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Deep learning algorithms have been successfully used in medical image classification. In the next stage, the technology of acquiring explainable knowledge from medical images is highly desired. Here we show that deep learning algorithm enables automated acquisition of explainable features from diagnostic annotation-free histopathology images. We compare the prediction accuracy of prostate cancer recurrence using our algorithm-generated features with that of diagnosis by expert pathologists using established criteria on 13,188 whole-mount pathology images consisting of over 86 billion image patches. Our method not only reveals findings established by humans but also features that have not been recognized, showing higher accuracy than human in prognostic prediction. Combining both our algorithm-generated features and human-established criteria predicts the recurrence more accurately than using either method alone. We confirm robustness of our method using external validation datasets including 2276 pathology images. This study opens up fields of machine learning analysis for discovering uncharted knowledge.

Regulatory T cells (Tregs) play an important role in creating an immunosuppressive microenvironment in cancer tissues. However, the mechanisms by which Tregs are activated and suppress cancer immunity remain unclear. To elucidate these mechanisms, we performed a T cell receptor (TCR) repertoire analysis of Tregs and conventional T cells in peripheral blood, draining lymph nodes (DLNs), and cancer tissues of patients with head and neck squamous cell cancer (HNSCC). We found that the TCR repertoire was skewed in cancer tissue and metastatic DLNs (M‐DLNs) compared with non‐metastatic DLNs, and TCR repertoire similarities in Tregs and CD8+ T cells between M‐DLNs and cancer tissue were high compared with those at other sites. These results suggest that Tregs and CD8+ T cells are activated in M‐DLNs and cancer tissues by cancer antigens, such as neoantigens, and shared antigens and Tregs suppress CD8+ T cell function in a cancer antigen‐specific manner in M‐DLNs and cancer tissue. Moreover, M‐DLNs might be a source of Tregs and CD8+ T cells recruited into the cancer tissue. Therefore, targeting Tregs in M‐DLNs in an antigen‐specific manner is expected to be a novel immunotherapeutic strategy for HNSCCs. [ABSTRACT FROM AUTHOR]

Aim: The spread of lung adenocarcinoma cells into the bronchi and bronchioles is not well documented. We termed this histological finding "endobronchial spreading of adenocarcinoma" (EBSA) and investigated its prevalence and clinical significance. Methods and Results: We reviewed 320 resected specimens from patients diagnosed with invasive adenocarcinoma, and EBSA was observed in 144 patients (45%). EBSA was significantly associated with advanced pathological stage, higher histological grade, larger tumour invasion, lymphovascular infiltration, and spread through air spaces. Patients with EBSA had significantly shorter relapse‐free survival (RFS) and cancer‐specific survival (CSS) in univariate analysis (P < 0.001). In a subgroup analysis of patient with small‐sized (invasion size ≤30 mm) adenocarcinoma in the localized stage, EBSA was an independent inferior prognostic indicator in multivariate analysis. In a subgroup analysis of patients with small‐sized Grade 1 nonmucinous adenocarcinoma (n = 61), EBSA was observed in 11 patients, and the presence of EBSA was associated with significantly shorter RFS and CSS (P = 0.026 and P = 0.001, respectively). Conclusion: Our results demonstrated that EBSA is a significant risk factor for disease recurrence and cancer‐related deaths. EBSA can be regarded as a distinctive pattern of invasion and its recognition can be beneficial in the diagnosis of lung adenocarcinoma. [ABSTRACT FROM AUTHOR]

Clinical and genomic features of prostate cancer (PCa) vary considerably between Asian and Western populations. PTEN loss is the most frequent abnormality in intraductal carcinoma of the prostate (IDC‐P) in Western populations. However, its prevalence and significance in Asian populations have not yet been well studied. In the present study, we evaluated PTEN expression in IDC‐P in a Japanese population and its association with ERG expression. This study included 45 and 59 patients with PCa with and without IDC‐P, respectively, who underwent radical prostatectomy. PTEN loss was observed in 10 patients with PCa with IDC‐P (22%) and nine patients with PCa without IDC‐P (17%). ERG expression was relatively frequent in patients with PCa with PTEN loss, although a significant difference was not observed. The co‐occurrence of PTEN loss and ERG expression was observed in four patients with PCa with IDC‐P and one without IDC‐P. PTEN loss and ERG expression did not affect progression‐free survival, regardless of the presence of IDC‐P. The frequency of PTEN loss in IDC‐P is lower in Asian patients than in Western patients. Our results indicate that mechanisms underlying IDC‐P in Asian populations are different from those of Western populations. [ABSTRACT FROM AUTHOR]

Neck dissection for cervical lymph node metastasis is an established procedure for head and neck cancer (HNC). However, with the advent of immunotherapy, head and neck surgical oncologists need to rethink removing all lymph nodes, including those with immune function. We investigated the anti-cancer immune response of the cervical lymph nodes in four patients with human papillomavirus type 16 (HPV16)-positive head and neck squamous cell carcinoma. Using lymphocytes extracted from local, metastatic, and non-metastatic lymph nodes and peripheral blood from these patients, we performed an intracellular flow cytometric cytokine assay using anti-IFNγ and anti-TNF-α monoclonal antibodies to detect HPV16 E6- and E7-specific T cells. HPV status and p16 immunostaining were determined by in situ detection using the HPV RNAscope method and immunohistochemistry. In one case, E6-specific and E7-specific CD8+ T cells were detected in proximal metastatic nodes and distal non-metastatic nodes. This finding suggests that non-metastatic nodes should be preserved for their immune function during neck dissection and that the immune function of non-metastatic lymph nodes is important when administering immunotherapy. In this context, head and neck surgical oncologists treating HNC should consider the place of immunotherapy and neck dissection in the treatment of HNC. [ABSTRACT FROM AUTHOR]

