Prognostic Impact of the Immunoscore Based on Whole-Slide Image Analysis of CD3+ Tumor-Infiltrating Lymphocytes in Diffuse Large B-Cell Lymphoma.

An Immunoscore based on tumor-infiltrating T-cell density was validated as a prognostic factor in patients with solid tumors. However, the potential utility of the Immunoscore in predicting the prognosis of patients with diffuse large B-cell lymphoma (DLBCL) is unclear. Here, the prognostic value of an Immunoscore based on tumor-infiltrating CD3+ T-cell density was evaluated in 104 patients with DLBCL who underwent R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) therapy. Digitally scanned whole-slide images were analyzed using Aperio ImageScope software. CD3+ cell densities in the whole tumor area were quantitated using 3 different methods, including number of CD3+ cells/area (mm2), ratio of CD3+ cells to total cells, and ratio of CD3+ cells to CD20+ cells. There was a high concordance among the 3 methods. Patients with low CD3+ cell density had an elevated serum lactate dehydrogenase level and a high Ki-67 proliferation index (all, P < .05). Patients with low CD3+ cell density, according to all 3 methods, had worse overall survival (OS) and worse progression-free survival (P < .05, all). They also had poor OS, independent of MYC/BCL2 double expression (DE) status, Eastern Cooperative Oncology Group performance status, or Ann Arbor stage (all, P < .05). These results were validated using 2 publicly available data sets. In both validation cohorts, patients with low CD3E mRNA expression had an elevated serum lactate dehydrogenase level, extranodal site involvement, and DE status (P < .05). They also had worse progression-free survival (P = .067 and P = .002, respectively) and OS (both P < .05). A low CD3E mRNA level was predictive of poor OS, independent of DE status. An Immunoscore based on whole-slide image analysis of CD3+ T-cell infiltration was sufficient to predict survival in patients with DLBCL. Low CD3+ cell density was a poor prognostic factor, independent of other prognostic parameters and DE status.

Characterization of Kikuchi-Fujimoto Disease in Children and Risk Factors Associated with Its Course.

OBJECTIVE: To outline the characteristics of Kikuchi-Fujimoto disease (KFD) in children and analyze factors associated with severe and recurring courses. METHODS: Electronic medical records of children histopathologically diagnosed with KFD at Seoul National University Bundang Hospital from March 2015 to April 2021 were retrospectively reviewed. RESULTS: A total of 114 cases (62 males) were identified. The mean patient age was 12.0 ± 3.5 years. Most patients came to medical attention with cervical lymph node enlargement (97.4%) and fever (85%); 62% had a high-grade fever (≥39°C). Prolonged fever (≥14 days) was seen in 44.3% and was associated with a high-grade fever (P = .004). Splenomegaly, oral ulcer, or rash was present in 10.5%, 9.6%, and 15.8%, respectively. Laboratory findings showed leukopenia, anemia, and thrombocytopenia in 74.1%, 49%, and 24%, respectively. Sixty percent of cases had a self-limited course. Antibiotics were initially prescribed in 20%. A corticosteroid was prescribed in 40% of patients and was associated with oral ulcer (P = .045) and anemia (P = .025). Twelve patients (10.5%) had a recurrence with a median interval of 19 months. No risk factor for recurrence was identified in multivariable analysis. Clinical characteristics of KFD were similar between our current and previous studies. However, antibiotics use decreased (P < .001); nonsteroidal anti-inflammatory drugs use increased (P < .001), and, although statistically not significant, corticosteroid treatment also increased. CONCLUSIONS: Over a span of 18 years, the clinical characteristics of KFD did not change. Patients presenting with high-grade fever, oral ulcer, or anemia may benefit from corticosteroid intervention. All patients should be monitored for recurrence.

Estrogen receptor α as a predictive biomarker for survival in human papillomavirus-positive oropharyngeal squamous cell carcinoma.

