Publications by authors named "Shuangping Guo"

41 Publications

TOPK: A new predictor of the therapeutic response to neoadjuvant chemotherapy and prognosis in triple-negative breast cancer.

Pathol Res Pract 2021 Aug 28;226:153603. Epub 2021 Aug 28.

State Key Laboratory of Cancer Biology, Department of Pathology, Xijing Hospital and School of Basic Medicine, Air Force Medical University, Xi'an, China. Electronic address:

Background: Triple-negative breast cancer (TNBC) has a high probability of relapse and poor overall survival. Neoadjuvant chemotherapy (NACT) is currently a routine treatment strategy for TNBC, but some patients do not respond well. T-LAK cell-originated protein kinase (TOPK) is highly expressed in breast cancer cells and contributes to cancer cell proliferation. The present study aimed to investigate the correlation of TOPK expression with NACT treatment response and prognosis in TNBC.

Methods: We collected 66 pairs of TNBC samples before and after NACT with docetaxel+ epirubicin+ cyclophosphamide (TEC). The Miller-Payne (MP) system was used to assess the therapeutic response to NACT in TNBC patients.

Results: Immunohistochemistry analysis showed that TNBC patients with high TOPK expression before NACT had a poor treatment response and a poor prognosis. The expression of TOPK after NACT was significantly higher than that before NACT in patients with MP grade 1-3. In contrast, patients with MP grade 4-5 had significantly lower TOPK expression after NACT than before NACT, and the expression change in Ki-67 in patients with MP grade 4-5 exhibited the same trend. Survival analysis revealed that patients with TNBC accompanied by elevated TOPK expression before NACT had a worse prognosis than those with lower TOPK expression.

Conclusion: TOPK may be a novel predictor for the therapeutic response to NACT and prognosis for patients with TNBC.
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http://dx.doi.org/10.1016/j.prp.2021.153603DOI Listing
August 2021

Identification of Jmjd3 as an Essential Epigenetic Regulator of Gene Temporal Collinear Activation for Body Axial Patterning in Mice.

Front Cell Dev Biol 2021 21;9:642931. Epub 2021 Jul 21.

Department of Otolaryngology, Tangdu Hospital, The Fourth Military Medical University, Xi'an, China.

Body axial patterning develops a rostral-to-caudal sequence and relies on the temporal colinear activation of genes. However, the underlying mechanism of gene temporal colinear activation remains largely elusive. Here, with small-molecule inhibitors and conditional gene knockout mice, we identified Jmjd3, a subunit of TrxG, as an essential regulator of temporal colinear activation of genes with its H3K27me3 demethylase activity. We demonstrated that Jmjd3 not only initiates but also maintains the temporal collinear expression of genes. However, we detected no antagonistic roles between Jmjd3 and Ezh2, a core subunit of PcG repressive complex 2, during the processes of axial skeletal patterning. Our findings provide new insights into the regulation of gene temporal collinear activation for body axial patterning in mice.
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http://dx.doi.org/10.3389/fcell.2021.642931DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8333871PMC
July 2021

Some pleomorphic adenomas of the breast share PLAG1 rearrangements with the analogous tumour of the salivary glands.

Histopathology 2021 Jul 22. Epub 2021 Jul 22.

Department of Pathology, The Basic Medicine Science and the First Affiliated Hospital of the Air Force Military Medical University, Xi'an, Shaan Xi Province, China.

Aims: Pleomorphic adenoma (PA) of the breast, and especially its malignant transformation, is extremely rare and represents a diagnostic pitfall. Molecular alterations in this entity have not been investigated. We aimed to examine the clinicopathological features of our breast PAs and perform molecular analysis.

Methods And Results: Seven cases of breast PA, including two cases of carcinoma ex PA, were analysed. PLAG1 and HMGA2 gene rearrangements were assayed by fluorescence in-situ hybridisation (FISH) and RNA sequencing (RNA-Seq), respectively. Reverse transcription-polymerase chain reaction (RT-PCR) and Sanger sequencing were used to verify RNA sequencing results. All seven cases of breast PA occurred in women. The histological features were similar to the analogous tumour in salivary glands, including a dual epithelial-myoepithelial component and negativity of oestrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) by immunohistochemistry. Of the two cases with carcinoma ex PA, one demonstrated minimal invasion and one was extensively invasive. PLAG1 rearrangements were identified in two cases (28.6%), but no rearrangements of HMG2A were found. A novel fusion product in PAs, TRPS1-PLAG1, was identified in one case. No patients had recurrence or metastasis with a follow-up period of 6-158 months.

Conclusions: Breast PA is rare, but it is an important differential diagnosis of breast pathology with the potential to develop carcinoma ex PA. We report a novel TRPS1-PLAG1 fusion gene in breast PA.
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http://dx.doi.org/10.1111/his.14461DOI Listing
July 2021

Tumor Immune Microenvironment Components and Checkpoint Molecules in Anaplastic Variant of Diffuse Large B-Cell Lymphoma.

Front Oncol 2021 16;11:638154. Epub 2021 Jun 16.

State Key Laboratory of Cancer Biology, Department of Pathology, Xijing Hospital and School of Basic Medicine, Air Force Medical University, Xi'an, China.

Background: Anaplastic diffuse large B-cell lymphoma(A-DLBCL) is a rare morphological subtype characterized by the presence of polygonal, bizarre-shaped tumor cells. Our previous research found that A-DLBCL displays many genetic alterations and biological features that differ greatly from those of ordinary DLBCL. However, the status of tumor immune microenvironment components and checkpoint molecules in A-DLBCL remains unclear.

Methods: Thirty A-DLBCL patients were enrolled to study tumor immune microenvironment components and checkpoint molecules and their associations with clinicopathological features and prognosis.

Results: Patients with A-DLBCL presented higher expression of PD-L1 (40% 10%, P=0.004) than patients with ordinary DLBCL. FISH analysis showed that extra copies of PD-L1 were more frequent in A-DLBCL cases than in ordinary DLBCL cases (23.3% 4.0%, P=0.001). The numbers of PD-1 TILs (tumor infiltrating lymphocytes) and CD8T cells were significantly lower in A-DLBCL versus ordinary DLBCL. In contrast, the numbers of GATA3 Th2 cells, FOXP3 Tregs and CD33 myeloid-derived suppressor cells (MDSCs) were significantly higher in A-DLBCL than in ordinary DLBCL. The associations between clinicopathological features and tumor immune microenvironment cell frequency were analyzed in A-DLBCL patients. Briefly, the number of PD-1 TILs was lower and the number of CD33 MDSCs was higher in patients with mutated compared to those with wild-type . The number of FOXP3 Tregs was much lower in patients with a noncomplete response (CR) to chemotherapy than in those with a complete response. The number of CD8 T cells showed a decreasing trend in patients with high International Prognostic Index (IPI) scores and in those with concurrent MYC and BCL2 and/or BCL6 abnormalities. Univariate survival analysis showed that patients with PD-L1, mPD-L1(PD-L1 nonmalignant stromal cells) or mPD-L1 status had a significantly poorer overall survival (OS) than those with PD-L1 status. An increase in the number of CD3 T cells, FOXP3 Treg cells and T-bet Th1 cells was significantly associated with prolonged OS in patients with A-DLBCL.

Conclusion: Our study suggests that A-DLBCL displays a distinct pattern of tumor immune microenvironment components and checkpoint molecules that distinguish it from ordinary DLBCL. The analysis of tumor immune microenvironment components and checkpoint molecules could help in predicting the prognosis of A-DLBCL patients and determining therapeutic strategies targeting the tumor immune microenvironment.
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http://dx.doi.org/10.3389/fonc.2021.638154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8242181PMC
June 2021

Disruption of Jmjd3/p16 Signaling Pathway Causes Bizarre Parosteal Osteochondromatous Proliferation (BPOP)-like Lesion in Mice.