Simple Summary: Diffuse large B-cell lymphoma (DLBCL) is the most common type of malignant lymphoid neoplasm and includes morphologically and molecularly heterogeneous disease subtypes. Genetic aberrations of tumor cells are strongly related to the signature of the tumor microenvironment. In this review, we summarize common genetic aberrations associated with immune escape, immune cell subs involved in DLBCL pathogenesis, and distinct microenvironmental signatures identified using next-generation sequencing and single-cell technologies. We also discuss the pathogenic role of immunosenescence in Epstein-Barr virus-positive DLBCL. Moreover, as DLBCL exhibits unique pathogenesis in immune-privileged sites, we also present a hypothetical model of DLBCL development in immune-privileged sites. Diffuse large B-cell lymphoma (DLBCL) is an aggressive malignancy and is the most common type of malignant lymphoid neoplasm. While some DLBCLs exhibit strong cell-autonomous survival and proliferation activity, others depend on interactions with non-malignant cells for their survival and proliferation. Recent next-generation sequencing studies have linked these interactions with the molecular classification of DLBCL. For example, germinal center B-cell-like DLBCL tends to show strong associations with follicular T cells and epigenetic regulation of immune recognition molecules, whereas activated B-cell-like DLBCL shows frequent genetic aberrations affecting the class I major histocompatibility complex. Single-cell technologies have also provided detailed information about cell–cell interactions and the cell composition of the microenvironment of DLBCL. Aging-related immunological deterioration, i.e., immunosenescence, also plays an important role in DLBCL pathogenesis, especially in Epstein-Barr virus-positive DLBCL. Moreover, DLBCL in "immune-privileged sites"—where multiple immune-modulating mechanisms exist—shows unique biological features, including frequent down-regulation of immune recognition molecules and an immune-tolerogenic tumor microenvironment. These advances in understanding the immunology of DLBCL may contribute to the development of novel therapies targeting immune systems. [ABSTRACT FROM AUTHOR]

Patients with advanced/recurrent mucoepidermoid carcinoma (MEC) have a poor prognosis. This study aimed to establish and characterize human mucoepidermoid carcinoma cell lines from the initial surgical specimen and biopsy specimen upon recurrence from the same patient to provide a resource for MEC research. MEC specimens from the initial surgical procedure and biopsy upon recurrence were used to establish cell lines. The established cell lines were cytogenetically characterized using multi-color fluorescence in situ hybridization and detection, and the sequence of the CRTC1-MAML2 chimeric gene was determined. Furthermore, the susceptibility of head and neck mucoepidermoid carcinoma to standard treatment drugs such as cisplatin, 5-fluorouracil, and cetuximab was investigated. We successfully established unique MEC cell lines, AMU-MEC1, from an initial surgical specimen and AMU-MEC1-R1 and AMU-MEC1-R2 from the recurrent biopsy specimen in the same patient. These cell lines exhibited epithelial morphology and developed in vitro-like cobblestones. They shared eight chromosomal abnormalities, including der(19)ins(19;11)(p13;?), which resulted in a chimeric CRTC1-MAML2 gene, indicating the same origin of the cell lines. The susceptibility of all cell lines to cisplatin and 5-fluorouracil was low. Interestingly, EGFR dependency for cell growth decreased in AMU-MEC-R1 and AMU-MEC-R2 but was retained in AMU-MEC1. These cytogenetic and biochemical findings suggest that the established cell lines can be used to investigate the disease progression mechanisms and develop novel therapeutics for MEC. [ABSTRACT FROM AUTHOR]

Peripheral T-cell lymphomas (PTCLs) are uncommon neoplasms derived from mature T cells or NK cells. PTCLs comprise numerous disease entities, with over 30 distinct entities listed in the latest WHO classification. They predominantly affect adults and elderly people and usually exhibit an aggressive clinical course with poor prognosis. According to their presentation, PTCLs can be divided into nodal, extranodal or cutaneous, and leukemic types. The most frequent primary sites of PTCLs are lymph nodes, with over half of cases showing nodal presentation. Nodal PTCLs include ALK-positive and ALK-negative anaplastic large cell lymphoma; nodal T-cell lymphoma with T follicular helper cell origin; and PTCL, not otherwise specified. Adult T-cell leukemia/lymphoma also frequently affects lymph nodes. Recent pathological and molecular findings in nodal PTCLs have profoundly advanced the identification of tumor signatures and the refinement of the classification. Therefore, the therapies and pathological diagnosis of nodal PTCLs are continually evolving. This paper aims to provide a summary and update of the pathological and molecular features of nodal PTCLs, which will be helpful for diagnostic practice. [ABSTRACT FROM AUTHOR]

Simple Summary: Hodgkin lymphomas (HLs) include two main types, classic HL (CHL) and nodular lymphocyte predominant HL (NLPHL). Recent molecular findings in HLs have contributed to dramatic changes in the treatment and identification of tumor characteristics. For example, PD-1/PD-L1 blockade and brentuximab vedotin, an anti-CD30 antibody bearing a cytotoxic compound, are now widely used in patients with CHL. Biological continuity between NLPHL and T-cell/histiocyte-rich large B-cell lymphoma has been highlighted. An era of novel therapeutics for HL has begun. The aim of this paper is to review the morphologic, immunophenotypic, and molecular features of CHL and NLPHL, which must be understood for the development of novel therapeutics. Hodgkin lymphomas (HLs) are lymphoid neoplasms derived from B cells and consist histologically of large neoplastic cells known as Hodgkin and Reed–Sternberg cells and abundant reactive bystander cells. HLs include two main types, classic HL (CHL) and nodular lymphocyte predominant HL (NLPHL). Recent molecular analyses have revealed that an immune evasion mechanism, particularly the PD-1/PD-L1 pathway, plays a key role in the development of CHL. Other highlighted key pathways in CHL are NF-κB and JAK/STAT. These advances have dramatically changed the treatment for CHL, particularly relapsed/refractory CHL. For example, PD-1 inhibitors are now widely used in relapsed/refractory CHL. Compared with CHL, NLPHL is more characterized by preserved B cell features. Overlapping morphological and molecular features between NLPHL and T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL) have been reported, and biological continuity between these two entities has been highlighted. Some THRLBCLs are considered to represent progression from NLPHLs. With considerable new understanding becoming available from molecular studies in HLs, therapies and classification of HLs are continually evolving. This paper offers a summary of and update on the pathological and molecular features of HLs for a better understanding of the diseases. [ABSTRACT FROM AUTHOR]