BACKGROUND: Although oropharyngeal squamous cell carcinoma (OPSCC) with human papillomavirus (HPV) infection has a good prognosis, the accurate prediction of survival and risk of treatment failure is essential to design deintensification regimens. Here, we investigated estrogen receptor α (ERα) as a prognostic biomarker with therapeutic implications in OPSCC alongside factors associated with HPV infection. METHODS: We performed immunohistochemistry for ERα and p53 using formalin-fixed, paraffin-embedded tissues and assessed the HPV status using p16 immunohistochemistry and HPV DNA testing in 113 consecutive patients with OPSCC treated with surgical resection or radiotherapy/chemoradiotherapy. RESULTS: ERα expression and p53 alteration was observed in 35.4% and 21.2% OPSCCs; 45.6% and 1.3% p16+/HPV+ OPSCCs; and 11.5% and 76.9% p16- OPSCCs, respectively. These data suggest that OPSCC pathogenesis varies with HPV status. Furthermore, ERα expression was associated with improved overall survival (OS) in both HPV+ (p16+/HPV+ OPSCC) and p16+ (p16+ OPSCC irrespective of HPV status) models (p = 0.005 and p = 0.006, respectively) and with improved OS adjusted for stage (p = 0.037, hazard ratio: 0.109, 95% confidence interval 0.013-0.871) in the p16+ model. CONCLUSIONS: ERα is a potential predictive biomarker for improved survival in both HPV+ and p16+ OPSCC models.

Cluster of Lymphadenitis due to Nontuberculous Mycobacterium in Children and Adolescents 8-15 Years of Age.

BACKGROUND: Nontuberculous mycobacteria (NTM) lymphadenitis is an under-recognized entity, and data of the true burden in children are limited. Without a high index of suspicion, diagnosis may be delayed and microbiological detection is challenging. Here, we report a cluster of NTM lymphadenitis experienced in Korean children. METHODS: Subjects under 19 years of age diagnosed with NTM lymphadenitis during November 2016-April 2017 and April 2018 were included. Electronic medical records were reviewed for clinical, laboratory and pathological findings. Information regarding underlying health conditions and environmental exposure factors was obtained through interview and questionnaires. RESULTS: A total of ten subjects were diagnosed during 18 months. All subjects were 8-15 years of age, previously healthy, male and had unilateral, nontender, cervicofacial lymphadenitis for more than 3 weeks with no significant systemic symptoms and no response to empirical antibiotics. Lymph nodes involved were submandibular (n = 8), preauricular (n = 6) and submental (n = 1). Five patients had two infected nodes and violaceous discoloration was seen in seven subjects. Biopsy specimens revealed chronic granulomatous inflammation and acid-fast bacteria culture identified Mycobacterium haemophilum in two cases and NTM polymerase chain reaction was positive in two cases. Survey revealed various common exposure sources. CONCLUSION: NTM lymphadenitis is rare but increasing in detection and it may occur in children and adolescents. Diagnosis requires high index of suspicion and communication between clinicians and the laboratory is essential for identification of NTM.

Clinicopathologic implications of TNFAIP3/A20 deletions in extranodal NK/T-cell lymphoma.

The A20/Tumor necrosis factor-alpha-induced protein 3 (A20/TNFAIP3) is a negative regulator of NF-κB signaling. We analyzed the clinicopathologic implications of A20 deletions in extranodal NK/T-cell lymphoma (NKTL). Fluorescence in situ hybridization analysis of the A20 gene was performed using archived formalin-fixed tissues in 49 cases of NKTL. Among the 49 NKTL patients (median age, 48 y [10-79]), stage I-II (75% [36/48]) and upper aerodigestive tract (UAT)-origin (84% [41/49]) were predominant. All A20 deletions were monoallelic and found in cases with UAT-origin, accounting for 18% (9/49) of all NKTLs and 22% (9/41) of UAT-origin. In univariate analysis, overall survival (OS) and progression-free survival (PFS) were associated with stage, international prognostic index (IPI), B symptoms and number of extranodal sites, and OS with performance status and non-UAT-origin, but none with A20 deletion. In multivariate analysis, IPI predicted OS (P = .008 [HR = 23.4]) and PFS (P = .005 [HR = 34.0]). Risk was divided by B symptoms (P = .001 [OS]; P = .034 [PFS]) in low IPI subset (n = 36), and by A20 deletion (P = .029 [PFS]) in high IPI subset (n = 13). These results suggest a clinicopathologic implication of A20 in progression of NKTL.

