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The main purpose of surgery for cervical lymphoma is only for tissue sampling. To establish a patient-friendly diagnostic approach, we investigated the feasibility of ultrasound-guided core biopsy with flow cytometry in the patients with suspected cervical lymphoma.We prospectively recruited patients with suspected cervical lymphoma from Nov 2017 till Jan 2021 in a referral medical center and performed retrospective interpretation of the prospectively acquired data. Ultrasound-guided core biopsy as the tissue sampling approach for the targeted lesions was performed in all patients. The ultrasound-guided core biopsy samples were analyzed by immunohistochemical stains and flow cytometry. The sample quality and the rate of definite and decisive diagnosis obtained by ultrasound-guided core biopsy alone and ultrasound-guided core biopsy with flow cytometry were evaluated.Total 81 consecutive patients were recruited for analysis. All ultrasound-guided core biopsy samples were qualified for analysis of pathology and flow cytometry. Pathologically, the diagnoses were definite and compatible with their flow cytometry results in 70 patients (86.42%). Either newly-diagnosed or recurrent cervical lymphoma/lymphoproliferative disorders with histologic transformation could be diagnosed by ultrasound-guided core biopsy with flow cytometry. Nine of the 11 patients with pathologically indefinite diagnosis became clinically decisive when flow cytometry was incorporated into the process, which improved the rate of decisive diagnosis to 98.77% (Odds ratio [95% CI]: 6.21 [1.28, 58.96]).Ultrasound-guided core biopsy combined with flow cytometry is suggested to serve as the first-line and patient-friendly diagnostic approach for the patients with suspected cervical lymphoma.

Supplementary Data from Identification and Targeting of the Developmental Blockade in Extranodal Natural Killer/T-cell Lymphoma

Supplementary Figure from Identification and Targeting of the Developmental Blockade in Extranodal Natural Killer/T-cell Lymphoma

Extranodal natural killer/T-cell lymphoma (ENKTL) is an aggressive, rare lymphoma of natural killer (NK) cell origin with poor clinical outcomes. Here we used phenotypic and molecular profiling, including epigenetic analyses, to investigate how ENKTL ontogeny relates to normal NK-cell development. We demonstrate that neoplastic NK cells are stably, but reversibly, arrested at earlier stages of NK-cell maturation. Genes downregulated in the most epigenetic immature tumors were associated with polycomb silencing along with genomic gain and overexpression of EZH2. ENKTL cells exhibited genome-wide DNA hypermethylation. Tumor-specific DNA methylation gains were associated with polycomb-marked regions, involving extensive gene silencing and loss of transcription factor binding. To investigate therapeutic targeting, we treated novel patient-derived xenograft (PDX) models of ENKTL with the DNA hypomethylating agent, 5-azacytidine. Treatment led to reexpression of NK-cell developmental genes, phenotypic NK-cell differentiation, and prolongation of survival. These studies lay the foundation for epigenetic-directed therapy in ENKTL.Significance:Through epigenetic and transcriptomic analyses of ENKTL, a rare, aggressive malignancy, along with normal NK-cell developmental intermediates, we identified that extreme DNA hypermethylation targets genes required for NK-cell development. Disrupting this epigenetic blockade in novel PDX models led to ENKTL differentiation and improved survival.This article is highlighted in the In This Issue feature, p. 85

S100A8/A9 is a proinflammatory protein and plays an essential role in the pathogenesis of myelodysplastic syndromes (MDS) via the S100A8/A9-Toll-like receptors axis. While S100A8/A9 levels have been used as biomarkers in many inflammatory diseases, their clinical relevance has not been conclusively resolved in MDS. To address this, we used an enzyme-linked immunosorbent assay to quantify S100A8/A9 heterodimers in bone marrow (BM) plasma from 215 MDS patients and compared S100A8/A9 levels across patients with various disease risks and genotypes. S100A8/A9 levels correlated with ASXL1 variant allele frequencies significantly. Moreover, mutant ASXL1 with concurrent RUNX1, STAG2, ZRSR2, or EZH2 mutations was associated with higher S100A8/A9 levels. We further showed that higher S100A8/A9 independently predicted inferior leukemia-free survival and overall survival in MDS patients, irrespective of age, Revised International Prognostic Scoring System subgroups, and known detrimental mutations. Lastly, through deep-sequenced transcriptomic analysis, we demonstrated that higher S100A8/A9 in the BM intimated a perturbed microenvironment with enhanced myeloid-derived suppressor cell-mediated tumor immune escape signal, altered metabolism, and impairment in the functions and quantities of CD8+ T cells and NK cells. S100A8/A9 in the BM microenvironment may be a potential biomarker in the prognostication of MDS and target for novel therapy.