Hodgkin lymphomas (HLs) are lymphoid neoplasms that are morphologically defined as being composed of dysplastic cells, namely, Hodgkin and Reed–Sternberg cells, in a reactive inflammatory background. The biological nature of HLs has long been unclear; however, our understanding of HL-related genetics and tumor microenvironment interactions is rapidly expanding. For example, cell surface overexpression of programmed cell death 1 ligand 1 (CD274/PD-L1) is now considered a defining feature of an HL subset, and targeting such immune checkpoint molecules is a promising therapeutic option. Still, HLs comprise multiple disease subtypes, and some HL features may overlap with its morphological mimics, posing challenging diagnostic and therapeutic problems. In this review, we summarize the recent advances in understanding the biology of HLs, and discuss approaches to differentiating HL and its mimics. [ABSTRACT FROM AUTHOR]

The expression of programmed death ligand-1 (PD-L1) is controlled by complex mechanisms. The elucidation of the molecular mechanisms of PD-L1 expression is important for the exploration of new insights into PD-1 blockade therapy. Detailed mechanisms of the in situ expression of PD-L1 in tissues of oral squamous cell carcinomas (OSCCs) have not yet been clarified. We examined the mechanisms of PD-L1 expression focusing on the phosphorylation of downstream molecules of epidermal growth factor (EGF) and interferon gamma (IFN-γ) signaling in vitro and in vivo by immunoblotting and multi-fluorescence immunohistochemistry (MF-IHC), respectively. The in vitro experiments demonstrated that PD-L1 expression in OSCC cell lines is upregulated by EGF via the EGF receptor (EGFR)/PI3K/AKT pathway, the EGFR/STAT1 pathway, and the EGFR/MEK/ERK pathway, and by IFN-γ via the JAK2/STAT1 pathway. MF-IHC demonstrated that STAT1 and EGFR phosphorylation was frequently shown in PD-L1-positive cases and STAT1 phosphorylation was correlated with lymphocyte infiltration and EGFR phosphorylation. Moreover, the phosphorylation pattern of the related molecules in PD-L1-positive cells differed among the cases investigated. These findings indicate that PD-L1 expression mechanisms differ depending on the tissue environment and suggest that the examination of the tissue environment and molecular alterations of cancer cells affecting PD-L1 expression make it necessary for each patient to choose the appropriate combination drugs for PD-1 blockade cancer treatment. [ABSTRACT FROM AUTHOR]

Immunotherapy with immune‐checkpoint therapy has recently been used to treat oral squamous cell carcinomas (OSCCs). However, improvements in current immunotherapy are expected because response rates are limited. Transforming growth factor‐β (TGF‐β) creates an immunosuppressive tumor microenvironment (TME) by inducing the production of regulatory T‐cells (Tregs) and cancer‐associated fibroblasts and inhibiting the function of cytotoxic T‐lymphocytes (CTLs) and natural killer cells. TGF‐β may be an important target in the development of novel cancer immunotherapies. In this study, we investigated the suppressive effect of TGF‐β on CTL function in vitro using OSCC cell lines and their specific CTLs. Moreover, TGFB1 mRNA expression and T‐cell infiltration in 25 OSCC tissues were examined by in situ hybridization and multifluorescence immunohistochemistry. We found that TGF‐β suppressed the function of antigen‐specific CTLs in the priming and effector phases in vitro. Additionally, TGF‐β inhibitor effectively restored the CTL function, and TGFB1 mRNA was primarily expressed in the tumor invasive front. Interestingly, we found a significant negative correlation between TGFB1 mRNA expression and the CD8+ T‐cell/Treg ratio and between TGFB1 mRNA expression and the Ki‐67 expression in CD8+ T‐cells, indicating that TGF‐β also suppressed the function of CTLs in situ. Our findings suggest that the regulation of TGF‐β function restores the immunosuppressive TME to active status and is important for developing new immunotherapeutic strategies, such as a combination of immune‐checkpoint inhibitors and TGF‐β inhibitors, for OSCCs. [ABSTRACT FROM AUTHOR]

Primary diffuse large B‐cell lymphoma (DLBCL) of the central nervous system (PCNS‐DLBCL) is rare. Thirty‐nine patients consecutively diagnosed as having PCNS‐DLBCL were analyzed to highlight the prognostic value of the expression of programmed cell death ligand‐1 (PD‐L1) by neoplastic cells and immune cells in the microenvironment. They were positive for CD20 in all (100%), CD5 in two (5%), CD10 in nine (23%), BCL‐2 in 27 (69%), BCL‐6 in 34 (87%), and MUM‐1 in 37 (95%). Only one case was positive for neoplastic PD‐L1, with an unexpectedly long clinical course of 92 months. The remaining 38 cases were further divided into three groups based on the percentage of PD‐L1+ cells among microenvironmental immune cells. Cutoffs of < 5%, 5–40%, and ≥ 40% successfully stratified mean prognoses with three‐year overall survival (OS) of 21%, 63%, and 100% (P = 0.009), respectively. Progression‐free survival (PFS) and OS were different between the groups with and without methotrexate (MTX)‐containing chemotherapy (P = 0.007 and P < 0.001, respectively). Multivariate analysis identified three independent adverse factors of OS: PD‐L1 negativity (< 5%) on microenvironmental immune cells (P = 0.027), deep structure involvement (P = 0.034), and performance status (PS) 2–4 (P = 0.009). The study showed that PD‐L1 expression on immune cells in the microenvironment was associated with prognosis among patients with PCNS‐DLBCL. [ABSTRACT FROM AUTHOR]