Clinicopathologic implication of PD-L1 and phosphorylated STAT3 expression in diffuse large B cell lymphoma.

BACKGROUND: Antitumor immune response of programmed cell death ligand (PD-L1) has shown clinical value not only in Hodgkin lymphoma and EBV-associated lymphomas but also in EBV-negative diffuse large B cell lymphoma (DLBCL) of non-germinal center B cell-like (non-GCB) subtype. Signal transducer and activator of transcription 3 (STAT3) is known to induce PD-L1 in immune cells and its activated form, phosphorylated STAT3 (pSTAT3), is also frequently expressed in non-GCB DLBCL. Herein, we investigated associations between PD-L1 expression/gene alteration, pSTAT3 expression and clinicopathologic variables in EBV-negative DLBCL. METHODS: In 107 cases of DLBCLs with non-GCB subtype (67%; 72/107), GCB subtype (25%; 27/107) and unclassifiable cases (8%; 8/107), we performed PD-L1 and pSTAT3 immunohistochemistry and fluorescence in situ hybridization for PD-L1 gene translocation and copy number gain/amplification. RESULTS: PD-L1 was expressed in tumor cells (PD-L1t) in 21% (23/107; 30% cutoff), immune cells (PD-L1i) in 36% (38/107; 20% cutoff), and pSTAT3 in tumor nuclei in 41% (44/107; 40% cutoff). PD-L1 gene alteration was observed in 10% (10/102) including translocation in 6% (6/102) and copy number gain/amplification in 4% (4/102). Non-GCB subtype was associated with PD-L1t and pSTAT3 (p = 0.006 and p = 0.042), and tended to have PD-L1 gene alteration (p = 0.058). Tumoral PD-L1 expression without gene alteration (PD-L1t+ GA-) correlated with pSTAT3-positive tumor cell proportions (%) (p = 0.033). In survival analysis, pSTAT3 expression independently predicted shorter PFS in total cohort (p = 0.017) and R-CHOP-treated group (p = 0.007), and in pSTAT3-negative R-CHOP-treated subset, PD-L1 expression in immune cells (PD-L1i) correlated with shorter PFS (p = 0.042). CONCLUSIONS: Gene alteration and protein expression of PD-L1 and pSTAT3 expression were closely related in DLBCL and constituted features of non-GCB subtype. In addition to known clinical significance of pSTAT3, immune cell expression of PD-L1 (PD-L1i) had also clinical value in pSTAT3-dependent manner. These findings may provide an insight into immunotherapeutic strategy and risk stratification in DLBCL patients.

Clinicopathologic implication of microRNA-197 in diffuse large B cell lymphoma.