Isolated primary neurolymphomatosis is a rare manifestation of lymphoma, which is challenging to diagnose as there is only involvement of the nervous system, and nerve biopsy is not frequently pursued due to the high risk of irreversible complications.We present a case of isolated primary neurolymphomatosis of diffuse large B-cell lymphoma restricted to only the right brachial plexus and right axillary nerve. The clinical course has been indolent for several years. The initial examination, including MRI and the cerebrospinal fluid study, did not yield any evidence of malignancy. Eventually, due to the patient's symptom progression and the follow-up imaging findings, we conducted a partial nerve biopsy of the brachial plexus to confirm the malignancy. His neurological symptoms did not further deteriorate post-biopsy.Isolated primary neurolymphomatosis with an indolent course is rare and challenging to diagnose. Serial MRI and fluorodeoxyglucose-positron emission tomography reveal clues for tumor involvement. Partial nerve biopsy or targeted fascicular nerve biopsy could be an alternative for achieving a pathologic diagnosis.

The increased expression of programmed death-ligands 1 and 2 (PD-L1 and PD-L2, respectively) on tumour cells contributes to immune evasion, suggesting that these proteins are attractive therapeutic targets. This study aimed to evaluate the validity of cerebrospinal fluid (CSF) soluble PD-L1 (sPD-L1) and soluble PD-L2 (sPD-L2) as biomarkers for primary central nervous system lymphoma (PCNSL). We determined the CSF concentrations of sPD-L1 and sPD-L2 in 46 patients with PCNSL using enzyme-linked immunosorbent assays (ELISAs). A control group comprised 153 patients with other brain tumours, inflammatory/infectious status, or neurodegenerative diseases. Only CSF sPD-L1 levels were significantly higher in patients with PCNSL relative to the controls. CSF sPD-L1 also exhibited superior overall discrimination performance compared to CSF sPD-L2 in diagnosing PCNSL. Compared with patients with PCNSL with low CSF sPD-L1 levels, more patients with high levels had high serum lactate dehydrogenase levels, leptomeningeal involvement, and deep-brain involvement. Furthermore, CSF sPD-L1 could predict poor survival in PCNSL but CSF sPD-L2 could not. Intriguingly, CSF sPD-L1 levels were correlated with disease status and their dynamic changes post treatment could predict time to relapse. In conclusion, this study identified CSF sPD-L1 as a promising prognostic biomarker, indicating a therapeutic potential of PD-L1 blockade in PCNSL.

Introduction Histopathological characteristics of cytomegalovirus (CMV) lymphadenitis have been well described. Rare studies have reported the immune status and clinical features. Clinically, experts believed that CMV lymphadenitis develops in immunocompromised and immunocompetent patients. Infectious mononucleosis (IM)-like syndrome is the most well-known clinical presentation. Methods We reviewed archived CMV immunohistochemical stains on lymphoid tissues. The clinicopathological features of CMV-positive cases were studied. Results For lymph nodes, we detected CMV in 29% (5/17) allogeneic peripheral blood hematopoietic stem cell transplantation (PBSCT) recipients, 29% (4/14) post-autologous PBSCT patients, 13% (6/47) patients treated with intravenous chemotherapy, and 9% (9/96) immunocompetent patients. We detected CMV in 7% (2/24) of tonsils but not in the nasopharynx, tongue base, or spleen specimens. The patients with iatrogenic immunodeficiency ranged from 37 to 76 years old. CMV infections developed a few years after lymphoma treatment (median duration after allogeneic PBSCT, 932 days; after autologous PBSCT, 370 days; and after chemotherapy, 626 days). The most common clinical presentation was neck mass (13/25, 42%), followed by asymptomatic image finding (10/25, 40%). Positron emission tomography/computed tomography (PET/CT) scan showed increased uptake compared to the liver in all patients (11/11, 100%). Of 10 lymphoma patients, 8 (80%) had a Deauville score of 4–5; they accounted for 30% (8/27) of lymphoma patients with false-positive PET/CT scan results. All cases were self-limiting. 96% (23/25) cases had Epstein–Barr virus coinfection, and EBER-positive cells were predominantly in a few germinal centers. Conclusions Cytomegalovirus (CMV) lymphadenitis and tonsillitis were subclinical infections, not primary CMV infection with IM-like syndrome. The lymphadenopathy typically developed a few years after lymphoma treatments in the middle-aged and the elderly. The lesions mimicked lymphoma relapse in PET scans. Therefore, recognizing CMV infection in lymphoid tissues is of clinical importance. Graphic abstract