J Bone Miner Res 2021 Jun 25. Epub 2021 Jun 25.

Department of Oncology, Tangdu Hospital, The Fourth Military Medical University, Xi'an, China.

Bizarre parosteal osteochondromatous proliferation (BPOP), or Nora's lesion, is a rare benign osteochondromatous lesion. At present, the molecular etiology of BPOP remains unclear. JMJD3(KDM6B) is an H3K27me3 demethylase and counteracts polycomb-mediated transcription repression. Previously, Jmjd3 was shown to be critical for bone development and osteoarthritis. Here, we report that conditional deletion of Jmjd3 in chondrogenic cells unexpectedly resulted in BPOP-like lesion in mice. Biochemical investigations revealed that Jmjd3 inhibited BPOP-like lesion through p16 . Immunohistochemistry and RT-qPCR assays indicated JMJD3 and p16 level were significantly reduced in human BPOP lesion compared with normal subjects. This was further confirmed by Jmjd3/Ink4a double-gene knockout mice experiments. Therefore, our results indicated the pathway of Jmjd3/p16 may be essential for the development of BPOP in human. © 2021 American Society for Bone and Mineral Research (ASBMR).
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http://dx.doi.org/10.1002/jbmr.4401DOI Listing
June 2021

Joint Landmark and Structure Learning for Automatic Evaluation of Developmental Dysplasia of the Hip.

IEEE J Biomed Health Inform 2021 Jun 8;PP. Epub 2021 Jun 8.

The ultrasound (US) screening of the infant hip is vital for early diagnosis of developmental dysplasia of the hip (DDH). The US diagnosis of DDH refers to measuring alpha and beta angles that quantify hip joint development. These two angles are calculated from key anatomical landmarks and structures of the hip. However, this measurement process is not trivial for sonographers and usually requires a thorough understanding of complex anatomical structures. In this study, we propose a multi-task framework to learn the relationships among landmarks and structures jointly and automatically evaluate DDH. Our multi-task networks are equipped with three novel modules. Firstly, we adopt Mask R-CNN as the basic framework to detect and segment key anatomical structures and add one landmark detection branch to form a new multi-task framework. Secondly, we propose a novel shape similarity loss to refine the incomplete anatomical structure prediction robustly and accurately. Thirdly, we further incorporate the landmark-structure consistent prior to ensure the consistency of the bony rim estimated from the segmented structure and the detected landmark. In our experiments, 1,231 US images of the infant hip from 632 patients are collected, of which 247 images from 126 patients are tested. The average errors in alpha and beta angles are 2.221 and 2.899. About 93% and 85% estimates of alpha and beta angles have errors less than 5 degrees, respectively. Experimental results demonstrate that the proposed method can accurately and robustly realize the automatic evaluation of DDH, showing great potential for clinical application.
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http://dx.doi.org/10.1109/JBHI.2021.3087494DOI Listing
June 2021

Genomic Mutation Profile of Primary Gastrointestinal Diffuse Large B-Cell Lymphoma.

Front Oncol 2021 5;11:622648. Epub 2021 Mar 5.

State Key Laboratory of Cancer Biology, Department of Pathology, Xijing Hospital and School of Basic Medicine, Fourth Military Medical University, Xi'an, China.

Primary gastrointestinal diffuse large B-cell lymphoma (GI-DLBCL) is the most common gastrointestinal lymphoma, but its genetic features are poorly understood. We performed whole-exome sequencing of 25 primary tumor samples from patients with GI-DLBCL and 23 matched normal tissue samples. Oncogenic mutations were screened, and the correlations between genetic mutations and clinicopathological characteristics were analyzed. Twenty-five patients with GI-DLBCL were enrolled in the genetic mutation analysis with a median of 184 (range 79-382) protein-altering variants per patient. We identified recurrent oncogenic mutations in GI-DLBCL, including those in , and . Compared with nodal DLBCL, GI-DLBCL exhibited an increased mutation frequency of and reduced mutation frequencies of , and . Moreover, GI-DLBCL exhibited fewer and mutations than DLBCL in the testis and central nervous system. GI-DLBCLs with , and mutations exhibited a tendency toward a high proliferation index. and mutations often occurred in tumors with early clinical staging. Our data provide a comprehensive understanding of the landscape of mutations in a small subset of GI-DLBCLs. The genetic mutation profiles of GI-DLBCL differ from those of nodal DLBCL and DLBCL in immune-privileged sites. The different mutated genes are related to the NF-κB and JAK-STAT pathways, and the different pathogenetic mechanisms leading to the development of DLBCL may be influenced by the tissue microenvironment. Differences in genetic alterations might influence the clinicopathological characteristics of GI-DLBCL.
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http://dx.doi.org/10.3389/fonc.2021.622648DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7973209PMC
March 2021

Decreased infiltration of CD4 Th1 cells indicates a good response to ursodeoxycholic acid (UDCA) in primary biliary cholangitis.

Pathol Res Pract 2021 Jan 16;217:153291. Epub 2020 Nov 16.

State Key Laboratory of Cancer Biology, Department of Pathology, Xijing Hospital and School of Basic Medicine, Fourth Military Medical University, Xi'an 710032, China. Electronic address:

Background: Primary biliary cholangitis (PBC) is characterized by nonsuppurative destructive cholangitis and is thought to be an autoimmune disorder. Currently, ursodeoxycholic acid (UDCA) is the only FDA approved first-line therapy for PBC, but up to nearly one-third of patients do not achieve a complete response to this treatment. Adaptive immune cells, including T cells and B cells, have been found in the portal tracts and the bile duct epithelium and play a role in the pathogenesis of PBC, but the importance of these cells for evaluating the therapeutic response to UDCA in PBC has not yet been studied.

Methods: In this study, we collected liver puncture biopsy specimens from 34 matched patients with PBC before and after UDCA treatment and investigated the relationship between the infiltration of adaptive immune cells and the treatment response to UDCA. The extent of immune cell infiltration was determined by immunohistochemical analysis. Responses were defined based on Paris-I criteria.

Results: After 1 year of treatment, 25/34 patients responded to UDCA treatment according to Paris-I criteria (responders), and 9/34 patients were nonresponders. Immunohistochemical analysis showed that UDCA responders exhibited significantly less CD4 T cell infiltration after UDCA treatment than before (50.4 ± 7.5/HPF vs 30.0 ± 7.9/HPF, P = 0.002). In contrast, UDCA nonresponders exhibited significantly more CD4 T cell infiltration after UDCA treatment than before (32.2 ± 8.0/HPF vs 75.0 ± 13.9/HPF, P = 0.045). Moreover, patients who exhibited a reduction in CD4 T cell infiltration after UDCA treatment had a higher response rate than those that exhibited an increase in CD4 T cell infiltration (85.7 % vs 53.8 %, P = 0.041). However, CD3 T cell, CD8 T cell, and CD20 B cell infiltration was not significantly different before and after treatment in either UDCA responders or nonresponders. Furthermore, we found that the number of infiltrating T-bet Th1 cells was much lower after UDCA treatment than before in responders (10.5 ± 5.7/HPF vs. 5.16 ± 4.0/HPF, P = 0.0214) but much higher in nonresponders after treatment than before (1.89±1.2/HPF vs. 12.3±5.4/HPF, P = 0.043). However, there was no difference in the extent of GATA3 Th2 or FOXP3 Treg infiltration before and after treatment in either UDCA responders or nonresponders.