BACKGROUND: Diffuse large B cell lymphoma (DLBCL) contains heterogeneous subtypes with various molecular dysregulation at the gene, protein and microRNA levels. Compared with the GCB subtype, the non-germinal center B-like (non-GCB)/activated B cell-like (ABC) subtype exhibits frequent progression despite standard immunochemotherapy. We aimed to investigate the effects of miR-197 on the progression and chemosensitivity of DLBCL with respect to the GCB and non-GCB/ABC subtypes. METHODS: To screen distinctively expressed microRNAs, microRNA expression patterns were analyzed in 10 DLBCL cases by microarray chip assays. Using quantitative real-time polymerase chain reaction (qRT-PCR), associations between miR-197 expression levels and clinicopathologic variables were investigated in 51 DLBCL tissue samples. The effects of miR-197 on doxorubicin chemosensitivity were investigated using the OCI-Ly1 and SUDHL9 cell lines. RESULTS: MicroRNA expression profiling by hierarchical clustering revealed that miR-197 was one of the distinctively expressed microRNAs in DLBCL. Quantitative analysis using qRT-PCR revealed that miR-197 levels were not correlated with clinicopathologic variables, including the international prognostic index, but low miR-197 levels were significantly associated with lymphoma progression defined by refractoriness, relapse or death in the rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP)-treated subgroup (n = 43; p = 0.004). Among the three molecular groups, i.e., the GCB, non-GCB/miR-197low and non-GCB/miR-197high groups, progression was most frequently observed in the non-GCB/miR-197low group in the full cohort (p = 0.013) and the R-CHOP cohort (p = 0.008). In survival analysis, low miR-197 levels were independently predictive of shorter progression-free survival in the R-CHOP cohort (p = 0.031; HR = 27.9) and the non-GCB subgroup (p = 0.037; HR = 21.5) but not in the GCB subgroup. Using SUDHL9 (ABC type) and OCI-Ly1 (GCB type) cells, the effects of doxorubicin on reducing cell viability were enhanced by miR-197 transfection. In apoptosis assays, miR-197 transfection enhanced doxorubicin-induced apoptosis in SUDHL9 cells but not in OCI-Ly1 cells, suggesting a chemosensitizing effect of miR-197 in ABC DLBCL. CONCLUSIONS: These results suggest the role of miR-197 as a biomarker with potential therapeutic implications.

Low expression of CD40L in tumor-free lymph node of oral cavity cancer related with poor prognosis.

BACKGROUND: Recently, the genetic alterations associated with tumor progression and impaired host immunity against transformed cells draw increased attention. Here, we characterized the differential gene expression patterns and protein expression in tumor-free lymph node from recurrent and non-recurrent tumors to identify independent prognostic markers for oral squamous cell carcinoma (OSCC). METHODS: A cDNA microarray analysis was performed to identify the differentially expressed genes in regional tumor-free lymph nodes from OSCC patients with and without recurrence. Then, the protein expression of the selected genes was analyzed by immunohistochemistry in 60 OSCC patients to determine their association with survival. RESULTS: Widespread down-regulation of genes involved in antigen processing and recognition in lymph nodes was a distinctive feature. In univariate Kaplan-Meier analysis, lower expression of CD40L and CD80 in tumor-free lymph nodes was significantly correlated with poorer survival. In multivariate Cox regression analysis, CD40L was identified as an independent prognostic marker of disease-free survival. CONCLUSION: Our data indicate that impaired host immunity (decreased CD40L expression) along with the TNM staging might be an important factor determining the prognosis of OSCC.

Clinicopathological analysis of programmed cell death 1 and programmed cell death ligand 1 expression in the tumour microenvironments of diffuse large B cell lymphomas.

AIMS: To investigate the clinicopathological characteristics of programmed cell death ligand 1 (PD-L1) and programmed cell death 1 (PD-1) expression in the tumour microenvironments of diffuse large B cell lymphoma (DLBCL). METHODS AND RESULTS: Tumour tissues from 126 DLBCL patients were immunostained for PD-L1 and PD-1. The expression of PD-L1 by tumour cells and/or tumour-infiltrating immune cells (mainly macrophages) was evaluated, and the number of tumour-infiltrating PD-1(+) cells was assessed. PD-L1 expression in tumour cells was observed in 61.1% of DLBCLs, with a weak intensity in 29.4%, moderate intensity in 21.4% and strong intensity in 10.3% of cases. Strong PD-L1 expression in tumour cells was associated significantly with the presence of B symptoms (adjusted P = 0.005) and Epstein-Barr virus (EBV) infection (adjusted P = 0.015), and tended to be higher in activated B cell-like immunophenotype (16.7%) than germinal centre B cell-like immunophenotype (2.5%) (adjusted P = 0.271). DLBCLs with PD-L1 expression in tumour cells/macrophages showed similar clinicopathological characteristics. The quantity of PD-1(+) tumour-infiltrating lymphocytes correlated positively with the level of PD-L1 expression in tumour cells (P = 0.042) or in tumour cells/macrophages (P = 0.03). Increased infiltration of PD-1(+) cells was associated with prolonged progression-free survival (P = 0.005) and overall survival (P = 0.026) in DLBCL patients treated with rituximab-cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP), whereas PD-L1 expression had no prognostic significance. CONCLUSIONS: PD-L1 and PD-1 were expressed variably in DLBCLs by tumour cells and tumour-infiltrating immune cells and might be potential therapeutic targets using PD-1/PD-L1 blockade.