Intralymphatic spread is a rare finding and is associated with poor prognosis in diffuse large B cell lymphoma (DLBCL). Here, we report a case of relapsed DLBCL with mucosal intralymphatic spread. A 69-year-old man had been diagnosed with gastric DLBCL stage IIE at 57 years. He had a relapse with generalized lymphadenopathy and extranodal involvement at 61 years; then, second complete remission was achieved after salvage chemotherapy. He then had a second relapse with involvement of the terminal ileum, spinal cord, and left tonsil. The terminal ileum showed intralymphatic spread in the lamina propria of the intestinal villi, which was confirmed by D2–40 immunostaining. Eleven months later, another biopsy showed prominent intralymphatic spread in the mucosa of the terminal ileum. After salvage therapies, the spinal cord and tonsillar tumors resolved, but the intestinal tumors were refractory. The patient eventually died of progressive disease. In contrast to previously reported cases, the involved lymphatic vessels were observed in the mucosa, and the lymphoma cells expressed CD5 in the first colonoscopic biopsy. This rare case broadens the spectrum of intralymphatic spread in DLBCL.

Mantle cell lymphoma (MCL) is a B-cell non-Hodgkin lymphoma often with extranodal involvement at diagnosis, and yet how this feature correlates with survival awaits elucidation. To address this issue, a correlative analysis between clinical features of 127 MCL patients and their overall survival (OS) was conducted. In this cohort, the median age at MCL diagnosis was 62 years and 81% were males. Eighty-four percent of patients were Ann Arbor stage 4, and 15% were blastoid variants. In patients with gastrointestinal MCL, approximately 40% had gastric involvement. In treatment, CHOP-based induction chemotherapy was given to 61.1% of patients. One-third of patients undertook autologous stem cell transplant (SCT), and 4.7% had allogeneic SCT. The median OS was 82 months and well-stratified in MIPI risk groups. In the multivariate analysis for OS, blastoid variants and gastric involvement were both independent risk factors whereas auto-SCT had a protective effect. Overall, this study corroborated with the current understandings and international therapeutic standards for MCL. Auto-SCT associated with a better OS while allo-SCT remained an option for blastoid variants and those who failed Auto-SCT. Interestingly, patients with gastric involvement tended to have worse survival, a finding that spawns more studies to investigate the mechanism.

Extranodal natural killer/T-cell lymphoma (ENKTL) is an aggressive, rare lymphoma of natural killer (NK) cell origin with poor clinical outcomes. Here we used phenotypic and molecular profiling, including epigenetic analyses, to investigate how ENKTL ontogeny relates to normal NK-cell development. We demonstrate that neoplastic NK cells are stably, but reversibly, arrested at earlier stages of NK-cell maturation. Genes downregulated in the most epigenetic immature tumors were associated with polycomb silencing along with genomic gain and overexpression of EZH2. ENKTL cells exhibited genome-wide DNA hypermethylation. Tumor-specific DNA methylation gains were associated with polycomb-marked regions, involving extensive gene silencing and loss of transcription factor binding. To investigate therapeutic targeting, we treated novel patient-derived xenograft (PDX) models of ENKTL with the DNA hypomethylating agent, 5-azacytidine. Treatment led to reexpression of NK-cell developmental genes, phenotypic NK-cell differentiation, and prolongation of survival. These studies lay the foundation for epigenetic-directed therapy in ENKTL. Significance: Through epigenetic and transcriptomic analyses of ENKTL, a rare, aggressive malignancy, along with normal NK-cell developmental intermediates, we identified that extreme DNA hypermethylation targets genes required for NK-cell development. Disrupting this epigenetic blockade in novel PDX models led to ENKTL differentiation and improved survival. This article is highlighted in the In This Issue feature, p. 85