Conclusion: Collectively, our results suggest that a decrease in the number of liver-infiltrating CD4 Th1 cells is associated with a good response of PBC patients to UDCA treatment. Immunohistochemical analysis of CD4 and T-bet in PBC liver specimens may be a potential approach for evaluating the therapeutic response to UDCA.
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http://dx.doi.org/10.1016/j.prp.2020.153291DOI Listing
January 2021

The clinicopathological and molecular features of sinusoidal large B-cell lymphoma.

Mod Pathol 2021 05 24;34(5):922-933. Epub 2020 Sep 24.

State Key Laboratory of Cancer Biology, Department of Pathology, Xijing Hospital and School of Basic Medicine, Fourth Military Medical University, Xi'an, 710032, China.

We report 17 cases of sinusoidal large B-cell lymphoma (SLBCL). Clinical, morphologic, immunophenotypic, and molecular features were detected and analyzed. All cases showed an obvious sinusoidal growth pattern, usually associated with residual atrophic lymphoid tissue. All tumors contained large pleomorphic lymphoid cells and one or more prominent nucleoli, with abundant amphophilic cytoplasms; 15/17 cases showed anaplastic morphologic features. The patient age ranged from 43 to 80 years (median 57 years), and 7 males and 10 females were included. Eleven of 15 (73.3%) patients had Ann Arbor stage III or IV disease, and 10/15 (66.6%) patients had an International Prognostic Index (IPI) score ≥3. Immunophenotypically, 16/17 (94.1%) cases displayed a nongerminal center B-cell (non-GCB) immunophenotype. Furthermore, 16/17 (94.1%) cases were positive for CD30, and p53 was expressed in 10/16 (62.5%) cases. In total, 12/14 (85.7%) cases expressed BCL2 and MYC simultaneously (double expression), and 11/14 (78.6%) cases showed PD-L1 positivity (6/11 had a PD-L1 tumor proportion score ≥50%). Cytogenetically, concurrent MYC and BCL2 and/or BCL6 abnormalities (break-apart or extra copy) were detected in 10/15 cases, and 7/13 (53.8%) cases harbored a PD-L1/L2 amplification. TP53 mutation was found in 7/13 (53.8%) cases by Sanger sequencing. Whole-exome and large-panel sequencing results revealed high mutation frequencies of TP53 (4/7), MYD88 (3/7), KMT2D (3/7), CREBBP (3/7), and PIM1 (3/7). Among the 13 patients with SLBCL treated with aggressive chemotherapy regimens, the median overall survival (OS) was 18 months, and the 2-year OS rate was 34.6%. The OS of patients with SLBCL was markedly worse than that of 35 control group patients with common diffuse large B-cell lymphoma (DLBCL) without sinusoidal features (P < 0.001). SLBCL may represent a specific type of DLBCL that has characteristic pathologic features. The cancer is aggressive in most clinical cases, and outcomes are poor. SLBCL and anaplastic DLBCL (A-DLBCL) have many overlapping clinicopathological and molecular features.
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http://dx.doi.org/10.1038/s41379-020-00685-7DOI Listing
May 2021

p63 expression is associated with high histological grade, aberrant p53 expression and TP53 mutation in HER2-positive breast carcinoma.

J Clin Pathol 2021 Oct 1;74(10):641-645. Epub 2020 Sep 1.

Department of Pathology, The Basic Medicine Science and the First Affiliated Hospital of the Air Force Military Medical University, Xi'an, China.

Aim: p63, a member of the p53 family, is a myoepithelial cell marker usually expressed in metaplastic breast carcinoma and its expression suggests a myoepithelial phenotype. However, its expression and association with clinicopathological features of human epidermal growth factor receptor 2 (HER 2)-positive breast carcinoma is poorly investigated.

Materials And Methods: Sixty-seven patients with oestrogen receptor-negative and progesterone receptor-negative, HER2-positive breast carcinoma who received anti-HER2-based neoadjuvant±adjuvant therapy was retrospectively analysed.

Results: Twenty cases were p63-positive and 47 cases were p63-negative. The clinicopathological features and tumour responses after neoadjuvant therapy and outcomes were analysed. Among HER2-positive tumours, expression of p63 was significantly associated with younger age (42.5 vs 55.9; p=0.010). Expression of p63 was also significantly associated with histological grade 3 (11/20 (55%) vs 11/47 (23.4%); p=0.012) and negatively associated with grade 2 (9/20 (45%) vs 36/47 (76.6%); p=0.012). Intriguingly, p63-positive breast carcinomas showed significant aberrant p53 expression by immunohistochemistry (16/18 (88.9%) vs 29/47 (61.7%); p=0.03) and of mutation by Sanger sequencing (15/16 (93.8%) vs 12/22 (54.5%); p=0.009). No significant difference in tumour response after anti-HER2 neoadjuvant therapy nor in survival were found between p63-positive and p63-negative breast carcinomas.

Conclusion: Expression of p63 in HER2-positive breast carcinoma is significantly associated with younger age, poor differentiation, high histological grade and aberrant expression of p53 and of mutation. HER2-positive breast carcinoma with a myoepithelial immunophenotype shows distinctive clinicopathological features representing a distinct subtype of HER2-positive breast carcinoma. Further, these findings suggest an interaction between p63 and mutant p53 in the tumorigenesis of HER2-positive breast carcinomas.
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http://dx.doi.org/10.1136/jclinpath-2020-206643DOI Listing
October 2021

Expression of RSK4, CD44 and MMP-9 is upregulated and positively correlated in metastatic ccRCC.

Diagn Pathol 2020 Mar 24;15(1):28. Epub 2020 Mar 24.

State Key Laboratory of Cancer Biology, Department of Pathology, Xijing Hospital and School of Basic Medicine, Fourth Military Medical University, Changle West Road #169, Xi'an, 710032, Shaan Xi Province, China.

Background: To investigate the expression and function of RSK4, MMP-9 and CD44 in primary clear cell renal cell carcinoma (primary ccRCC) and metastatic clear cell renal cell carcinoma (metastatic ccRCC), as well as the correlation with clinicopathological features of patients.

Method: The expression levels of RSK4, CD44 and MMP-9 in 52 primary ccRCC samples and 48 metastatic ccRCC samples were detected by immunohistochemistry, and the relationship between RSK4, CD44 and MMP-9 expression and clinicopathological features as well as prognosis of metastatic ccRCC patients was statistically analysed. Ectopic RSK4 expression in ccRCC cell lines was performed to determine its effect on cell cycle regulation, tumour invasiveness, and metastatic capability.

Results: The positive rates of RSK4, MMP-9 and CD44 expression in metastatic ccRCC tissues were 75, 68.75 and 91.7%, respectively, while the rates in primary ccRCC tissues were 44.2, 34.6 and 69.2%, respectively. Thus, the positive rates in metastatic ccRCC were higher than those in primary ccRCC (P = 0. 002; P = 0. 002; P = 0. 001). However, the expression of RSK4, CD44 and MMP-9 was unrelated to age, gender, or metastatic sites (P > 0.05) but was related to WHO/ISUP nucleolar grade (P = 0.019; P = 0.026; P = 0.049). In metastatic ccRCC, expression among the three proteins showed a positive correlation (P = 0.008). Moreover, expression between RSK4 and CD44 (P = 0.019) and MMP-9 and CD44 (P = 0.05) also showed positive correlations, whereas RSK4 and MMP-9 showed no significant correlation (P = 1.00). Molecular studies showed that overexpression of RSK4 could enhance the invasive and migratory abilities of ccRCC cell lines through the regulation of CD44 and MMP-9 expression and vice versa.