MYC overexpression correlates with MYC amplification or translocation, and is associated with poor prognosis in mantle cell lymphoma.

AIMS: We aimed to investigate MYC expression and chromosomal aberration in mantle cell lymphoma (MCL), and the clinical significance of these factors. METHODS AND RESULTS: Sixty-five patients with MCL, including 54 classic, nine blastoid and two pleomorphic variants, were enrolled. Expression of MYC, Ki67 and p53 was assessed by immunohistochemistry. MYC amplification or translocation was examined by fluorescence in-situ hybridization. MYC expression was higher in blastoid/pleomorphic MCL variants (mean, 19.0%) than in classic MCL (mean, 1.9%; P < 0.001). Expression of p53 and Ki67 was also significantly higher in these variants. MYC amplification was found in two of 53 cases tested, both of which were blastoid variants with high MYC expression (29.7% and 20.4%). MYC translocation was found in two of 52 cases tested, both of which were pleomorphic variants with remarkably high MYC expression (68.5% and 71.0%). High MYC or p53 expression was significantly associated with shortened overall survival and progression-free survival in univariable and multivariable analyses (all P < 0.05). CONCLUSIONS: MYC overexpression is a negative predictor of MCL patient outcomes. MYC gene amplification or translocation might be related to the pathogenesis of MCL, particularly in blastoid/pleomorphic variants.

Diffusion-weighted imaging for evaluating lymph node eradication after neoadjuvant chemoradiation therapy in locally advanced rectal cancer.

BACKGROUND: As lymph node (LN) eradication is the prerequisite for clinical surveillance or local excision for patients who have achieved a complete response after preoperative chemoradiation therapy (CRT), the radiological evaluation of LN eradication is important. PURPOSE: To evaluate the added value of diffusion-weighted imaging (DWI) in the evaluation of LN eradication after CRT in patients with locally advanced rectal cancer (LARC). MATERIAL AND METHODS: Ninety-five consecutive patients (64 men, 31 women; mean age, 59 years; range, 32-82 years) who underwent pre- and post-CRT 1.5-T MRI with DWI (b = 0, 1000 s/mm(2)) were enrolled. To evaluate the added value of DWI in the evaluation of LN eradication after CRT, two radiologists first independently read the pre- and post-CRT T2-weighted (T2W) images and then read the combined T2W imaging set and the pre- and post-CRT DWIs with a 4-week interval. The radiologists recorded their confidence scores for LN eradication using a 5-point scale on a per-patient basis. The diagnostic performances were compared between the two reading sessions for each reader with pair-wise comparisons of receiver-operating characteristic curves. Histopathological reports served as the reference standards for LN eradication. RESULTS: The study population consisted of an LN-eradicated group (n = 66) and a non-eradicated group (n = 29). The diagnostic performances did not significantly differ between the two reading sessions for the two readers (AUCs for reader 1, 0.770 and 0.774, P = 0.8155; for reader 2, 0.794 and 0.798, P = 0.8588). CONCLUSION: Adding DWI to T2W imaging provided no additional diagnostic benefit for the evaluation of LN eradication following CRT in patients with LARC.

Targeting HIF1α peri-operatively increased post-surgery survival in a tongue cancer animal model.