Objective. Cholesteatoma is a clinically heterogeneous disease, with some patients showing spontaneous regression, while others experiencing an aggressive, lethal disease. Cholesteatoma in children can be divided into two types: congenital and acquired. Identifying good prognostic markers is needed to help select patients who will require immediate surgical intervention. Matrix metalloproteinase-2 (MMP2) was previously reported to play an important role in cholesteatoma progression, by promoting bone destruction and keratinocyte infiltration. Herein, we analyzed MMP2 mRNA expression level in cholesteatoma using RNA-in situ hybridization in formalin-fixed, paraffin-embedded (FFPE) tissue samples. Methods. Sixty patients with cholesteatoma under 15 years old, who underwent their primary surgery at Aichi Medical University's Otolaryngology Department, were analyzed for MMP2 expression level, using RNA-in situ hybridization. Results. There were no significant differences in MMP2 mRNA expression level between congenital cholesteatoma and acquired cholesteatomas. In congenital cholesteatoma, higher MMP2 signals were observed in the open type than in the closed type (p < 0.001). In acquired cholesteatoma, higher MMP2 signals were observed in the pars tensa than in the pars flaccida (p < 0.001). MMP2 mRNA expression level was almost exclusively found in the fibroblasts or in the inflammatory cells in the stroma, but not in the epithelium. Conclusion. Our study reveals that MMP2 mRNA expression level is strongly associated with the subtypes of cholesteatoma. The findings suggest that the level of expression of MMP2 mRNA may be related to the pathogenesis and aggressive features of cholesteatoma. [ABSTRACT FROM AUTHOR]

The programmed death 1 (PD1)/PD1 ligand (PD-L1) axis plays an important role in the pathogenesis of Epstein-Barr virus-positive diffuse large B cell lymphoma, not otherwise specified (EBV+ DLBCL, NOS). Here, we describe PD-L1 expression by EBV+ DLBCL, NOS in order to evaluate its possible contribution to the pathogenesis of this tumor. The study included 57 cases of EBV+ DLBCL, NOS. The median patient age was 69 years and 95% (n = 54) were aged > 45. Extranodal lesions were present in 39 (69%) at initial diagnosis. PD-L1 expression (mAb SP142-positive staining) was present in more than 5% of tumor cells in only six cases (11%), in clear contrast to the 77% reported in cases aged under 45 years. Among the PD-L1+ cases, three were nodal lesions. All six PD-L1+ cases progressed in the 3 years after diagnosis and four of the six patients died of the disease within 2 years. PD-L1+ cases had significantly shorter PFS (P = 0.002) and relatively short OS (P = 0.26), compared with PD-L1- cases. EBV+ DLBCL, NOS in the elderly infrequently expressed PD-L1 and had poor prognosis. PD-L1 expression in EBV+ DLBCL, NOS of the elderly sheds light on the pathogenetic role of immune senescence. [ABSTRACT FROM AUTHOR]

Histiocytic and dendritic cell (H/DC) neoplasms are heterogeneous, originating from myeloid‐ or stromal‐derived cells. Multiple reports describe the cross‐lineage transdifferentiation of neoplastic B cells into H/DC neoplasms. Most such cases are from Western countries, and rarely from Japan or East Asia. Here we report 17 cases of H/DC neoplasms in Japanese patients, with analysis of t(14;18) by fluorescence in situ hybridization, and of neoplastic programmed death‐ligand 1 (PD‐L1) expression by immunostaining (clones SP142, E1J2J, and 28‐8). These 17 cases were diagnosed according to the 2017 World Health Organization (WHO) classification, and included two histiocytic sarcomas (HS), two interdigitating cell (IDC) sarcomas, one Langerhans cell sarcoma, two dendritic cell sarcomas, and 10 follicular dendritic cell (FDC) sarcomas. No case had any past history of follicular lymphoma (FL). Two cases of HS and one IDC sarcoma, all of which were myeloid‐driven, were found to exhibit t(14;18). In the latter case, at 30 months after IDC sarcoma diagnosis, FL development was detected. Three (30%) FDC sarcoma cases exhibited neoplastic PD‐L1 expression with all the three PD‐L1 antibody clones. This is the first report of t(14;18) and neoplastic PD‐L1 expression on H/DC neoplasms among Japanese patients, each of which appeared to be associated with HS and FDC sarcoma, respectively. [ABSTRACT FROM AUTHOR]

Recent studies of tumor microenvironments have revealed that clonal B cells reacting to tumor‐derived antigens play an important role in anti‐tumor immunity. We report a case of a 72‐year‐old Japanese man with a complaint of fever for 1 month. Computed tomography revealed a 48 mm mass in his right kidney. The patient underwent a right nephrectomy and histology revealed clear cell renal cell carcinoma (ccRCC) of Fuhrman Grade 4 with rhabdoid morphology. Focally, marked plasmacytoid cell infiltration was detected in the carcinoma. These plasmacytoid cells were immunohistochemically positive for immunoglobulin (Ig) G, and kappa light chain restriction was confirmed using mRNA in situ hybridization. Programmed death‐ligand 1 (PD‐L1) immunostaining and RNA in situ hybridization of transforming growth factor beta (TGF‐β) revealed that both PD‐L1 and TGF‐β were highly expressed in the area with clonal plasmacytoid cell infiltration. The patient developed bone metastasis 3 months after surgery, and plasmacytoma was not detected during the observation period. We identified a potential link between an immunosuppressive microenvironment and clonal B cell proliferation. The latter posed a differential diagnosis problem between reactive and neoplastic clonal B cell proliferation vis‐à‐vis a plasmacytoma complicating carcinoma. [ABSTRACT FROM AUTHOR]