Conclusions: The overexpression of RSK4, MMP-9 and CD44 is associated with the invasion and metastasis of ccRCC, indicating that they could be potential prognostic factors and serve as new potential therapeutic targets for ccRCC.
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http://dx.doi.org/10.1186/s13000-020-00948-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7093975PMC
March 2020

Progress in triple negative breast carcinoma pathophysiology: Potential therapeutic targets.

Pathol Res Pract 2020 Apr 13;216(4):152874. Epub 2020 Feb 13.

State Key Laboratory of Tumor Biology, Department of Pathology, Xi Jing Hospital, the Fourth Military Medical University, Xi'an, Shaan Xi Province,710032, China. Electronic address:

Triple-negative breast carcinoma (TNBC) is a subtype of breast carcinoma defined by negativity for estrogen receptor (ER) or progesterone receptor (PR) by immunohistochemical analysis and negativity for human epidermal growth factor receptor (Her2) by immunohistochemistry or in situ hybridization. TNBC is clinically marked by its high aggressiveness, particularly poor outcomes including a low survival rate, and the lack of specific and effective treatments. Therefore, new potential targets for the treatment of TNBC must be identified. This review summarizes recent evidence supporting novel targets and possible therapeutic regimens in the treatment of TNBC.
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http://dx.doi.org/10.1016/j.prp.2020.152874DOI Listing
April 2020

Hormone Receptor and Human Epidermal Growth Factor Receptor 2 Detection in Invasive Breast Carcinoma: A Retrospective Study of 12,467 Patients From 19 Chinese Representative Clinical Centers.

Clin Breast Cancer 2020 02 23;20(1):e65-e74. Epub 2019 Aug 23.

Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. Electronic address:

Introduction: We evaluated the current status of hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) detection in invasive breast carcinoma (IBC) in various laboratories across China.

Materials And Methods: The Breast Pathology Study Group of the Chinese Society of Pathologists collected HR and HER2 data from 12,467 IBC cases from 19 representative clinical centers in China. The data from every center were compared with the pooled data from the other centers.

Results: The assessment of HR status showed that the overall positive estrogen receptor (ER) and progesterone receptor (PR) rates were 71.7% and 63.7% (range, 60.9%-87.9% and 43.9%-84.8%), respectively. The ER results in 3 centers and the PR results in 6 centers were outside the 99.5% confidence interval and were considered to be outliers (P < .0005). Of the 12,467 cases, 62.4% were ER/PR, 9.3% were ER/PR, 1.3% were ER/PR, and 27.0% were ER/PR. The assessment of HER2 status showed that the overall positive rate of HER2 (with a definition of immunohistochemistry [IHC] 3+ or IHC2+/ in situ hybridization-positive) was 24.7% (range, 13.7%-35.7%) in each center. Three centers were outside the 99.5% confidence interval and were considered to be outliers (P < .0005). The proportion of HER2 IHC3+ was 21.1%. The positive rates of HER2 gene amplification in IHC 0/1+, 2+, 3+ cases were 2.0%, 17.6%, and 85.9%, respectively.

Conclusions: As the largest study of HR and HER2 status in Chinese patients with IBC, the data from the present study have indicated that the overall rates of HR and HER2 were comparable to those reported in previous studies. However, the rates varied among the laboratories. Individual centers had not met the target values, and they need to improve the detection.
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http://dx.doi.org/10.1016/j.clbc.2019.07.013DOI Listing
February 2020

Genetic alterations in cell cycle regulation-associated genes may promote primary progression of gastrointestinal stromal tumors.

Lab Invest 2020 03 30;100(3):426-437. Epub 2019 Sep 30.

State Key Laboratory of Cancer Biology, Department of Pathology, Xijing Hospital and School of Basic Medicine, The Fourth Military Medical University, Xi'an, Shaan Xi, China.

Gastrointestinal stromal tumors (GISTs) are one of the most common mesenchymal tumor types and usually contain KIT or PDGFRA mutations. GISTs with concomitant low- and high-grade components are seen in clinical practice. Herein, we retrospectively analyzed the histological characteristics and immunohistochemical results of 22 GIST cases with concomitant low- and high-grade tumors. Whole-exome sequencing (WES) was performed on ten pairs of high-grade GIST specimens and matched low-grade samples. Differential oncogenes mutated only in high-grade GISTs were identified, which were confirmed by Sanger sequencing. Fluorescence in situ hybridization was employed to detect MYC copy number variation. High-grade GISTs were more likely to have lower CD34 expression and a higher Ki-67 proliferation index compared to the matched low-grade tumors. WES identified 30 differential cancer-associated genes mutated only in high-grade GISTs; Sanger sequencing confirmed ten relevant differential oncogenic mutations in nine genes (MGA, ARID1A, LATS2, MAX, PIK3CA, RB1, RPS6KB2, SDHA, and SETD2). Two patients had MGA mutations, whereas other gene mutations occurred in only one patient. Most of the differential cancer-associated genes are mainly involved in cell cycle control. MYC copy number gain was a common genetic variation. High-grade GISTs revealed more MYC copy number gains than matched low-grade tumors, and low-grade GISTs with coexisting high-grade components showed more MYC copy number gains than pure low-grade GISTs. Moreover, MYC copy number gain was positively correlated with the mitotic index and Ki-67 proliferation index. Alterations in cell cycle regulation-associated genes, such as genetic mutations and MYC copy number gain, may promote primary progression from low-grade GISTs to high-grade tumors by regulating tumor cell proliferation.
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http://dx.doi.org/10.1038/s41374-019-0322-xDOI Listing
March 2020

Lineage-negative lymphoma with a helper innate lymphoid cell phenotype.

Virchows Arch 2020 Feb 14;476(2):285-293. Epub 2019 Sep 14.

State Key Laboratory of Cancer Biology, Department of Pathology, Xijing Hospital and School of Basic Medicine, Fourth Military Medical University, Xi'an, 710032, China.

Helper innate lymphoid cells (ILCs) were recently recognized as lineage-negative lymphoid cells that do not express rearranged receptors and have important effector and regulatory functions in innate immunity. However, to our knowledge, no cases of hematological malignancies arising from helper ILCs have ever been reported in the literature. Here, we report a case of a 17-year-old man with multiple lymphadenopathy who was diagnosed with lineage-negative lymphoma that displayed a helper ILC phenotype. Histological examination showed large monomorphic atypical lymphoid cells with prominent nucleoli and abundant eosinophilic cytoplasms with scattered and patchy distributions. Large amounts of histiocytes and infiltrating lymphocytes were observed in the background. Immunostaining revealed positive LCA and CD79a expression but negative expression of all lineage markers. IG and TCR rearrangement analysis showed no clonal rearrangements. Tumor cells strongly expressed helper ILC phenotypic markers, such as CD127, IL-1R, GATA3, ST2, IL-17Rβ, and RANKL, and helper ILC-produced cytokines, such as IL-4 and GM-CSF. PD-L1/PD-L2-positive histiocytes and FOXP3-positive Tregs were observed in the tumor microenvironment. Flow cytometry of bone marrow at recurrence was positive for IL-1R and negative for T, B, NK, and myelogenous lineage markers. TP53 sequencing showed that exon 5 was replaced with an intergenic sequence of chromosome 21. Next-generation sequencing demonstrated a novel IGLV2-14/IGLL5 fusion and mutations or deletions of tumor suppressor genes, such as PTPRB, PPP2CB, and UPK1A. This tumor was very aggressive, resistant to chemotherapy, recurred with bone marrow involvement, and caused the death of the patient within 6 months. To our knowledge, this is the first report of a hematological malignancy potentially arising from helper ILCs. We propose negativity for lineage markers and positivity for CD127/IL-1R in combination with specific transcription factor expression as markers of this tumor. This finding represents a novel addition to the growing spectrum of hematological malignancies.
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http://dx.doi.org/10.1007/s00428-019-02658-xDOI Listing
February 2020

Rare cases of primary central nervous system anaplastic variant of diffuse large B-cell lymphoma.