BACKGROUND: The purpose of the present study was to evaluate the relationship between hypoxia-inducible factor 1 alpha subunit (HIF1α) and tumor initiation in squamous cell carcinoma cell lines and whether targeting HIF1α perioperatively might exert positive effects on survival or recurrence in an animal model. METHODS: The expression of HIF1α and tumorigenic potential in nude mice was compared using human head and neck squamous cell carcinoma cell lines (SNU1041, SNU1066, SNU1076, PCI01, PCI13, PCI50). A recurrent tongue cancer model was established by first injecting tumor cells in the lateral tongue and then excising the tongue masses for replanting in the neck. The effect of HIF1α inhibitors was assessed using this animal model. RESULTS: We observed good correlation between tumorigenic potential and HIF1α nuclear expression in the cell lines tested. Furthermore, knockdown of HIF1α inhibited tumor growth in the animal model. After in vitro testing of five HIF1α inhibitors, echinomycin and LAQ824 were selected for the animal study. Pre- and postoperative treatment with echinomycin showed significant improvement in postsurgery survival and recurrence. CONCLUSIONS: Our results suggested that adjuvant targeting of HIF1α before and after surgery could be a new targeted therapy strategy for squamous cell carcinoma.

Apparent diffusion coefficient for lymph node characterization after chemoradiation therapy for locally advanced rectal cancer.

BACKGROUND: Because further treatment plans depends on lymph node (LN) status after neoadjuvant chemoradiation therapy (CRT), the accurate characterization of LN is important. PURPOSE: To evaluate the diagnostic performance of apparent diffusion coefficient (ADC) for LN characterization after CRT and to compare the performance with that of LN size. MATERIAL AND METHODS: Fifty-three patients (36 men, 17 women; mean age, 58 years; age range, 34-79 years) who underwent CRT and subsequent surgery were included. All patients underwent 1.5-T magnetic resonance imaging (MRI). Each regional LN on post-CRT MRI was identified in consensus by two radiologists after reviewing the pre-CRT MRI. The ADC value and size in each LN was measured. To compare the mean ADC values and sizes of the metastatic and non-metastatic LNs after CRT, the t-test was used. To calculate the performance, a ROC curve analysis was performed. The histopathological examinations served as the reference standard. RESULTS: A total of 115 LNs (29 metastatic and 86 non-metastatic) were matched and analyzed. The mean ADC of the metastatic LNs was significantly higher than that of the non-metastatic LNs (1.36 ± 0.27 × 10(-3)mm(2)/s; 1.13 ± 0.23 × 10(-3)mm(2)/s, P < 0.0001). The mean size of the metastatic LNs was also significantly larger than that of the non-metastatic LNs (5.6 ± 3.1; 3.9 ± 1.2, P = 0.0078). There was no significant difference between the areas under the curve of the ADC and size (0.742 [95% CI, 0.652-0.819]; 0.680 [0.586-0.764], respectively, P = 0.4090). CONCLUSION: The performance of ADC for LN characterization after CRT was comparable to that of LN size.

Overexpression of sphingosine-1-phosphate receptor 1 and phospho-signal transducer and activator of transcription 3 is associated with poor prognosis in rituximab-treated diffuse large B-cell lymphomas.

BACKGROUND: Sphingosine-1-phosphate receptor-1 (S1PR1) and signal transducer and activator of transcription-3 (STAT3) play important roles in immune responses with potential oncogenic roles. METHODS: We analyzed S1PR1/STAT3 pathway activation using immunohistochemistry in rituximab-treated diffuse large B-cell lymphomas (DLBCL; N=103). RESULTS: Nuclear expression of pSTAT3 (but not S1PR1) was associated with non-GCB phenotype (p=0.010). In univariate survival analysis, S1PR1 expression (S1PR1+) was a poor prognostic factor in total DLBCLs (p=0.018), as well as in nodal (p=0.041), high-stage (III, IV) (p=0.002), and high-international prognostic index (IPI; 3-5) (p=0.014) subgroups, while nuclear expression of pSTAT3 (pSTAT3+) was associated with poor prognosis in the low-stage (I, II) subgroup (p=0.022). The S1PR1/pSTAT3 risk-categories, containing high-risk (S1PR1+), intermediate-risk (S1PR1-/pSTAT3+), and low-risk (S1PR1-/pSTAT3-), predicted overall survival (p=0.010). This prognostication tended to be valid in each stage (p=0.059 in low-stage; p=0.006 in high-stage) and each IPI subgroups (p=0.055 [low-IPI]; p=0.034 [high-IPI]). S1PR1 alone and S1PR1/pSTAT3 risk-category were significant independent prognostic indicators in multivariate analyses incorporating IPI and B symptoms (S1PR1 [p=0.005; HR=3.0]; S1PR1/pSTAT3 risk-category [p=0.019: overall; p=0.024, HR=2.7 for S1PR1-/pSTAT3+ vs. S1PR1+; p=0.021, HR=3.8 for S1PR1-/pSTAT3- vs. S1PR1+]). CONCLUSIONS: Therefore, S1PR1 and S1PR1/pSTAT3 risk-category may contribute to risk stratification in rituximab-treated DLBCLs, and S1PR1 and STAT3 might be therapeutic targets for DLBCL.