Nuclear grade is one of the most important prognostic factors in clear cell renal cell carcinoma (CCRCC). Although CCRCCs usually have intratumoral heterogeneity with various nuclear atypia including nucleolar prominence, it is unclear whether a similar degree of nuclear grade component demonstrates the same proliferative activity. We aimed to reveal whether the presence of a higher nuclear grade has an effect on proliferative activity among each assigned nuclear grade in CCRCCs. We enrolled 129 CCRCC patients containing at least two different nuclear grades. We separately assessed nuclear grade using the Fuhrman and World Health Organization and International Society of Urologic Pathologists (WHO/ISUP) grading systems. In addition, we selected blocks containing different nuclear grade and assessed the Ki‐67 labeling index (LI) for each using a computer‐based analysis system. Ki‐67 LIs significantly correlated with both Fuhrman and WHO/ISUP grades (P < 0.001 and P < 0.001). Of note, the LIs among Fuhrman and WHO/ISUP grades 1 and 2 were also statistically significant according to the highest nuclear grade (P < 0.01 for both grades 1 and 2). Our data suggests that the highest nuclear grade influences the proliferative activity in tumor components regardless of the morphologically assigned nuclear grades. The exact evaluation of Ki‐67 LI in CCRCC can provide a more precise information of the malignant potential. [ABSTRACT FROM AUTHOR]

Management of advanced hormone‐naïve prostate cancer (HNPC) is a critical public health issue. Useful prognostic markers are thus needed to select patients who will benefit from recently introduced upfront therapies. p16 expression is an adverse prognostic marker in prostate cancer. The present study aimed to determine whether p16 expression would serve as an adverse prognostic marker in advanced HNPC. A total of 79 patients diagnosed by needle biopsy with adenocarcinoma Gleason score ≥8 between 2010 and 2013 at Aichi Medical University were included in this study. The median patient age was 73 (range 52–87) years. The median follow‐up was 62 months (range 2–98). Fourteen patients had p16‐positive samples. Fifteen patients died from prostate cancer, 10 of whom were in the p16‐positive group. p16 positivity was associated with clinical T stage (P < 0.001), presence of IDC‐P (P < 0.001), distant metastasis (P < 0.001) and lymph node metastasis (P < 0.001). These results indicate that p16 expression is associated with adverse prognostic factor of prostate cancer and suggest that p16 expression may provide useful information for treatment planning and identifying suitable candidates for upfront chemotherapy or androgen receptor axis‐targeted therapy. [ABSTRACT FROM AUTHOR]

Inhibitors of programmed cell‐death 1 (PD‐1) and programmed cell‐death ligand 1 (PD‐L1) have revolutionized cancer therapy. Nodal cytotoxic T‐cell lymphoma (CTL) is characterized by a poorer prognosis compared to nodal non‐CTLs. Here we investigated PD‐L1 expression in 50 nodal CTL patients, with and without EBV association (25 of each). We identified seven patients (14%) with neoplastic PD‐L1 (nPD‐L1) expression on tumor cells, including three males and four females, with a median age of 66 years. One of the seven cases was TCRαβ type, three were TCRγδ type and three were TCR‐silent type. Six of the seven cases exhibited a lethal clinical course despite multi‐agent chemotherapy, of whom four patients died within one year of diagnosis. Morphological findings were uniform, with six cases showing centroblastoid appearance. Among nPD‐L1+ cases, two of three examined had structural variations of PD‐L1 disrupting 3′‐UTR region. Notably, all of the TCRγδ‐type nodal CTL cases showed nPD‐L1 or miPD‐L1 positivity (3 and 10 cases, respectively). TCRγδ‐type cases comprised 42% of nPD‐L1+ cases (P = 0.043 vs. PD‐L1−), and 35% of miPD‐L1+ cases (P = 0.037 vs. PD‐L1−). The results indicate that PD‐L1+ nodal CTL cases, especially of the TCRγδ type, are potential candidates for anti‐PD‐1/PD‐L1 therapies. [ABSTRACT FROM AUTHOR]

Epstein–Barr virus (EBV) is prevalent among healthy individuals, and is implicated in numerous reactive and neoplastic processes in the immune system. The authors originally identified a series of senile or age‐related EBV‐associated B‐cell lymphoproliferative disorders (LPD) bearing a resemblance to immunodeficiency‐associated ones. These LPDs may be associated with immune senescence and are now incorporated into the revised 4th edition of 2017 WHO lymphoma classification as EBV‐positive (EBV+) diffuse large B‐cell lymphoma (DLBCL), not otherwise specified (NOS). These EBV+ B‐cells often have a Hodgkin/Reed‐Sternberg (HRS)‐like appearance and are shared beyond the diagnostic categories of mature B‐cell neoplasms, mature T‐cell neoplasms, classic Hodgkin lymphoma, and immunodeficiency‐associated LPD. In addition, peculiar new diseases, such as EBV+ mucocutaneous ulcer and EBV+ DLBCL affecting the young, were recognized. On the other hand, lymphoma classification is now evolving in accord with deeper understanding of the biology of programmed death ligand 1 (PD‐L1). Assessing PD‐L1 positivity by staining with the anti‐PD‐L1 monoclonal antibody SP142 provides new insight by discriminating between immune evasion and senescence or immunodeficiency. The aim of the present review is to briefly summarize the diagnostic use of immunostaining with SP142 in malignant lymphomas and/or LPDs that feature tumor and nonmalignant large B‐cells harboring EBV. [ABSTRACT FROM AUTHOR]