Diagn Pathol 2019 May 20;14(1):45. Epub 2019 May 20.

State Key Laboratory of Cancer Biology, Department of Pathology, Xijing Hospital and School of Basic Medicine, Fourth Military Medical University, Xi'an, 710032, China.

Background: Primary central nervous system (CNS) diffuse large B-cell lymphoma (DLBCL) is a rare intracranial tumor, defined as DLBCL arising from the brain, spinal cord, leptomeninges and eye, with an overall annual incidence of 5 cases per million. The primary CNS anaplastic variant of DLBCL (A-DLBCL) is even less common; to our knowledge, there are only two other case reports in the literature. The aim of this report is to present rare cases of primary CNS A-DLBCL and study their clinicopathologic and genetic features.

Case Presentation: We report 3 patients, two men and one woman, aged 54, 55 and 67 years old, with primary CNS A-DLBCL. All 3 patients had a high International Extranodal Lymphoma Study Group (IELSG) score; although the patients were treated with methotrexate-based regimens and/or with radiation therapy, the overall survival was only 2, 5, and 8 months. All 3 patients presented with characteristic features of perivascular space infiltration with bizarre-shaped tumor cells, leading to the diagnosis of primary CNS A-DLBCL. Concurrent of MYC and BCL2 and/or BCL6 abnormalities and MYC/BCL2 double-expressor DLBCL occurred in all 3 patients; two patients had MYC/BCL2/BCL6 triple extra copies, and one patient had MYC extra copy and BCL6 translocation. All 3 patients displayed mutations in MYD88 L265P and nuclear positivity for RELA, RELB and/or c-Rel, indicating constitutive activation of the NF-κB pathway.

Conclusions: These cases shed light on the unique genetic alterations and biological features of primary CNS A-DLBCL. Patients with primary CNS A-DLBCL may often have a MYC/BCL2 double-expressor and concurrent MYC and BCL2 and/or BCL6 genetic abnormalities, as well as constitutive activation of the NF-κB pathway. Primary CNS A-DLBCL follows a very aggressive disease course and poor prognosis. In the future, a large number of cases should be analyzed, and the evaluation of molecular genetic characteristics could help with practical and therapeutic implications for primary CNS A-DLBCL.
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http://dx.doi.org/10.1186/s13000-019-0826-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6528307PMC
May 2019

MET-overexpressing myxofibrosarcoma frequently exhibit polysomy of chromosome 7 but not MET amplification, especially in high-grade cases: clinical and pathological review of 30 myxofibrosarcoma cases.

Diagn Pathol 2018 Aug 21;13(1):56. Epub 2018 Aug 21.

State Key Laboratory of Cancer Biology, Department of Pathology, Xijing Hospital, Fourth Military Medical University, West Road #169, Xi'an, Changle, 710032, China.

Background: Myxofibrosarcoma (MFS) is one of the most common soft tissue sarcomas. Previous studies have shown that MET protein overexpressed in MFS patients and can serve as a prognostic factor. The reasons for MET protein overexpression include amplification of the MET gene, which is located on chromosome 7q. Triggered by an index case harboring chromosome 7 polysomy rather than MET gene amplification in myxofibrosarcoma, we investigated chromosome 7 polysomy in more cases.

Methods: Immunohistochemistry and fluorescence in situ hybridization (FISH) were performed in 30 MFS cases (including 2 epithelioid variant) to detect the expression of MET protein and gene status.

Results: MET was overexpressed in 14 cases out of 30, while thirteen cases were in higher FNCLCC grades (Grade 2-3). FISH showed that 11 cases having 3 signals on average of Met and more than 3 signals (Mean: 4.6) of centromere 7q (CEP7q). The MET/CEP7 ratio was about 0.65 on average, suggesting that chromosome 7 polysomy, rather than Met gene amplification, leading to the overexpression of MET protein in MFS. MET overexpression and chromosome 7 polysomy are positively correlated with higher Ki-67 index and higher grade and might have a high risk of local recurrence and metastasis.

Conclusions: It might reveals another explain of MET overexpression in myxofibrosarcoma, providing a clue for the therapy of MFS.
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http://dx.doi.org/10.1186/s13000-018-0733-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6102798PMC
August 2018

A decision tree-based prediction model for fluorescence hybridization gene status in HER2 immunohistochemistry-2+ breast cancers: a 2538-case multicenter study on consecutive surgical specimens.

J Cancer 2018 6;9(13):2327-2333. Epub 2018 Jun 6.

Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, China.

To investigate the proportion of gene amplifications and the association between the HER2-IHC-staining pattern and gene status in IHC-2+ breast cancers according to 2013 American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines. We retrospectively analyzed and re-evaluated the IHC-staining pattern of 2538 IHC-2+ surgical specimens of breast cancer from November 2014 to October 2015 in 12 institutions. All cases used for building a prediction model of gene amplification according to the IHC-staining pattern and were randomly divided into a training set (n = 1914) or validation set (n = 624). The overall fluorescence hybridization (FISH) amplification, non-amplification and equivocation rates in HER2 IHC-2+ cases were 17.8%, 76.2% and 6.0%, respectively. In the training set, cases that had ≤ 10% of cells with intense, complete and circumferential membrane staining or had > 85% of cells with complete membrane staining of any staining intensity tended to be gene amplified (77.0% and 60.5%, respectively). And cases with weak and incomplete membrane staining had the lowest amplification rate of 6.1%. The prediction model was constructed based on IHC-staining pattern in the training set and validated using a validation set. The positive and negative prediction values were 51.6% and 79.2%, respectively, in the validation set. Moreover, the copy number per cell was much higher in cases with amplification-associated staining patterns (7.84 and 8.75) than in cases with non-amplification-associated staining patterns (2.97 to 4.41, < 0.05). In HER2 IHC-2+ breast cancers, the staining pattern is associated with the gene status. This finding is compatible with recommendations of 2013 ASCO/CAP guidelines.
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http://dx.doi.org/10.7150/jca.25586DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6036724PMC
June 2018

Autophagy defects and related genetic variations in renal cell carcinoma with eosinophilic cytoplasmic inclusions.

Sci Rep 2018 07 2;8(1):9972. Epub 2018 Jul 2.

State Key Laboratory of Cancer Biology, Department of Pathology, Xijing Hospital and School of Basic Medicine, Fourth Military Medical University, Xi'an, 710032, China.

The relationship between autophagy and tumour is well studied, but tumour cell morphological changes associated with autophagy defects are rarely reported, especially in renal cell carcinoma (RCC). We collected 10 renal tumour samples with characteristic eosinophilic cytoplasmic inclusions (ECIs) and found that the ECIs were majorly composed of sequestosome 1/P62, neighbor of BRCA1 gene 1 (NBR1), PEX14, and CATALASE1 (CAT1). Further, transmission electron microscopy analysis revealed that ECIs were aggregates of proteinaceous material and peroxisomes. These results confirmed that ECIs in RCCs were the products of autophagy defects. The presence of ECIs was correlated with high Fuhrman grade components of RCCs. Whole-exome sequencing (WES) and Sanger sequencing confirmed that tumours with ECIs showed somatic mutations or high frequency of genetic variations in autophagy-related (ATG) genes, such as ATG7, ATG5, and ATG10. These results indicate that nucleotide changes in ATG genes are associated with autophagy defect, ECI formation, and even tumour grade in RCCs.
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http://dx.doi.org/10.1038/s41598-018-28369-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6028630PMC
July 2018

Expression of programmed cell death 1/programmed cell death ligand 1 in the tumor microenvironments of primary gastrointestinal diffuse large B cell lymphomas.

