Publications by authors named "Xinyan Lu"

90 Publications

Epigenomic landscape and 3D genome structure in pediatric high-grade glioma.

Sci Adv 2021 Jun 2;7(23). Epub 2021 Jun 2.

Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.

Pediatric high-grade gliomas (pHGGs), including glioblastoma multiforme (GBM) and diffuse intrinsic pontine glioma (DIPG), are morbid brain tumors. Even with treatment survival is poor, making pHGG the number one cause of cancer death in children. Up to 80% of DIPGs harbor a somatic missense mutation in genes encoding histone H3. To investigate whether H3K27M is associated with distinct chromatin structure that alters transcription regulation, we generated the first high-resolution Hi-C maps of pHGG cell lines and tumor tissue. By integrating transcriptome (RNA-seq), enhancer landscape (ChIP-seq), genome structure (Hi-C), and chromatin accessibility (ATAC-seq) datasets from H3K27M and wild-type specimens, we identified tumor-specific enhancers and regulatory networks for known oncogenes. We identified genomic structural variations that lead to potential enhancer hijacking and gene coamplification, including , , and Together, our results imply three-dimensional genome alterations may play a critical role in the pHGG epigenetic landscape and contribute to tumorigenesis.
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http://dx.doi.org/10.1126/sciadv.abg4126DOI Listing
June 2021

Exposure to legacy and novel perfluoroalkyl substance disturbs the metabolic homeostasis in pregnant women and fetuses: A metabolome-wide association study.

Environ Int 2021 May 13;156:106627. Epub 2021 May 13.

State Key Laboratory of Pollution Control and Resource Reuse, School of the Environment, Nanjing University, Nanjing, People's Republic of China.

Background: Perfluoroalkyl substances (PFASs) exist extensively and several of these have been verified to be toxic. Prenatal exposure to PFASs has attracted much attention. Metabolome-wide association analyses can be used to explore the toxicity mechanisms of PFASs by identifying associated biomarkers.

Objectives: To evaluate associations between the metabolites in maternal and cord serum and internal exposure to several common PFASs.

Methods: Paired maternal and cord serum samples were collected from 84 pregnant women who gave birth between 2015 and 2016. Seven legacy and two novel PFASs were measured. A nontarget metabolomic method and an iterative metabolite annotation based on metabolic pathways were applied to characterize the metabolic profiles. Linear regression adjusted with the false discovery rate and covariates was used to indicate the associations.

Results: A total of 279 features in maternal serum and 338 features in cord serum were identified as metabolites associated with PFAS exposure. Perfluorooctanoic acid (PFOA) and perfluorohexane sulfonic acid (PFHxS) were two PFASs associated with more metabolites, while the two novel chlorinated polyfluorinated ether sulfonic acids (Cl-PFESAs) showed less relevance to the metabolome. With pathway enrichment analysis, we found that three fatty acid metabolisms and retinol metabolism were correlated with PFAS exposure in maternal blood, and that sterol metabolism showed the correlation in both maternal serum and cord serum.

Conclusions: We identified metabolites and pathways in pregnant women and fetuses associated with the exposure to several PFAS, indicating a promising application for metabolome-wide association studies. Additional research is needed to confirm causation.
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http://dx.doi.org/10.1016/j.envint.2021.106627DOI Listing
May 2021

Distinctive Clinicopathologic Features of Monomorphic B-cell Post-transplant Lymphoproliferative Disorders in Children.

Pediatr Dev Pathol 2021 Apr 19:10935266211007254. Epub 2021 Apr 19.

Ann & Robert H. Lurie Children's Hospital of Chicago, Department of Pathology and Laboratory Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois.

Introduction: Post-transplant lymphoproliferative disorders (PTLDs) comprise a heterogeneous group of Epstein-Barr virus (EBV)-positive or negative lymphoid or plasmacytic lesions in solid organ or hematopoietic stem cell (HSC) transplant recipients. Although PTLDs in adults have been extensively studied, the clinicopathologic features of monomorphic B-cell PTLD in children, particularly EBV-negative forms, are still poorly understood.