Context.— Bone marrow (BM) samples are obtained through aspiration and trephine biopsy. Hemophagocytic lymphohistiocytosis (HLH) has been largely studied in BM aspirate smears. Objective.— To investigate the histologic features of HLH in trephine biopsy. Design.— Patients with hemophagocytosis in BM aspirate smears were assigned to HLH (n = 127) and non-HLH (n = 203) groups. We quantified hematoxylin-eosin and CD68 immunohistochemical staining of their trephine biopsies. Results.— No significant correlation was noted in the hemophagocytosis count between aspirate smears and trephine biopsies. Compared with the non-HLH group, the HLH group had a higher hemophagocytosis count (13 versus 9 per tissue section, P = .046), lower percentage of the adipocytic area (36.7% versus 50.3%, P < .001), and higher percentage of the foamy area (19.1% versus 14.5%, P < .001). The HLH group had more histiocyte infiltrates (total histiocyte density, 9.2% versus 7.3%; P < .001) and more fat-infiltrating histiocytes (histiocyte density of the fat-associated part [HD-FA], 7.6% versus 6.2%; P < .001). We identified the following poor prognostic factors in the HLH group: age 50 years or older (median overall survival [mOS], 95 versus 499 days; P = .04), Epstein-Barr virus–positive T-cell lymphoproliferative diseases (EBV+TLPDs) (mOS, 51 versus 425 days; P < .001), hemophagocytosis count of 6 or higher per tissue section (mOS, 66 versus 435 days; P = .02), and HD-FA of 9% or greater (mOS, 61 versus 359 days; P = .02). Multivariate analysis revealed that age 50 years or older (hazard ratio [HR], 2.38; P < .001), EBV+TLPDs (HR, 2.07; P < .001), and hemophagocytosis count of 6 or higher per tissue section (HR, 2.07; P = .002) were independent prognostic factors for HLH. Conclusions.— The HLH group had higher hemophagocytic activity, higher cellularity, a more foamy appearance, more histiocyte infiltrates, and more fat-infiltrating histiocytes. High hemophagocytic activity and marked histiocyte infiltrates in the BM fat were associated with poorer prognosis.

Adult-onset immunodeficiency syndrome (AOIS) caused by anti-interferon-γ autoantibodies is an emerging disease. Affected patients present typically with systemic lymphadenopathy, fatigue, and fever. We studied 36 biopsy specimens, 31 lymph nodes, and 5 extranodal sites, of AOIS confirmed by serum autoantibody or QuantiFERON-TB Gold In-Tube assay. We describe the morphologic features and the results of ancillary studies, including special stains, immunohistochemistry, and molecular testing. The overall median age of these patients was 60.5 years (range, 41 to 83 y) with a male-to-female ratio of 20:16. All biopsy specimens showed nontuberculous mycobacterial infection, and most cases showed the following histologic features: capsular thickening with intranodal sclerosing fibrosis, irregularly distributed ill-formed granulomas or histiocytic aggregates with neutrophilic infiltration, interfollicular expansion by a polymorphic infiltrate with some Hodgkin-like cells that commonly effaces most of the nodal architecture and proliferation of high endothelial venules. In situ hybridization analysis for Epstein-Barr virus-encoded RNA showed scattered (

Objectives Distinguishing Kikuchi disease (KD) from lupus lymphadenitis (LL) histologically is nearly impossible. We applied C4d immunohistochemical (IHC) stain to develop diagnostic tools. Methods We retrospectively investigated clinicopathological features and C4d IHC staining in an LL-enriched development cohort (19 LL and 81 KD specimens), proposed risk stratification criteria and trained machine learning models, and validated them in an external cohort (2 LL and 55 KD specimens). Results Clinically, we observed that LL was associated with an older average age (33 vs 25 years; P=0.005), higher proportion of biopsy sites other than the neck [4/19 (21%) vs 1/81 (1%); P=0.004], and higher proportion of generalized lymphadenopathy compared with KD [9/16 (56%) vs 7/31 (23%); P=0.028]. Histologically, LL involved a larger tissue area than KD did (P=0.006). LL specimens exhibited more frequent interfollicular pattern [5/19 (26%) vs 3/81 (4%); P=0.001] and plasma cell infiltrates (P=0.002), and less frequent histiocytic infiltrates in the necrotic area (P=0.030). Xanthomatous infiltrates were noted in 6/19 (32%) LL specimens. Immunohistochemically, C4d endothelial staining in the necrotic area [11/17 (65%) vs 2/62 (3%); P Conclusions Integrating clinicopathological and C4d findings could distinguish LL from KD.