Background: Intravascular large B‐cell lymphoma (IVLBCL) is a rare form of diffuse large B‐cell lymphoma (DLBCL) arising in extranodal sites. PD‐L1 expression of tumor cells has been reported in IVLBCL cells, but its clinicopathological relevance remains to be elucidated. Aims: This study was aimed to reveal the characteristics of PD‐L1+ IVLBCL. Methods and results: Neoplastic PD‐L1 expression was examined in 34 cases of IVLBCL and clinicopathological characteristics between patients with PD‐L1+ and PD‐L1− IVLBCL were compared. We assessed PD‐L1 expression with SP142 antibody. Twelve (35%) of 34 cases showed positivity for PD‐L1. The PD‐L1+ group had significantly lower survival rates compared to the PD‐L1− group. The PD‐L1+ IVLBCL group also had a significantly lower age distribution and a lower frequency of patients older than 60 years compared to the PD‐L1− group. Very recently, we speculate that there is possible link between PD‐L1+ IVLBCL and PD‐L1+ extranodal DLBCL‐NOS (eDLBCL) because features of the two groups showed overlapping. Therefore, we compared the clinicopathological characteristics of the PD‐L1+ IVLBCL and PD‐L1+ eDLBCL. There were no significant differences in clinicopathological parameters and prognosis. Conclusion: The worse prognosis of the PD‐L1+ group might be caused by immune evasion mechanisms, which are linked to PD‐L1 expression. Therefore, PD‐L1+ IVLBCL cases might be regarded as good candidates for targeted immunotherapy. We also highlighted the overlapping features of PD‐L1+ IVLBCL and PD‐L1+ eDLBCL. This result suggests that they should be regarded as one entity, immune evasion‐related extranodal large B‐cell lymphoma. [ABSTRACT FROM AUTHOR]

Immune‐checkpoint inhibitors improve the survival of head and neck squamous cell carcinoma (HNSCC) patients. Although recent studies have demonstrated that the tumor immune microenvironment (TIME) has critical roles in immunotherapy, the precise mechanisms involved are unclear. Therefore, further investigations of TIME are required for the improvement of immunotherapy. The frequency of effector regulatory T‐cells (eTregs) and the expression of immune‐checkpoint molecules (ICM) on eTregs and conventional T‐cells (Tconvs) both in peripheral blood lymphocytes (PBL) and tumor‐infiltrating lymphocytes (TIL) from HNSCC patients were analyzed by flow cytometry and their distributions were evaluated by multi‐color immunofluorescence microscopy. High frequency eTreg infiltration into HNSCC tissues was observed and high expressions of CD25, FOXP3, stimulatory‐ICM (4‐1BB, ICOS, OX40 and GITR) and inhibitory‐ICM (programmed cell death‐1 [PD‐1] and cytotoxic T‐lymphocyte‐associated protein‐4 [CTLA‐4]) were found on invasive eTregs. In contrast, the expression of stimulatory‐ICM on Tconvs was low and the expression of inhibitory‐ICM was high. In addition, ICM‐ligands (programmed cell death‐1 [PD‐L1], galectin‐9 and CEACAM‐1) were frequently expressed on cancer cells. PD‐L1 and galectin‐9 were also expressed on macrophages. PD‐1+ T‐cells interacted with PD‐L1+ cancer cells or PD‐L1+ macrophages. This suggested that in TIL, eTregs are highly activated, but Tconvs are exhausted or inactivated by eTregs and immune‐checkpoint systems, and ICM and eTregs are strongly involved in the creation of an immunosuppressive environment in HNSCC tissues. These suggested eTreg targeting drugs are expected to be a combination partner with immune‐checkpoint inhibitors that will improve immunotherapy of HNSCC. [ABSTRACT FROM AUTHOR]

Objectives: We describe results of programmed death ligand 1 (PD-L1) immunohistochemical assessment in methotrexate (MTX)-associated lymphoproliferative disorders (LPDs) and highlight the characteristics of classic Hodgkin lymphoma (CHL) type MTX-LPD.Methods: Fifty cases of MTX-LPD, including CHL type (n = 9), diffuse large B-cell lymphoma type (n = 15), and polymorphic B-cell LPD (n = 21), were investigated.Results: Staining with anti-PD-L1 clone SP142 was exclusively found in CHL type (89%) but not in the others. Cases of CHL type MTX-LPD involved nodal disease and were associated with Epstein-Barr virus. They were histopathologically characterized by a vaguely nodular pattern, predominance of mononuclear cells, and strong expression of at least one pan-B-cell marker. Their clinical course was variable, with spontaneous regression in 5 patients, relapse in 2, and a fatal course in 1.Conclusions: The PD-L1 (clone SP142) workup aids the diagnostic approach to patients with MTX-LPD. CHL type MTX-LPD appears to represent a unique morphologic variant of CHL. [ABSTRACT FROM AUTHOR]

Composite lymphoma is a well‐known diagnostic entity exhibiting the synchronous occurrence of two or more distinct types of lymphomas in the same specimen. Here we report two patients, a 14‐year‐old female (Case 1) and a 45‐year‐old male (Case 2), with mediastinal composite lymphoma, comprising nodular sclerosis classic Hodgkin lymphoma (NSCHL) and primary mediastinal large B‐cell lymphoma (PMBL). Both patients had a mediastinal mass, and manifested two different histologic components in the same biopsy, one characteristic of NSCHL and the other PMBL. The NSCHL areas included Hodgkin and Reed–Sternberg (HRS) cells with typical immunophenotypic features (CD30‐positive and CD20‐negative), whereas the sheets of large tumor cells characteristic of PMBL were strongly and uniformly CD20‐positive. Interestingly, although both cases showed neoplastic PD‐L1 (nPD‐L1) positivity on the HRS cells of NSCHL, they differed regarding nPD‐L1 expression on the PMBL tumor cells. In Case 1, the nPD‐L1‐negative PMBL component was anatomically situated outside the NSCHL lesion. On the other hand, in Case 2, the nPD‐L1‐positive PMBL component was characterized by transitional or continuous areas with the NSCHL component. These findings suggested that nPD‐L1 expression may define two subtypes of PMBL that are more similar to or distinct from classic Hodgkin lymphoma. [ABSTRACT FROM AUTHOR]