Long-term prognosis of clinically early IgA nephropathy is not always favorable.

BACKGROUND: The long-term prognosis of clinically early IgA nephropathy (IgAN) patients remains to be clarified. We investigated the long-term outcomes of IgAN patients with an apparently benign presentation and evaluated prognostic factors for renal survival. METHODS: We included patients with biopsy-proven IgAN who had estimated glomerular filtration rates (eGFR) ≥ 60 mL/min/1.73 m2, normal blood pressure, and proteinuria <0.5 g/day at the time of biopsy. The primary outcome was progression to end-stage renal disease (ESRD). The secondary outcome was a 50% increase in serum creatinine level or an increase in proteinuria to >1 g/day. RESULTS: The analysis included 153 patients who met the inclusion criteria. At diagnosis, their median systolic blood pressure was 120 (110-130) mmHg, eGFR was 85.9 (74.9-100.1) mL/min/1.73 m2, and proteinuria was 0.25 (0.13-0.38) g/day. Of these, 4 patients died and 6 reached ESRD. The 30-year renal survival rate was 85.5%. Three patients had increased serum creatinine levels and 11 developed proteinuria. Remission was observed in 35 (22.9%) patients. A moderate or severe degree of interstitial fibrosis (adjusted odd ratio [OR] 5.93, 95% confidence interval [CI] 1.44-24.45, P=0.014) and hypoalbuminemia (adjusted OR 6.18, 95% CI 1.20-31.79, P=0.029) were independent predictors of the secondary outcome. CONCLUSIONS: This study showed that the prognosis of early IgAN was not always favorable, even resulting in progression to ESRD in some cases. Hypoalbuminemia and interstitial fibrosis should also be considered important prognostic factors in clinically early IgAN patients.

Transformation of t(14;18)-negative follicular lymphoma to plasmablastic lymphoma: a case report with analysis of genetic evolution.