TO THE EDITOR: Follicular lymphoma (FL) is characterized by the t(14;18)(q32;q21) chromosomal translocation,[1][1] found in ∼85% of manifest FL (mFL) cases. The t(14;18) is also present in early precursor lesions of FL and in a significant fraction of healthy individuals.[2][2],[3][3] This

Primary cardiac lymphoma (PCL) is very rare, with the variable clinical manifestations potentially leading to a delayed diagnosis. PCL is usually detected incidentally through image studies, whereas the diagnosis can be confirmed via analysis of pericardial effusion, endomyocardial biopsy tissue, or surgical specimens. Although no standard therapy has been established for PCL, without treatment, the prognosis is grave, with the estimated overall survival being approximately 1 year.We report a difficult diagnosis and complicated case of fulminant PCL, which is the first comprehensively reported case of PCL with secondary hemophagocytosis. A man presented with progressive dyspnea for 3 weeks, and then sudden cardiac death with ventricular fibrillation occurred. After resuscitation, echocardiography revealed a thickened left ventricular wall and severe mitral regurgitation, and computed tomography showed a right atrial mass with diffuse myocardial lesions. PCL was confirmed through a pathological analysis of specimens collected during mitral valvuloplasty, which also implied extensive myocardial involvement. Bone marrow biopsy demonstrated no evidence of lymphoma involvement, but secondary hemophagocytosis was noted. Despite aggressive chemotherapy, the patient died of sepsis with multiorgan failure 26 days after the operation. Keywords: Heart neoplasms, Hemophagocytosis, Death, Sudden, Lymphoma, Cardiac

Intralymphatic spread is common in solid cancers, but has been rarely studied in lymphomas. Review of 635 extranodal specimens from 475 diffuse large B-cell lymphoma (DLBCL) patients revealed intralymphatic spread in 10 surgical resection specimens from 10 patients including 9 de novo DLBCLs and 1 Richter transformation. The prevalence in de novo DLBCL with extranodal involvements was 1.65%. The most common involved site of intralymphatic spread was the gastrointestinal tract, followed by the female genital tract and breasts. Lymphatic vessels, lined by D2-40-positive endothelial cells, were expanded by lymphoma cells, reminiscent of intravascular lymphoma or tumor emboli. None of the involved lymphatic vessels were located in the mucosa. Patients with intralymphatic spread had a trend of lower overall response rate and a trend of higher progressive disease than those without intralymphatic spread. Compared with patients without intralymphatic spread, those patients with intralymphatic spread had a shorter median overall survival (14.3 vs. 96.2 mo; P=0.004) and a shorter median progression-free survival (11.2 vs. 64.2 mo; P=0.01), respectively. Multivariate analyses showed that intralymphatic spread was an independent poor prognostic factor for overall survival (hazard ratio, 3.029; 95% confidence interval, 1.315-6.978; P=0.009), irrespective of the National Comprehensive Cancer Network-International Prognostic Index, B symptoms, and serum albumin levels. Among patients who underwent surgical resection, intralymphatic spread was still an independent prognostic factor. In conclusion, our study demonstrated extranodal intralymphatic spread in DLBCL. Inspiringly, this rare morphologic finding may serve as a new negative prognostic indicator in DLBCL with extranodal involvements.

Summary FGFR1 translocation may cause myeloid or lymphoid neoplasm but rarely systemic mastocytosis (SM). Conversely, SM is associated with myeloproliferative neoplasm (MPN) but rarely lymphoblastic lymphoma (LBL) or FGFR1 translocation. We report the first case of FGFR1 translocation in a patient with concurrent LBL, MPN, and SM. A 21-year-old male patient presented with diffuse lymphadenopathies and leukocytosis. TdT + /cytoCD3 + /CD79a weakly+ LBL was identified in the lymph node. Bone marrow had MPN, SM, and TdT + /CD79a + /cytoCD3 weakly+ LBL. The cytogenetic study, reverse-transcription polymerase chain reaction, and sequencing revealed t(8;13)(p11;q12) involving FGFR1 and ZMYM2 . Under the hyper–cyclophosphamide, vincristine, doxorubicin, and dexamethasone regimen, complete remission of LBL was achieved despite persistent MPN and SM in the bone marrow. This rare case implies FGFR1 translocation in a precursor cell capable of differentiation into mast cells and lymphoblasts, strengthening the relationship between the 2 tumors in the World Health Organization classification: myeloid and lymphoid neoplasms with FGFR1 abnormalities, and SM with an associated hematologic neoplasm.