Pathol Res Pract 2018 Apr 12;214(4):507-512. Epub 2018 Mar 12.

State Key Laboratory of Tumor Biology, Department of Pathology, The Basic Medicine Science and Xi Jing Hospital, The Fourth Military Medical University, Xi'an, Shaan Xi Province, 710032, China. Electronic address:

Background: Gastrointestinal diffuse large B cell lymphoma (GI DLBCL) is the most common gastrointestinal lymphoma. However, there has not been a comprehensive investigation into the expression patterns of programmed cell death 1 (PD-1) and programmed cell death ligand 1(PD-L1) in GI DLBCL tissues.

Methods: PD-1 protein expression in tumor-infiltrating lymphocytes (TILs) was evaluated by immunohistochemical staining, and expression of PD-L1 was evaluated by using PD-L1/PAX5 immunohistochemical double staining in 92 GI DLBCL specimens.

Results: The prevalence of positive PD-L1 expression (PD-L1 + ) in GI DLBCL cells and positive PD-L1 expression in non-cancer cells of the GI DLBCL microenvironment (microenvironmental PD-L1, mPD-L1) were 11.96% (11 of 92) and 41.98% (34 of 81), respectively. PD-L1 expression in GI DLBCL was significantly associated with involvement of extranodal sites ≥ 2 (P = 0.034) and mPD-L1 expression was significantly associated with ECOG performance status (score ≥ 2) (P = 0.041). PD-L1 expression and mPD-L1 expression had no prognostic significance (P > 0.05) on disease outcome. PD-1+ TILs were significantly lower in patients with extranodal site involvement (P = 0.011) and the quantity of PD-1 + TILs correlated positively with the level of PDL1 expression in non malignant microenvironment cells (P = 0.001). Patients with high levels of PD-1+ TILs had better prognosis (P = 0.0005).

Conclusions: The expression patterns of PD-L1 in patients with GI DLBCL are different from patients with common DLBCL. Immunotherapies that target the PD-1/PD-L1 pathway may have therapeutic potential in GI DLBCL.
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http://dx.doi.org/10.1016/j.prp.2018.03.001DOI Listing
April 2018

Primary Astrocytic Tumours and Paired Recurrences have Similar Biological Features in IDH1, TP53 and TERTp Mutation and MGMT, ATRX Loss.

Sci Rep 2017 10 12;7(1):13038. Epub 2017 Oct 12.

State Key Laboratory of Cancer Biology, Department of Pathology, Xijing Hospital; and School of Basic Medicine, The Fourth Military Medical University, Xi'an, Shaan Xi Province, China.

Astrocytic tumours are the most common type of primary malignant brain tumour. Most astrocytic tumours will recur at some point after surgery. Currently, the combination of radiotherapy and chemotherapy does not prevent the recurrence of astrocytic tumours. In this study, we investigated the consistency in isocitrate dehydrogenase 1 (IDH1), tumour protein p53 (TP53) and telomerase reverse transcriptase promoter (TERTp) mutations during astrocytic tumour recurrence. We also evaluated the protein loss of O-6-methylguanine-DNA methyltransferase (MGMT) and alpha-thalassemia/mental retardation, X-linked (ATRX) during disease recurrence. We then determined the prognostic significance of these findings in terms of progression-free survival (PFS) using Kaplan-Meier analysis and Cox regression models. Our results showed that in most cases, IDH1, TP53 and TERTp mutation status and MGMT and ATRX protein expression levels were stable during recurrence, which may indicate that these alterations occurred early in astrocytic tumour development. Furthermore, in IDH1 wild type group, the patients who were negative for MGMT and had a low Ki67 index showed a longer PFS. Therefore, we suggest that IDH1 mutation combined with MGMT expression level and Ki67 index might be an effective biomarker panel for evaluating the PFS of patients with astrocytic tumours.
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http://dx.doi.org/10.1038/s41598-017-13272-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5638900PMC
October 2017

EZH2 overexpression in primary gastrointestinal diffuse large B-cell lymphoma and its association with the clinicopathological features.

Hum Pathol 2017 06 22;64:213-221. Epub 2017 Apr 22.

State Key Laboratory of Tumor Biology, Department of Pathology, the Basic Medicine Science and Xi Jing Hospital, the Fourth Military Medical University, Xi'an, Shaan Xi Province, 710032, China. Electronic address:

Gastrointestinal diffuse large B-cell lymphoma (GI DLBCL) is the most common gastrointestinal lymphoma. Enhancer of zeste homolog 2 (EZH2) has been implicated in the pathogenesis of several cancers. However, EZH2 has not been studied in GI DLBCL. Thus, we investigated EZH2 expression and EZH2 Y641 mutation in 100 GI DLBCL specimens by immunohistochemistry and sequencing. In addition, trimethylated H3K27 (H3K27me3), BCL2, c-MYC, and Ki-67 expression and Helicobacter pylori infection were detected, and BCL2 and c-MYC gene translocation was assessed. EZH2 was overexpressed in 50% of cases. EZH2 overexpression was significantly associated with higher stage (P = .014), higher International Prognostic Index score (P = .003), reduced overall survival rate (P = .030), and H3K27me3 (P = .001) and c-MYC expression (P = .008). We detected EZH2 mutations in 1 of 33 (3.0%) DLBCLs with a germinal center immunophenotype. The frequency of EZH2 Y641 mutation in GI DLBCL was significantly lower than that in patients with DLBCL without gastrointestinal features (P = .022). BCL2 and c-MYC translocation was detected in 6.5% and 5.1% of cases, respectively. BCL2 translocation was detected exclusively in the germinal center B-cell-like subtype. Chronic gastroenteritis was present in all cases, and 36.4% of gastric DLBCL cases had H pylori infection. The data indicate that primary GI DLBCL is closely related with chronic inflammation and has a low frequency of molecular abnormality, and EZH2 overexpression is significantly associated with inferior outcome in patients with primary GI DLBCL; evaluating EZH2 expression has therapeutic implications.
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http://dx.doi.org/10.1016/j.humpath.2017.04.011DOI Listing
June 2017

Anaplastic Variant of Diffuse Large B-cell Lymphoma Displays Intricate Genetic Alterations and Distinct Biological Features.

Am J Surg Pathol 2017 Oct;41(10):1322-1332

*State Key Laboratory of Cancer Biology, Department of Pathology, Xijing Hospital, Fourth Military Medical University, Xi'an †Department of Pathology, Fujian Cancer Hospital, Fuzhou ‡Department of Pathology, Hubei Cancer Hospital, Wuhan §Department of Pathology, Daping Hospital, Third Military Medical University, Chongqing ∥Department of Pathology, the First People's Hospital of Foshan, Foshan, China.