BACKGROUND: Follicular lymphoma (FL) is characterized by t(14;18)(q32;q21) involving the IGH and BCL2 genes. However, 10-15% of FLs lack the BCL2 rearrangement. These BCL2-rearrangement-negative FLs are clinically, pathologically, and genetically heterogeneous. The biological behavior and histological transformation of such FLs are not adequately characterized. Here, we report the first case of t(14;18)-negative FL that rapidly progressed to plasmablastic lymphoma (PBL). CASE PRESENTATION: A previously healthy 51-year-old man presented with leg swelling. Computed tomography (CT) showed enlarged lymph nodes (LNs) throughout the body, including both inguinal areas. Needle biopsy of an inguinal LN suggested low-grade B-cell non-Hodgkin lymphoma. Excisional biopsy of a neck LN showed proliferation of centrocytic and centroblastic cells with follicular and diffuse growth patterns. Immunohistochemical analysis showed that the cells were positive for CD20, BCL6, CD10, and CD23. BCL2 staining was negative in the follicles and weak to moderately positive in the interfollicular areas. BCL2 fluorescence in situ hybridization result was negative. Targeted next-generation sequencing (NGS) revealed mutations in the TNFRSF14, CREBBP, STAT6, BCL6, CD79B, CD79A, and KLHL6 genes, without evidence of BCL2 or BCL6 rearrangement. The pathologic and genetic features were consistent with t(14;18)-negative FL. Two months after one cycle of bendamustine and rituximab chemotherapy, the patient developed left flank pain. Positron emission tomography/CT showed new development of a large hypermetabolic mass in the retroperitoneum. Needle biopsy of the retroperitoneal mass demonstrated diffuse proliferation of large plasmablastic cells, which were negative for the B-cell markers, BCL2, BCL6, and CD10; they were positive for MUM-1, CD138, CD38, and C-MYC. The pathologic findings were consistent with PBL. The clonal relationship between the initial FL and subsequent PBL was analyzed via targeted NGS. The tumors shared the same CREBBP, STAT6, BCL6, and CD79B mutations, strongly suggesting that the PBL had transformed from a FL clone. The PBL also harbored BRAF V600E mutation and IGH::MYC fusion in addition to IGH::IRF4 fusion. CONCLUSIONS: We propose that transformation or divergent clonal evolution of FL into PBL can occur when relevant genetic mutations are present. This study broadens the spectrum of histological transformation of t(14;18)-negative FL and emphasizes its biological and clinical heterogeneity.

Assessment of TP53 and CDKN2A status as predictive markers of malignant transformation of sinonasal inverted papilloma.

The mechanism and predictive biomarkers of sinonasal inverted papilloma (IP) transformation into squamous cell carcinoma (SCC) are still unclear. We investigated the genetic mutations involved and the predictive biomarkers. Fourteen patients with SCC arising from IP and six patients with IPs without malignant transformation (sIP) were included. DNA was extracted separately from areas of normal tissue, IP, dysplasia, and SCC. Whole exome sequencing and immunohistochemistry was performed. Major oncogenic mutations were observed in the progression from IP to SCC. The most frequently mutated genes were TP53 (39%) and CDKN2A (27%). Mutations in TP53 and/or CDKN2A were observed in three of six IPs with malignant transformation (cIP); none were observed in sIPs. Tumor mutational burden (TMB) increased from IP to SCC (0.64/Mb, 1.11/Mb, and 1.25 for IP, dysplasia, and SCC, respectively). TMB was higher in the cIPs than in the sIPs (0.64/Mb vs 0.3/Mb). Three cIPs showed a diffuse strong or null pattern in p53, and one showed a total loss of p16, a distinct pattern from sIPs. Our result suggests that TP53 and CDKN2A status can be predictive markers of malignant transformation of IP. Furthermore, immunohistochemistry of p53 and p16 expression can be surrogate markers for TP53 and CDKN2A status.

Discordance between anaplastic lymphoma kinase status in primary non-small-cell lung cancers and their corresponding metastases.

AIMS: The anaplastic lymphoma kinase gene (ALK) has attracted considerable attention as a potential molecular target in non-small-cell lung cancer (NSCLC). However, it is unclear whether ALK alterations are acquired during the metastatic progression of NSCLC. METHODS AND RESULTS: ALK status and ALK expression were evaluated in a series of 67 primary NSCLCs and their corresponding metastatic lesions using fluorescence in-situ hybridization and immunohistochemistry. ALK rearrangement was detected in 7.5% (5/67) of the primary tumours and in 9.0% (6/67) of the metastases (P < 0.001). ALK copy number gain (CNG) was detected in 1.5% (1/67) of the primary tumours and in 35.8% (24/67) of the metastases. Whereas ALK rearrangement was detected only in adenocarcinomas, CNG was identified in various histological subtypes of NSCLC. ALK expression was detected in 11.9% (8/67) of the primary tumours and in 25.4% (17/67) of the metastatic lesions. CONCLUSIONS: ALK alteration and ALK expression can be acquired during metastatic progression in NSCLC, and ALK CNG is associated with ALK expression.