Background & Purpose The clinical course of mantle cell lymphoma (MCL) is often inflicted with tumor recurrence even though front-line autologous stem cell transplantation (ASCT) is the current standard of care. To elucidate the mechanism of post-transplant recurrence, this study aimed to interrogate the minimal residual disease (MRD) of MCL in the autologous grafts. Materials & Methods Paired samples of 17 MCL patients' lymphoma diagnostic FFPE specimens were analyzed in parallel with their harvested autologous stem cell grafts. Extracted genomic DNA was subjected to LymphoTrackⓇ Dx IGH/IGK assay coupled with Illumina MiSeq sequencer to characterize the post-recombination immunoglobulin VDJ sequences. Positivity of MRD was defined for any identical sequences identified both in the diagnostic FFPE and in the autologous graft DNA. As the control for recombined VDJ protein motif analysis, diagnostic FFPE samples from 23 patients with diffuse large B cell lymphoma (DLBCL) were analyzed with the same platform. Results Of the 17 patients undertaking autologous stem cell harvest, 11 patients achieved complete response and 6 were in partial response before stem cell harvest. Sixteen of these actually underwent transplantation while one died of disease before transplantation. MRD was detected via next-generation sequencing (NGS) in 5 patients' autologous grafts with variable MRD loads and recombined VDJ stereotypes (Table 1). VH3-21 was the most prominent stereotype (41%), followed by VH4-59 (14%). The median somatic hypermutation rate was 0.88% (range 0 - 5.17%). Interestingly, a 46-amino-acid domain in recombined VDJ sequences, which was hydroxyl and amine group-rich, differed between MCL and DLBCL: hydrophilic amino acids were enriched in 6 positions of this domain in MCL (p1%) correlated with shorter post-ASCT PFS and OS than those without MRD (medians, 1.9 months vs 27 months (p=0.024) in Figure 1c, and 11.9 months vs 66.8 months (p=0.001) in Figure 1d, respectively). Conclusions Identification of MRD in autologous grafts by deep-sequencing VDJ recombination helped stratify MCL patients' post-ASCT outcomes. Higher MRD loads correlated with inferior post-ASCT PFS and OS. The implication of recombined VDJ stereotypes and their impact on ASCT outcomes warrants further investigation. Disclosures Ko: Roche: Honoraria.

Forming strong interpersonal relationships enables an organization or individual to achieve more favorable outcomes. The objectives of this study were to examine the frequency of interpersonal interactions among safety professionals (SPs) employed at Taiwanese universities and the factors that affected this frequency. To accomplish these objectives, we mailed questionnaires to a simple random sampling of 200 university SPs. Moreover, an interpersonal relationship scale was developed in this study; exploratory factor and internal consistency analyses revealed that the scale was valid and reliable. Results derived from the questionnaire revealed that in SP interpersonal relationships, general affairs department personnel, laboratory or internship unit supervisors, and teaching staff ranked highest in frequency of interactions. Multivariate analysis of variance results showed that establishing a safety department exerted a statistically significant effect on SP interpersonal relationships. SPs employed by universities with safety departments interacted more frequently with both internal and external relationships. Therefore, we suggest that universities without a safety department establish such a department to strengthen the labor safety and health structure, thereby benefitting SPs in fulfilling responsibilities to promote safety and health management.

Epstein-Barr virus (EBV), an oncogenic human virus, is associated with several lymphoproliferative disorders, including Burkitt lymphoma, Hodgkin disease, diffuse large B-cell lymphoma (DLBCL), and posttransplant lymphoproliferative disorder (PTLD). In vitro, EBV transforms primary B cells into lymphoblastoid cell lines (LCLs). Recently, several studies have shown that receptor tyrosine kinases (RTKs) play important roles in EBV-associated neoplasia. However, details of the involvement of RTKs in EBV-regulated B-cell neoplasia and malignancies remain largely unclear. Here, we found that erythropoietin-producing hepatocellular receptor A4 (EphA4), which belongs to the largest RTK Eph family, was downregulated in primary B cells post-EBV infection at the transcriptional and translational levels. Overexpression and knockdown experiments confirmed that EBV-encoded latent membrane protein 1 (LMP1) was responsible for this EphA4 suppression. Mechanistically, LMP1 triggered the extracellular signal-regulated kinase (ERK) pathway and promoted Sp1 to suppress EphA4 promoter activity. Functionally, overexpression of EphA4 prevented LCLs from proliferation. Pathologically, the expression of EphA4 was detected in EBV(-) tonsils but not in EBV(+) PTLD. In addition, an inverse correlation of EphA4 expression and EBV presence was verified by immunochemical staining of EBV(+) and EBV(-) DLBCL, suggesting EBV infection was associated with reduced EphA4 expression. Analysis of a public data set showed that lower EphA4 expression was correlated with a poor survival rate of DLBCL patients. Our findings provide a novel mechanism by which EphA4 can be regulated by an oncogenic LMP1 protein and explore its possible function in B cells. The results provide new insights into the role of EphA4 in EBV(+) PTLD and DLBCL.

