ALCL in the present World Health Organization classification. Due to variations in morphology and immunophenotype, which may sometimes be atypical for lymphoma, many differential diagnoses should be considered, including solid cancers, lymphomas, and reactive processes. CD30 and ALK are key molecules involved in the pathogenesis, diagnosis, and treatment of ALCL. In addition, signal transducer and activator of transcription 3 (STAT3)-mediated mechanisms are relevant in both types of ALCL, and fusion/mutated receptor tyrosine kinases other than ALK have been reported in ALK-negative ALCL. ALK-positive ALCL has a better prognosis than ALK-negative ALCL or other peripheral T-cell lymphomas. Patients with ALK-positive ALCL are usually treated with anthracycline-based regimens, such as combination cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) or CHOEP (CHOP plus etoposide), which provide a favorable prognosis, except in patients with multiple International Prognostic Index factors. For targeted therapies, an anti-CD30 monoclonal antibody linked to a synthetic antimitotic agent (brentuximab vedotin) and ALK inhibitors (crizotinib, alectinib, and ceritinib) are being used in clinical settings.

Efficacy of chemotherapy in extremely elderly patients with diffuse large B-cell lymphoma.

The safety and effective dose of chemotherapy in treating non-Hodgkin lymphoma in elderly patients is yet to be established. In this study, we assessed the prognosis of diffuse large B-cell lymphoma (DLBCL) in elderly patients (≥75 years) treated with an optimal dose of R-CHOP. No significant differences were observed in progression-free survival between elderly patients and patients aged <74 years with DLBCL. Furthermore, no differences were observed between full-dose R-CHOP and 80% dose R-CHOP groups. Median relative dose intensity was 0.80 in elderly patients with DLBCL. Thus, our data suggested that 80% dose R-CHOP is tolerable and effective in these patients.