Methods: We retrospectively reviewed all our pediatric cases of monomorphic B-cell PTLDs diagnosed in the past 10 years. Clinical data were reviewed. Pathologic data including histologic types and EBV status were analyzed. Additional immunohistochemical stains, FISH studies, and gene mutational status were performed.

Results: 4 of 18 cases were EBV-negative. All 4 EBV-negative cases were strikingly confined to the gastrointestinal (GI) tract or abdominal lymph nodes, while tumors in EBV-positive cases were found at various anatomic sites; 2 of 4 EBV-negative cases carried mutations in gene. Our cohort also included 2 rare types of PTLD, one plasmablastic lymphoma and one high-grade B-cell lymphoma, not otherwise specified (HGBL, NOS).

Conclusion: We report that monomorphic B-cell PTLDs in children have distinctive clinical and pathological features. More studies are needed to clarify whether and how much these pediatric PTLDs differ from their adult counterparts.
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http://dx.doi.org/10.1177/10935266211007254DOI Listing
April 2021

Non-destructive detection of highway hidden layer defects using a ground-penetrating radar and adaptive particle swarm support vector machine.

PeerJ Comput Sci 2021 30;7:e417. Epub 2021 Mar 30.

School of Electric Power, North China University of Water Resource and Electric Power, Zhengzhou, China.

In this paper, a method that uses a ground-penetrating radar (GPR) and the adaptive particle swarm support vector machine (SVM) method is proposed for detecting and recognizing hidden layer defects in highways. Three common road features, namely cracks, voids, and subsidence, were collected using ground-penetrating imaging. Image segmentation was performed on acquired images. Original features were extracted from thresholded binary images and were compressed using the kl algorithm. The SVM classification algorithm was used for condition classification. For parameter optimization of the SVM algorithm, the grid search method and particle swarm optimization algorithm were used. The recognition rate using the grid search method was 88.333%; the PSO approach often yielded local maxima, and the recognition rate was 86.667%; the improved adaptive PSO algorithm avoided local maxima and increased the recognition rate to 91.667%.
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http://dx.doi.org/10.7717/peerj-cs.417DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8022505PMC
March 2021

Integrated histologic and molecular analysis of uterine leiomyosarcoma and 2 benign variants with nuclear atypia.

Cancer Sci 2021 May 22;112(5):2046-2059. Epub 2021 Mar 22.

Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.

Uterine leiomyosarcoma (LMS) is a rare but deadly disease. Due to poor understanding of the molecular and genetic causes of the disease, the diagnosis of LMS has been based primarily on histology. Nuclear atypia is one of hallmarks in LMS, however, it also occurs in 2 clinically benign variants, including smooth muscle tumors with fumarate hydratase alteration (SMT-FH) and leiomyoma with bizarre nuclei (LM-BN). In addition to nuclear atypia, many well recognized biomarkers used for LMS are also frequently overexpressed in LM-BN, and the histogenesis and molecular natures for LM-BN and LMS remain largely unknown. To characterize the molecular profiling of LMS, SMT-FH, and LM-BN, we performed integrated comprehensive genomic profiling including whole-genome sequencing (WGS) and RNA sequencing and genomic microarray analyses to assess genome-wide copy number alterations (CNAs) and immunohistochemistry (IHC) in all 3 tumor types. We found that both LM-BN and LMS showed genomic instability and harbored extensive CNAs throughout the whole genome. By contrast, the SMT-FH presented its characteristic 1q43-44 deletions in all cases tested, with minimal CNAs in the rest of genomic regions. Further analyses revealed that LMS and LM-BN groups showed similar patterns of CNAs that are tended to cluster together and separated from the SMT-FH group. The integrated molecular profiling enabled the detection of novel and traditional biomarkers and showed excellent discrimination between LM-BN and LMS. Our study suggests that LM-BN, despite having similar nuclear atypia to SMT-FH, showed similar genomic instability but distinct genomic alterations with its malignant counterpart of LMS. The integrated molecular profiling is of clinical importance in characterizing these rare uterine smooth muscle tumors.
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http://dx.doi.org/10.1111/cas.14775DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8088951PMC
May 2021

Distinct Mutation Pattern in Patients With Non-Small Cell Lung Cancer in Xuanwei Region of China: A Systematic Review and Meta-Analysis.