The identification of better regimens in currently available chemotherapeutic agents is crucial for treating patients with KRAS mutant metastatic colorectal cancer (mCRC). Records of mCRC patients who received first-line oxaliplatin- based or irinotecan-based regimens were reviewed retrospectively. Clinicopathologic features and treatment outcome of patients with first-line progression-free survival (PFS) and overall survival (OS) in association with KRAS mutation status were analyzed using the Cox proportional hazard model. Between 2007 and 2010, a total of 118 mCRC patients were enrolled. Among them, 67 were males and 51 were females. In patients who received first-line oxaliplatin-based regimens, the PFS was significantly longer in KRAS mutant patients (N = 32) than that in KRAS wild-type patients (N = 51). The median PFS was 8.5 months in KRAS mutant versus 5.8 months in KRAS wild-type patients (P = .008). In contrast, in patients who received first-line irinotecan-based regimens, the PFS was shorter in KRAS mutant patients (N = 15) than that in KRAS wild-type patients (N = 20). Median PFS was 3.9 months in KRAS mutant versus 6.0 months in KRAS wild-type patients (P = .23). Median OS between KRAS mutant and wild-type patients was not significantly different in both oxaliplatin-based and irinotecan-based regimens. In multivariate analyses, KRAS mutation remains an independent predictive factor for longer PFS in first-line oxaliplatin-based regimens. In conclusion, oxaliplatin-based chemotherapy in KRAS mutant mCRC might result in longer PFS than in KRAS wild-type mCRC.

Hematopoietic stem cell transplant (HSCT) recipients have a higher risk of cervical cancer. Papanicolaou (Pap) smear is the standard tool for screening cervical cancer, but there is limited research about the cervical cytology in HSCT recipients. Here, we retrospectively included adult female patients who underwent allogeneic or autologous HSCT at National Taiwan University Hospital during 2009 to 2015 and reviewed their Pap smears before and after HSCT. There were 248 allogeneic and 131 autologous HSCT recipients in our study. In allogeneic HSCT recipients, 38.7% (96 of 248) had pre-HSCT Pap smears and 17.1% (44 of 248) had post-HSCT Pap smears. In the autologous HSCT recipients, 35.1% (46 of 131) had pre-HSCT Pap smears and 13.7% (18 of 131) had post-HSCT Pap smears. Compared with allogeneic HSCT recipients without post-HSCT Pap smears, more recipients with post-HSCT Pap smears received bone marrow-derived stem cells (18.2% versus 4.9% respectively; P = .0077) and had longer overall survival (median overall survival, not reached versus 22.1 months; P .0001). The abnormal rates of post-HSCT Pap smear were 13% (6 of 44) and 11% (2 of 18) in allogeneic and autologous recipients respectively, higher than in the general Taiwanese population (1.22%). Infections were rare in post-HSCT Pap smears. Of note, 11% (5 of 44) of post-HSCT Pap smears from allogeneic recipients showed therapy-related atypia, manifesting as enlarged hyperchromatic nuclei, vacuolated cytoplasm, and occasional tadpole-like cells. These atypical cytological features mimic precancerous lesions, but cervical biopsies and human papilloma virus tests were negative. The atypical cytological features resolved spontaneously in the subsequent follow-up Pap smears. On average, Pap smears with therapy-related atypia were sampled at day +77, significantly earlier than those without therapy-related atypia (P = .016). Therapy-related atypia was more frequent in post-HSCT Pap smears sampled within 100 days after HSCT (before day +100, 4 of 5, 80%, versus after day +100, 1 of 39, 2.56%; P = .0002). The strong temporal relationship suggests these atypical cytological changes resulted from conditioning regimen, most likely busulfan-containing chemotherapy. No therapy-related atypia were observed after total body irradiation or nonbusulfan-containing chemotherapy. In conclusion, therapy-related atypia was common in post-HSCT Pap smears sampled within 100 days after HSCT. Clinical information is critical for correct cytological diagnosis.