Anaplastic diffuse large B-cell lymphoma (A-DLBCL) is a rare morphologic variant characterized by the presence of polygonal, bizarre-shaped tumor cells. However, the clinicopathologic and genetic features of this variant are largely unknown. In this study, we investigated 35 cases of A-DLBCL with regard to their clinical, pathologic, and genetic characteristics. The age of the patients ranged from 23 to 89 years (median age, 62 y) with a male to female ratio of 23:12. Twenty-two of 26 (85%) patients had Ann Arbor stage III or IV disease, and 17/26 (65%) patients had a high-intermediate or high International Prognostic Index score. For the 24 patients treated with aggressive chemotherapy regimens, the median overall survival (OS) was 16 months, and the 2-year OS rate was 36%. Immunophenotypically, 30/35 (86%) cases had a non-germinal center B-cell immunophenotype. CD30 expression was present in 18/35 (51%) cases, and the p53 protein stain was positive in 28/35 (80%) cases. Fifteen of 35 (43%) cases expressed both BCL2 and MYC (double expressor). Twenty-nine of 32 (91%) cases tested positive for RELA, RELB, or c-Rel in the nucleus, indicating activation of the NFκB signaling pathway. Cytogenetically, 11/27 (41%) cases had concurrent MYC and BCL2 and/or BCL6 abnormalities (translocation or extra copy), including 5 cases with triple abnormalities. TP53 mutation was found in 17/30 (57%) cases, whereas the MYD88 L265P, CD79B, and CARD11 mutations were found in 7/35, 4/30, and 5/30 cases, respectively. We compared the A-DLBCL group with 50 patients with DLBCL without anaplastic features (common DLBCL). The OS of patients with A-DLBCL was significantly worse than that of patients with DLBCL without anaplastic features (P=0.004). Cases of A-DLBCL more often had a high International Prognostic Index score and a non-germinal center B-cell immunophenotype, more frequently expressed CD30 and p53, and more often had mutations of TP53 and concurrent abnormalities of MYC and BCL2 and/or BCL6 (P<0.05). In conclusion, A-DLBCL displays clinicopathologic features that distinguish it from ordinary DLBCL. Most patients follow an aggressive clinical course and have a poor outcome. Cases of A-DLBCL have a high frequency of TP53 mutation and genetic abnormalities of MYC, BCL2, and BCL6.
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http://dx.doi.org/10.1097/PAS.0000000000000836DOI Listing
October 2017

Clinicopathological features of primary diffuse large B-cell lymphoma of the central nervous system - strong EZH2 expression implying diagnostic and therapeutic implication.

APMIS 2016 Dec 2;124(12):1054-1062. Epub 2016 Nov 2.

State Key Laboratory of Tumor Biology, Department of Pathology, Xi Jing Hospital, The Fourth Military Medical University, Xi'an, Shaan Xi Province, China.

Primary diffuse large B-cell lymphoma of the central nervous system (CNS DLBCL) is a rare entity which is difficult to diagnose and treat. The histone methyltransferase EZH2 was reported to be involved in the tumorigenesis of systemic DLBCL but has not been implicated in primary CNS DLBCL. The clinicopathological features of 33 cases of primary CNS DLBCL and expression of EZH2 and Y641 mutation were assessed. The tumor cells of the majority cases resembled centroblasts, and intriguingly, three cases of rare anaplastic variant were observed. Immunophenotypically, 25/33 (75.8%) cases were non-germinal center B-cell-like type. Several cases (10/33; 30.3%) co-expressed BCL2 and MYC, 6/33 (18.2%) expressed both BCL6 and MYC, and 5/33 (15.2%) expressed BCL2, BCL6, and MYC. MYC expression alone and BCL2/MYC co-expression were associated with poor prognosis. EZH2 was strongly expressed in all 33 cases independent of Y641 mutation and was significantly associated with the tumor proliferative index Ki67. However, no association was found between the level of EZH2 expression and outcomes of patients. In summary, the clinicopathological features including three rare anaplastic variant of primary CNS DLBCL are described. Strong expression of EZH2 in all the primary CNS DLBCL and association with high proliferative index provides further information for treatment and diagnosis of this distinctive entity.
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http://dx.doi.org/10.1111/apm.12623DOI Listing
December 2016

BRAF V600E mutation correlates with suppressive tumor immune microenvironment and reduced disease-free survival in Langerhans cell histiocytosis.

Oncoimmunology 2016 Jul 14;5(7):e1185582. Epub 2016 Jun 14.

Department of Pathology, State Key Laboratory of Cancer Biology, Xijing Hospital, Fourth Military Medical University , Xi'an, Shaanxi, People's Republic of China.

Langerhans cell histiocytosis (LCH) is a neoplasm of myeloid origin characterized by a clonal proliferation of CD1a(+)/CD207(+) dendritic cells. Recurrent BRAF V600E mutation has been reported in LCH. In the present report, we confirm the feasibility of the high-specificity monoclonal antibody VE1 for detecting BRAF V600E mutation in 36/97 (37.1%) retrospectively enrolled patients with LCH; concordant immunohistochemistry and Sanger sequencing results were seen in 94.8% of cases. We then assessed the tumor immune microenvironment status in LCH, and found that the GATA binding protein 3 (GATA3)(+)/T-bet(+) ratio could distinguish between clinical multi-system/single-system (SS) multifocal and SS unifocal LCH. Notably, we found that BRAF V600E mutation is significantly correlated with increased programmed cell death 1 ligand 1 (PDL1) expression and forkhead box protein 3 (FOXP3)(+) regulatory T cells (p < 0.001, 0.009, respectively). Moreover, Cox multivariate survival analysis showed that BRAF V600E mutation and PDL1 were independent prognostic factors of poor disease-free survival (DFS) in LCH (hazard ratio [HR] = 2.38, 95% confidence interval [CI] 1.02-5.56, p = 0.044; HR = 3.06, 95%CI 1.14-7.14, p = 0.025, respectively), and the superiority of PDL1 in sensitivity and specificity as biomarker for DFS in LCH was demonstrated by receiver operator characteristic (ROC) curves when compared with BRAF V600E and risk category. Collectively, this study identifies for the first time relationship between BRAF V600E mutation and a suppressive tumor immune microenvironment in LCH, resulting in disruption of host-tumor immune surveillance, which is DFS. Our findings may provide a rationale for combining immunotherapy and BRAF-targeted therapy for treating patients with BRAF V600E mutant LCH.
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http://dx.doi.org/10.1080/2162402X.2016.1185582DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5006923PMC
July 2016

BRAFV600E and MAP2K1 mutations in Langerhans cell histiocytosis occur predominantly in children.

Hematol Oncol 2017 Dec 6;35(4):845-851. Epub 2016 Sep 6.

Department of Pathology, State Key Laboratory of Cancer Biology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China.

Langerhans cell histiocytosis (LCH) is a proliferative disease of CD1a /CD207 dendritic cells. Recurrent BRAFV600E and MAP2K1 mutations have been reported in LCH. To investigate the relationship among the mutation, clinical findings, and differentiation status of LCH, respectively, we studied 97 cases of LCH by using Sanger sequencing and immunohistochemistry. The mutually exclusive BRAFV600E and MAP2K1 mutation rates were 32% and 17.5%, respectively. All MAP2K1 mutations were missense mutations without any in-frame deletions; 2 new recurrent missense mutations (ie, p.E38K and p.P105S) were also found. More BRAFV600E and MAP2K1 mutations occurred in children compared with those in adult patients (P = .001), and BRAF mutation was correlated with relapse (P = .009). To the differentiation-related markers, the BRAF/MAP2K1-mut LCH expressed CD14 but rarely expressed CD83 or CD86 (P < .001). On the contrary, BRAF/MAP2K1-wt LCH cells rarely expressed CD14 but expressed CD86, and some also expressed CD83 (P < .001). This indicated that the BRAF/MAP2K1-mut LCH cells had a more immature state than BRAF/MAP2K1-wt LCH cells. Moreover, we also found the BRAFV600E and MAP2K1 mutations were significantly associated with pERK expression (P < .001). Therefore, the RAS/RAF/MEK/ERK pathway might play a more important role in children than in adult patients with LCH.
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http://dx.doi.org/10.1002/hon.2344DOI Listing
December 2017

EZH2 overexpression in different immunophenotypes of breast carcinoma and association with clinicopathologic features.

Diagn Pathol 2016 Apr 26;11:41. Epub 2016 Apr 26.

Department of Pathology, Xi Jing Hospital, the Fourth Military Medical University, Xi'an, Shaan Xi Province, 710032, China.