Although several reports have highlighted neoplastic PD‐L1 (nPD‐L1) expression in classic Hodgkin lymphoma (CHL), some have addressed associations between its expression and detailed histopathologic features. Here we describe four cases of syncytial variant of CHL (SV‐CHL), with and without Epstein–Barr virus (EBV) association, and highlight the diagnostic utility of PD‐L1 (clone SP142) immunohistochemistry. The patients were a 61‐year‐old male, 45‐year‐old male, 85‐year‐old female, and 89‐year‐old female. All presented with cervical or axillary lymphadenopathy, which on biopsy had the established histopathologic features of SV‐CHL with a biphasic pattern of cohesive sheets of large tumor cells and typically scattered distribution of Hodgkin and Reed–Stenberg (HRS) cells. These tumor cells showed identical immunophenotypic findings for CD15, CD30, Fascin, PAX5, OCT2, BOB1 and EBV harboring, regardless of location. The exception was absent or decreased expression of nPD‐L1 from tumor cells in the confluent sheets, contrasting with HRS cell positivity in typical areas of CHL. These findings offer the first suggestion of possible downregulation of nPD‐L1 expression in association with the histopathologic progression of CHL. The results may be relevant for recognizing 'confluent' sheets in the diagnostic workup for SV‐CHL. [ABSTRACT FROM AUTHOR]

Epstein‐Barr virus (EBV)‐positive B cells have been detected in 66%‐86% of patients with angioimmunoblastic T‐cell lymphoma (AITL). However, it remains controversial whether EBV status has an impact on the survival of patients with AITL. In this study, we aimed to reevaluate the impact of EBV on the clinicopathological characteristics of AITL. In particular, we focused on the impact of EBV in younger patients with AITL. In total, 270 cases of AITL were studied. Epstein‐Barr virus‐positive B cells were detected in 191 (71%) cases (EBER+ group). Among the patients who received anthracycline‐based therapy, the EBER status did not affect the overall survival (OS) or progression‐free survival (PFS). In the younger group of AITL (≤60 years), PFS was significantly worse in the EBER− group compared to the EBER+ group (P =.0013). Furthermore, the multivariate analysis identified EBER‐negative status, thrombocytopenia, and elevated serum IgA level as significant adverse prognostic factors for PFS (P <.001, P <.001, and P =.002). Based on these findings, we constructed new prognostic model for the younger group, based on three adverse factors. We classified the patients into two risk groups: low risk (no or 1 adverse factor) and high risk (2 or 3 adverse factors). This new model for younger patients with AITL showed that both OS and PFS were significantly related to the level of risk (P <.0001). In summary, this study showed that, among younger patients with AITL, an EBER+ status significantly improved prognosis compared to an EBER− status. Our new prognostic model should be applicable to younger patients with AITL. [ABSTRACT FROM AUTHOR]

Anaplastic variant (av) of diffuse large B‐cell lymphoma (DLBCL) is morphologically defined in the 2017 World Health Organization classification, but still an enigmatic disease in its clinicopathologic distinctiveness, posing the differential diagnostic problem from gray zone lymphoma (GZL) and classic Hodgkin lymphoma (cHL). Thirty‐one cases previously diagnosed as avDLBCL were reassessed. Of these, 27 (87%) and 4 (13%) were node‐based and extranodal diseases, respectively. They were further reclassified into nodal avDLBCL (n = 18), nodal CD30+ DLBCL with T‐cell/histiocyte‐rich large B‐cell lymphoma‐like features (CD30+ DLBCL‐THRLBCL) (n = 6), GZL with features intermediate between DLBCL and cHL (n = 3) and CD30+ extranodal DLBCL, NOS (n = 4). The nodal avDLBCL cases had a sheet‐like proliferation of large cells and/or Hodgkin/Reed‐Sternberg (HRS)‐like cells in 12 (67%) notably with a sinusoidal pattern in 16 (89%). They showed an expression of CD20 and/or CD79a in all and CD30 in 15 of 18. All of them were negative for PD‐L1 on tumor cells, although HRS‐like cells showed negativity or partial loss of other B‐cell markers to varying degrees. The present study highlighted the distinctiveness of the nodal avDLBCL with sinusoidal pattern, but without neoplastic PD‐L1 expression, which provide refined diagnostic criteria for a more precise pathologic and clinical characterization of this disease. [ABSTRACT FROM AUTHOR]

Methotrexate (MTX) is currently used as first‐line anchor drug for rheumatoid arthritis (RA). Therefore, the number of MTX‐associated lymphoproliferative disorders, including Epstein–Barr virus‐positive mucocutaneous ulcer (EBVMCU), has increased. Some aspects of MTX‐associated EBVMCU (MTX‐EBVMCU), particularly clinical behavior and treatment for RA after MTX cessation, have not been well described. Herein, we report nine cases of MTX‐EBVMCU with clinical information regarding RA. Seven of nine patients showed spontaneous regression (SR) after immunosuppressive (IS) cessation. The other two required cytotoxic chemotherapy. Eventually, all achieved complete remission. No patients experienced EBVMCU relapse. Eight patients had RA flare after IS cessation. To control the RA activity, rituximab was administered to three patients. The remaining patients were treated by other agents. Regarding the RA activity, all were in the status of low disease activity or clinical remission. In conclusion, MTX‐associated EBVMCU has an indolent clinical course and SR after IS cessation can be expected. After the withdrawal of MTX, the majority of patients experience RA flare and required treatment. In our series, RA was well controlled without reinitiating MTX. Therefore, to prevent the EBVMCU relapse, it might be advisable to avoid MTX reintroduction, and rituximab might be the more preferable agent for RA treatment. [ABSTRACT FROM AUTHOR]