Yu S-C, Chen S-U, Lu W, Liu T-Y & Lin C-W (2011) Histopathology 58, 896–905 Expression of CD19 and lack of miR-223 distinguish extramedullary plasmacytoma from multiple myeloma Aims: Extramedullary plasmacytoma (EMP) and multiple myeloma (MM) are both plasma cell (PC) tumours that are usually distinguished by clinical manifestations, but not by histopathological examination alone. However, EMP may express B-cell markers, such as CD79a and CD20, and MM may express germinal centre B-cell (GCBC)-associated microRNAs, such as miR-93 and miR-181b. Down-regulation of miR-30a or up-regulation of miR-223 is associated with the transition from GCBCs into PCs or memory B-cells, respectively. We studied B-cell markers and microRNAs to establish criteria that could distinguish EMP from MM. Methods and Results: Immunostains for the B-cell markers CD19, CD20, CD79a and PAX5 were performed. Expression levels of microRNAs 30a, 93, 181b and 223 were measured by real-time reverse transcription polymerase chain reactions. 73% of EMPs expressed CD19 whereas MM cases were negative. EMP and MM had similar levels of miR-30a, miR-93, and miR-181b, but EMP lacked expression of miR-223. Conclusions: The presence of CD19 and lack of miR-223 suggested aberrant B-cell differentiation in EMP. Although the underlying mechanism for this differential expression was unclear, a CD19+/miR-223− phenotype could be used to distinguish EMP from the CD19−/miR-223+ phenotype of MM.

a Department of Nuclear Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan b Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan c Department of Surgery, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan d Department of Pathology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan e Division of Nuclear Medicine, Far Eastern Memorial Hospital, New Taipei City, Taiwan

Kikuchi-Fujimoto disease (KFD) is a self-limited disease without any need of surgical treatments. Sampling of tissue is the only invasive procedure during the clinical course. However, the standard sampling procedure with accuracy, minimal invasiveness, and esthetic maintenance has not been established yet. In this study, a retrospective review of clinical utility and pathological presentations of the ultrasound-guided core biopsy (USCB) and the open biopsy (OB) in consecutive KFD patients. From 2010 to 2012, 34 consecutive patients were enrolled. USCB was performed in 11 patients, and OB was done in 26 patients. KFD was confirmed in 82% cases by USCB. Similar pathological presentations were found both in the specimens of USCB and OB. In the three patients who had received both USCB and OB, KFD was confirmed by USCB in one case, while two by OB. Sampling errors were found both in USCB and OB. For diagnosing KFD, USCB can serve as the first-line diagnostic tool. OB can be applied only in the failed cases of USCB.

Adult T-cell leukemia/lymphoma (ATLL) is a T-cell neoplasm, associated with infection by the retrovirus human T-lymphotropic virus type 1 (HTLV-1). Central nervous system (CNS) involved by ATLL is often occurred in advanced disease, such as acute and lymphomatous variants. On the other hand, isolated CNS lymphoma is rare. We repot a 50-year-old woman who presented with multiple infiltrative brain lesions on the magnetic resonance (MR) imaging. Results of initial biopsy of brain tumor indicated CNS vasculitis. The patient received one course of high-dose methotrexate and MR imaging of brain revealed remission of infiltrative lesions. Two years later, new brain lesions were detected. Histopathologic examination of specimens via craniotomy revealed T-cell lymphoma. The patient responded poorly to subsequent chemotherapy, and salvage whole-brain irradiation was performed. Six months later, the patient had hepatosplenomegaly, hypercalcemia, and multiple lymphocytes with a cloverleaf appearance in circulation. Results of flow cytometry analysis of peripheral blood indicated ATLL and antibodies to human T-lymphotropic virus type 1 (HTLV-1) were detected. Clinicians should screen HTLV-1 infection when patients are diagnosed with peripheral T-cell lymphoma. Combined antiviral therapy and intensive chemotherapy may improve the outcomes of ATLL.

Objectives: Primary hepatic lymphoma is an uncommon cause of hepatic space-occupying lesions. Methods: We describe the case of a 73-year-old man with primary hepatic lymphoma, who presented with a low-grade fever and lower limb weakness which had progressed in the past 2 months. Results: Abdominal ultrasound and computed tomography showed multiple small hepatic tumors. Echo-guided biopsy of the hepatic tumor demonstrated primary hepatic diffuse large B cell lymphoma. Moreover, bone marrow was uninvolved, but the bone marrow smear disclosed hemophagocytosis, which is uncommon in diffuse large B cell lymphoma. Chemotherapy with bendamustine and rituximab treatment was initiated with a dramatic response: hepatic tumors markedly shrank in size shown by follow-up computed tomography and the patient returned to his normal life. Nevertheless, the response was sustained for only 8 months. Finally, the disease resisted further chemotherapy and this patient died of a severe Klebsiella pneumoniae infection. Conclusion: Chemotherapy with bendamustine and rituximab has shown a dramatic, but not durable, response in the present case with old age and multiple comorbidities.