Background: Enhancer of zest homolog 2 (EZH2), a histone 3 methyltransferase, is associated with aggressive behavior of many tumors and is a promising target of molecular therapy.

Methods: To better elucidate the relevance of EZH2 in breast cancer subtypes, we evaluated EZH2 expression in 226 invasive breast carcinomas with four distinct immunophenotypes and in association with clinicopathological features.

Results: Of these cases, 138 (61.1 %) were defined as EZH2-overexpressing with a multiplicative score > 3. EZH2 expression was inversely related to the status of ER and PR (Chi-square, p < 0.001), and it was significantly associated with HER2 positivity, high proliferative index, and high histologic grade (Chi-square, p < 0.05). ER-positive breast carcinoma with low proliferative index (Ki67 < 14 %) showed the lowest expression and triple-negative breast carcinoma showed the highest overexpression of EZH2, 18.5 % (10/54) versus 90.9 % (50/55) (Chi-square, p < 0.001). Intriguingly, 88 % (44/50) cases of grade 3 triple-negative breast carcinoma showed uniformly strong EZH2 expression with a multiplicative score of 9. The percentage of EZH2 overexpression in ER-positive breast carcinoma with a high proliferative index or HER2-positive cases were 61.2 and 74 %, respectively. Furthermore, EZH2 expression was significantly elevated in high-grade DCIS compared to benign lesions (90 % versus 0, p < 0.001). However, there is no association between EZH2 expression and the status of histone 3 lysine 27 trimethylation or other clinicopathologic features.

Conclusion: In summary, triple-negative breast carcinoma showed the highest overexpression of EZH2. EZH2 overexpression is associated aggressive pathologic features including high nuclear grade, high proliferative index, and positivity of HER2 of breast carcinoma.
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http://dx.doi.org/10.1186/s13000-016-0491-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4845361PMC
April 2016

Solid papillary carcinoma of the breast: A special entity needs to be distinguished from conventional invasive carcinoma avoiding over-treatment.

Breast 2016 Apr 29;26:67-72. Epub 2016 Jan 29.

Department of Pathology, Xi Jing Hospital, the Fourth Military Medical University, Xi'an, Shaan Xi Province, 710032, China. Electronic address:

Introduction: Solid papillary carcinoma of the breast, a newly-defined entity, is poorly recognized, and its nature and management is still debated.

Material And Methods: Eleven cases of pure solid papillary breast carcinoma in our archive and 253 cases reported in previous literature were retrospectively analyzed for their clinicopathological features and outcomes.

Results: The eleven cases occurred in elderly females. Grossly, all tumors were well-circumscribed and typically composed of solid papillary nodules. The tumor cells were bland-looking with low-grade atypia and mitoses < 5/10HPF. Immunophenotypically, all eleven cases showed positivity for ER and PR, negativity for CK5/6 and HER2, and a low proliferative index of Ki67. Five cases showed scattered positivity for myoepithelial marker p63, and four cases were positive for CK5/6 and CD10 around the nodules, whereas the other cases were completely negative for all myoepithelial markers. Five cases expressed the neuroendocrine marker synaptophysin, and six cases expressed chromogranin. In nine cases, mastectomy and axillary lymph nodes excision were performed, and only one showed micrometastasis in an axillary lymph node. There was no local recurrence or distant metastasis or breast carcinoma related-death during the follow-up periods of 50 months. Out of 253 solid papillary breast carcinomas reported in literature, the percentage of axillary lymph node metastasis was 4/136 (3%), with rare local recurrences and distant metastasis; only three patients died of breast carcinoma.

Conclusion: Solid papillary carcinoma of the breast is a rare entity with distinctive clinicopathological features and excellent prognosis and should be distinguished from conventional breast carcinoma to avoid over-treatment.
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http://dx.doi.org/10.1016/j.breast.2015.12.015DOI Listing
April 2016

A clinicopathologic study of paragangliomas of the urinary bladder: can the clinical behavior of the tumor be predicted?

Histol Histopathol 2016 Jul 10;31(7):785-91. Epub 2016 Mar 10.

Department of Pathology, Xi Jing Hospital, the Fourth Military Medical University, Xi'an, Shaan Xi Province, China.

Lymphovascular invasion (LVI) is an independent predictor of metastatic lymph node disease in penile carcinoma and is one factor used to guide clinical management. The presence of LVI with and without the use of the endothelial immunohistochemical (IHC) markers, ERG and CD31, was retrospectively assessed in 46 penectomy cases containing invasive penile carcinoma (43 squamous cell carcinoma and 3 non-squamous cell carcinoma). Concordance for the detection of LVI between the original report, upon pathology review, and with the use of IHC was determined and histologic pitfalls were identified. For penile squamous cell carcinoma, LVI was diagnosed in 27.9% of tumors in the original reports, 16.3% upon pathology review, and in 16.3% with use of ERG and CD31. Concordance of LVI identification in the original report compared to IHC was 74.4% while concordance of review compared to IHC was 95.3%. Using IHC data as the reference, false positive LVI diagnoses were more common in the original report than false negatives. Histologic mimickers of LVI including involvement of the penile corpora cavernosum or spongiosum vasculature, seromucinous colonization, and a nested pattern of tumor invasion were identified. We demonstrated that it was not uncommon for LVI in penile carcinoma to be overdiagnosed or underdiagnosed. The use of endothelial IHC markers, such as ERG or CD31, or additional pathology consultation is recommended for penectomy cases in which LVI is difficult to histologically discern.
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http://dx.doi.org/10.14670/HH-11-751DOI Listing
July 2016

Tumor invasion depth is a useful pathologic assessment for predicting outcomes in cervical squamous cell carcinoma after neoadjuvant radiotherapy.

Diagn Pathol 2015 Nov 4;10:200. Epub 2015 Nov 4.

State Key Laboratory of Cancer Biology, Department of Pathology Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi Province, 710032, P.R. China.

Background: To evaluate whether tumor invasion depth can be a reliable and easily applicable pathologic assessment strategy to predict outcomes using surgically resected cervical squamous cell carcinoma specimens from patients who have received neoadjuvant radiotherapy (RT) or concurrent chemoradiotherapy (CCRT).

Methods: We included 173 patients with cervical squamous cell carcinoma who received neoadjuvant CCRT (n = 125) or RT (n = 48) and underwent subsequent radical hysterectomy. Data for the pre-operative clinical International Federation of Gynecology and Obstetrics (FIGO) stage, post-operative pathologic FIGO stage, World Health Organization (WHO) double diameter measurement evaluation, response evaluation criteria in solid tumors (RECIST 1.1) criteria, tumor necrosis rate (TNR), and tumor regression grade (TRG) were investigated to identify correlations with outcomes related to distant metastasis and survival. The tumor invasion depth (TID) and the tumor invasion depth with cytokeratin immunostaining correction (TIDC) at the cervical internal surface were measured to assess their relations to patients' outcomes.

Results: Based on measurements taken via transvaginal ultrasound, the pre-operative clinical and post-operative pathologic FIGO staging as well as the WHO double diameter measurement evaluation and RECIST 1.1 criteria were predictive of distant metastasis and survival-related outcomes. Also, lymph node involvement was found to be an independent prognostic factor for recurrence and distant metastasis. Finally, univariate analysis showed both the TID and TIDC were highly related to distant metastasis, overall survival, and progression-free survival, irrespective of the clinical stage of carcinomas.

Conclusion: The TID or TIDC measured at the cervical internal surface is a useful and easily applied pathologic prognostic factor for distant metastasis and survival outcomes in patients with cervical squamous cell carcinoma treated with neoadjuvant RT or CCRT.
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http://dx.doi.org/10.1186/s13000-015-0426-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4632273PMC
November 2015
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