Front Oncol 2020 2;10:519073. Epub 2020 Nov 2.

Department of Medical Oncology, The Second Affiliated Hospital of Kunming Medical University, Kunming, China.

Background: In the Xuanwei region of China, lung cancer incidence and mortality are among the highest in China, attributed to severe air pollution generated by combustion of smoky coal. No study has yet comprehensively evaluated the prevalence of epidermal growth factor receptor () mutation characteristics in patients with non-small cell lung cancer (NSCLC) in Xuanwei. This meta-analysis was designed to analyze the mutation pattern in NSCLC patients in Xuanwei region of Yunnan Province in China.

Methods: Electronic databases were comprehensively searched and relevant literatures were retrieved. The odds ratio (OR) for mutations between Xuanwei region and non-Xuanwei region was calculated, and the absolute incidence of mutations in Xuanwei was pooled by mutation subtype.

Results: Seven studies involving 1,355 patients with NSCLC from Yunnan Province (442 in Xuanwei and 913 in other regions) were included. The mutation rate ranged between 30.19% and 55.56%. Higher uncommon mutations (OR: 5.69, 95%CI: 2.23-14.49, P<0.001) and lower common mutations (OR: 0.18, 95%CI: 0.07-0.45, P<0.001) were found in Xuanwei region, compared with non-Xuanwei region. Specifically, the uncommon mutation rate was 59.50% and common mutation rate was 40.50% in Xuanwei. The mutation incidence of exon 18 G719X (OR: 3.21, 95%CI: 1.48-6.97, P=0.003), exon 20 S768I (OR: 6.44; 95%CI: 2.66-15.60; P<0.001), and exon 18 G719X + 20 S768I (OR: 6.55; 95%CI: 1.92-22.33; P=0.003) in Xuanwei were significantly higher, while the frequency of 19 deletion (OR: 0.28, 95%CI: 0.11-0.77, P<0.001) and 21 L858R mutation (OR: 0.51, 95%CI: 0.31-0.84, P=0.007) were lower.

Conclusions: The results highlight the distinct mutation spectrum of NSCLC patients in Xuanwei region compared with other regions, with higher uncommon mutations but lower common mutations. The distinct Xuanwei featured genetic variations provide a unique model to further study carcinogenesis of lung cancer.
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http://dx.doi.org/10.3389/fonc.2020.519073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7667261PMC
November 2020

RNA m6A methylation promotes the formation of vasculogenic mimicry in hepatocellular carcinoma via Hippo pathway.

Angiogenesis 2021 02 13;24(1):83-96. Epub 2020 Sep 13.

State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, 38 Tongyan Road, Haihe Education Park, Tianjin, China.

Vasculogenic mimicry (VM) formed by aggressive tumor cells to mimic vasculogenic networks plays an important role in the tumor malignancy of HCC. However, the pathogenesis underlying VM is complex and has not been fully defined. m6A is a common mRNA modification and has many biological effects. However, the relationship between m6A and VM remains unclear. In this research, we found that m6A methyltransferase METTL3 in HCC tissues was positively correlated with VM. The m6A level of mRNA significantly increased in 3D cultured cells treated with VEGFa and was related to VM formation. Transcriptome sequencing analysis of 3D cultured cells with knockdown Mettl3 showed that the Hippo pathway was involved in m6A-mediated VM formation. Further mechanism research indicated that the m6A modification of YAP1 mRNA affected the translation of YAP1 mRNA. In conclusion, m6A methylation plays a key role in VM formation in HCC. METTL3 and YAP1 could be potential therapeutic targets via impairing VM formation in anti-metastatic strategies.
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http://dx.doi.org/10.1007/s10456-020-09744-8DOI Listing
February 2021

The survival impact of CKS1B gains or amplification is dependent on the background karyotype and TP53 deletion status in patients with myeloma.

Mod Pathol 2021 02 9;34(2):327-335. Epub 2020 Sep 9.

Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Gains or amplification (amp) of chromosome 1q21/CKS1B are reported to be a high-risk factor in myeloma. In this retrospective study, we analyzed the impact of CKS1B gain/amp on overall survival in the context of other genetic aberrations, such as TP53 deletion, FGFR3-IGH, IGH-MAF, MYEOV/CCND1-IGH, and RB1, as well as karyotype. The cohort included 132 myeloma patients with CKS1B gain/amp detected by fluorescence in-situ hybridization. There were 72 men and 60 women with a median age of 65 years (range 39-88 years). A normal, simple, or complex karyotype was observed in 39.5%, 5.4%, and 55% of patients, respectively. "Double hit," defined as CKS1B gain/amp coexisting with TP53 deletion, or "triple hit," defined as double hit plus t(4;14)FGFR3-IGH or t(14;16)IGH-MAF, were identified in 25 patients (18.9%) and five patients (3.8%), respectively. Double and triple hit were highly associated with a complex karyotype (p = 0.02). Ninety-nine patients (99/128, 77.3%) received stem cell transplantation. The median follow-up time was 48.2 months (range 2-104 months); 68 patients (51.5%) died, with a median overall survival of 58.8 months. Multivariate analysis (Cox model) showed that double hit with TP53 deletion (p = 0.0031), triple hit (p = 0.01), and complex karyotype (p = 0.0009) were each independently associated with poorer overall survival. Stem cell transplantation was associated with better overall survival, mainly in patients with a double or triple hit and complex karyotype (p = 0.003). These findings indicate that the inferior outcome of myeloma patients with CKS1B gain/amp is attributable to the high number of high-risk patients in this group. The prognostic impact of CKS1B gain/amp depends on the background karyotype and TP53 status.
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http://dx.doi.org/10.1038/s41379-020-00669-7DOI Listing
February 2021

Comprehensive molecular genetic studies of Epstein-Barr virus-negative aggressive Natural killer-cell leukemia/lymphoma.

Hum Pathol 2020 11 2;105:20-30. Epub 2020 Sep 2.

Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.

EBV-negative aggressive NK-cell leukemia/lymphoma (ANKL) is a recently recognized, rare NK-cell neoplasm that preferentially affects non-Asians and has a fulminant clinical course. Little is known about the genetic alterations of this disease. In this study, we performed comprehensive molecular genetic studies, including chromosomal analysis, fluorescence in situ hybridization, single nucleotide polymorphism (SNP) microarray, and next-generation sequencing (NGS), on 4 patients diagnosed in our institution. The results demonstrated that our EBV-negative ANKLs have highly complex genomic profiles characterized by near-triploid/near-tetraploid karyotype (3 of 3) with numerous structural abnormalities, inactivation of TP53 (3 of 3), overexpression of c-Myc (4 of 4), strong expression of PD-L1 in neoplastic cells (2 of 4), and gain of the 11q23-ter region (2 of 2). Our study provides important insights of EBV-negative ANKL, which share many of the genetic features with their EBV-positive counterpart. The strong expression of Programmed death-ligand 1 (PD-L1) suggests that immune checkpoint inhibitors may be further explored as a potential therapeutic option for this highly aggressive, chemotherapy-resistant NK-cell neoplasm.
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http://dx.doi.org/10.1016/j.humpath.2020.08.008DOI Listing
November 2020

Aggressive morphologic variants of mantle cell lymphoma characterized with high genomic instability showing frequent chromothripsis, CDKN2A/B loss, and TP53 mutations: A multi-institutional study.

Genes Chromosomes Cancer 2020 08 17;59(8):484-494. Epub 2020 Apr 17.

Department of Pathology, Northwestern Memorial Hospital, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.