We identified six patients with Epstein‐Barr virus (EBV)‐negative extranodal diffuse large B‐cell lymphoma (DLBCL) and immunohistochemical expression of PD‐L1 on their tumor cells by examining 283 DLBCL cases with the PD‐L1 SP142 clone between 2015 and 2017. They consisted of two men and four women with a median age of 71 years, and were examined in an autopsy (n = 1) and biopsies from the adrenal gland (n = 2), skin (n = 1), pelvic cavity (n = 1), and kidney (n = 1). All showed a monomorphic population of large transformed B‐cells leading to diagnoses of DLBCL with two intravascular large B‐cell lymphoma (IVLBCL) and one de novo CD5+ type and were featured by an invariable immunephenotype: CD3‐, CD20+, BCL‐2+, and MUM1+. In addition, CD5 and CD10 were each detected in one case. All cases expressed PD‐L1 on >10% to >90% of tumor cells, which was confirmed with two other PD‐L1 antibodies (E1J2J and 28‐8). Three untreated patients had a rapid, lethal clinical course within 7 months after diagnosis; while, the remaining three achieved complete remission after treatment and were alive at the last follow‐up. We suggest immune evasion‐related extranodal large B‐cell lymphoma should be recognized beyond the currently identified entities of IVLBCL and de novo CD5+ DLBCL. [ABSTRACT FROM AUTHOR]

Abstract: The incidence of end‐stage renal disease has increased owing to the greater prevalence of patients with chronic kidney disease and diabetes mellitus. End‐stage renal disease is usually accompanied by acquired cystic disease and is a risk factor for renal cell carcinoma. The present review discusses the etiology of renal cell carcinoma in end‐stage renal disease patients, focusing on two unique renal cell carcinoma histological subtypes: acquired cystic disease‐associated renal cell carcinoma and clear cell papillary renal cell carcinoma. Acquired cystic disease‐associated renal cell carcinoma occurs almost exclusively in patients who underwent hemodialysis, especially long‐term (>10 years) hemodialysis. Its histology is distinctive: a cribriform or sieve‐like architecture with intra‐ or intracystic lumina; tumor cells containing abundant eosinophilic cytoplasm and large nuclei with prominent nucleoli; and most notably, calcium oxalate crystal deposition. Recognition of the crystals is critical for diagnosing acquired cystic disease‐associated renal cell carcinoma. Acquired cystic disease‐associated renal cell carcinoma typically has an indolent clinical course, except in cases with sarcomatoid components. Clear cell papillary renal cell carcinoma also has an indolent course (no cases involving metastasis have been reported to date), and its features resemble those of both clear cell renal cell carcinoma and papillary renal cell carcinoma. Unlike acquired cystic disease‐associated renal cell carcinoma, which occurs only in end‐stage renal disease patients, clear cell papillary renal cell carcinoma occurs in non‐end‐stage renal disease patients as well. Additional renal tumors in end‐stage renal disease patients include anastomosing hemangiomas. Long‐term hemodialysis worsens the prognosis of end‐stage renal disease patients with renal cell carcinoma, regardless of its original histological subtype, presumably by inducing oxidative stress and sarcomatoid transformation. [ABSTRACT FROM AUTHOR]

Aims: The programmed death 1 (PD1)/PD1 ligand (PD‐L1) axis plays an important role in tumour cells escape from immune control. PD‐L1 immunohistochemistry is a useful predictor of immunotherapy response, but is still not used widely in the diagnostic setting. Here we describe results using PD‐L1 immunohistochemistry during routine diagnostics in lymphoma. Methods and results: Ninety‐one lymphoproliferative disease cases sharing tumour and non‐malignant Hodgkin–Reed‐Sternberg (HRS)‐like cells with and without Epstein–Barr virus (EBV) association were investigated by immunohistochemistry for PD‐L1 (clone SP142). PD‐L1 expression was present in more than 5% of tumour or non‐malignant HRS‐like cells in 100% of EBV+ classical (C) Hodgkin lymphoma (HL) (n = 10) and EBV‐negative nodular sclerosis CHL (n = 8); 40% of EBV+ diffuse large B cell lymphoma, not otherwise specified (DLBCL–NOS) (n = 20); and 4% of nodal peripheral T cell lymphoma of follicular helper T cell type (PTCL‐TFH) (n = 22). In contrast, nodular lymphocyte‐predominant HL (n = 4), lymphocyte‐rich CHL (n = 6), EBV+ hyperplasia (n = 8), plasmablastic lymphoma (n = 3) and anaplastic lymphoma kinase‐negative anaplastic large cell lymphoma (n = 5) seldom exhibited PD‐L1 in their large cells. Assessing PD‐L1 positivity in tumour and non‐malignant large cells was helpful in differentiating between CHL versus nodal PTCL–TFH (P < 0.0001) or EBV+ DLBCL–NOS (P = 0.0052) and between EBV+ DLBCL–NOS versus nodal PTCL‐TFH (P = 0.0052), with PD‐L1 expression indicating the first diagnosis in each of those sets. Conclusion: Immunohistochemical evaluation of PD‐L1 expression in tumour and non‐malignant HRS‐like large cells may be useful for assessing either immune escape or immunodeficiency in their pathogenesis. [ABSTRACT FROM AUTHOR]