Aggressive morphologic variants of mantle cell lymphoma (MCL), including blastoid and pleomorphic (B/P-MCL), are rare and associated with poor clinical outcomes. The genomic landscape of these variants remains incompletely explored. In this multi-institutional study, we describe recurrent mutations and novel genomic copy number alterations (CNAs) in B/P-MCL, using next generation sequencing and SNP-array. Chromothripsis, a recently described phenomenon of massive chromosomal rearrangements, was identified in eight of 13 (62%) B/P MCL cases, and a high degree of genomic complexity with frequent copy number gains and losses was also seen. In contrast, a comparative cohort of nine cases of conventional MCL (C-MCL) showed no chromothripsis and less complexity. Twelve of 13 (92%) B/P-MCL cases showed loss of CDKN2A/B (6 biallelic and 6 monoallelic losses); while only one C-MCL showed monoallelic CDKN2A/B loss. In B/P-MCL, TP53 was the most commonly mutated gene, with mutations present in eight cases (62%), six of which showed concurrent loss of chromosome 17p. Of the eight cases with chromothripsis, six (85%) harbored TP53 mutations. Other recurrent mutations in B/P-MCL included ATM (7, 53%), CCND1 (5, 38%), NOTCH1 (2, 18%), NOTCH2, and BIRC3 (each in 3, 23%). Here, we describe high genomic instability associated with chromothripsis and a high frequency of CDKN2A/B and TP53 alterations in the aggressive variants of MCL. The nonrandom chromothripsis events observed in B/P-MCL may be an indicator of clinically aggressive MCL. In addition, frequent CDKN2A deletion and high genomic instability may provide potential targets for alternative treatment.
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http://dx.doi.org/10.1002/gcc.22849DOI Listing
August 2020

Hispidulin exhibits potent anticancer activity in vitro and in vivo through activating ER stress in non‑small‑cell lung cancer cells.

Oncol Rep 2020 Jun 30;43(6):1995-2003. Epub 2020 Mar 30.

Department of Medical Oncology, The Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650101, P.R. China.

Hispidulin is a medicinal natural compound isolated from S. involucrata, which exhibits potent anticancer properties. However, there are few reports on its effects on lung cancer cells. Therefore, the current study investigated the effects of hispidulin on cell viability and apoptosis in human non‑small‑cell lung cancer (NSCLC) cell lines NCI‑H460 and A549 in vitro and in vivo. Methyl thiazolyl tetrazolium, colony formation assay, Hoechst 33342 staining, flow cytometry and western blotting were performed on Human NCI‑H460 and A549 cells. A mouse xenograft model was also established using NCI‑H460 cells. The results showed that the growth of NCI‑H460 and A549 cells was inhibited, while apoptosis was promoted by hispidulin via increased generation of reactive oxygen species (ROS) in a dose‑dependent manner. Furthermore, hispidulin triggered apoptosis in NSCLC cells through upregulating the expression of cleaved caspase‑3 and cleaved poly [ADP‑ribose] polymerase. All these effects were reversed upon pretreatment with glutathione, a selective ROS inhibitor. In addition, endoplasmic reticulum stress (ER stress) in NCI‑H460 cells was activated by hispidulin. Pretreatment with tauroursodeoxycholic acid, a specific ER stress inhibitor, effectively reduced the cell apoptosis induced by hispidulin. In conclusion, hispidulin induces ROS‑mediated apoptosis via activating the ER stress pathway. The current study provides theoretical basis for the antitumor effect of hispidulin in NSCLC.
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http://dx.doi.org/10.3892/or.2020.7568DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7160559PMC
June 2020

High-risk human papillomavirus-mediated adenocarcinoma of palatine tonsil.

Pathol Res Pract 2020 Aug 19;216(8):152924. Epub 2020 Mar 19.

Department of Head and Neck Surgery, Northwestern University Feinberg School of Medicine, Northwestern Memorial Hospital, 675 N St Clair St, Galter 15-200, Chicago, IL 60611, United States.

We describe the case of a human papillomavirus-mediated adenocarcinoma of palatine tonsil in a 51-year-old male. Histologically, the tumor exhibited a predominantly cribriform and tubular (glandular) growth of cuboidal and columnar cells with moderate amount of pale eosinophilic cytoplasm and oval or spindled nuclei with finely dispersed or coarse chromatin and small to medium-sized nucleoli. Foci of nuclear anaplasia and multinucleation, numerous mitotic figures, and necrosis (individual-cell and confluent) were seen. No squamous differentiation was identified. The tumor cells showed strong expression of CK7, p16 and HPV E6/E7 mRNA transcripts, and were negative for p40, CK5/6, AR, synaptophysin and chromogranin. Next generation sequencing showed 3 variants of unknown significance: FGF3 p.(R44fs); NF1 p.(S749 L) and POLE p. (S1506 L) with variant allele frequencies of 37 %; 20 %, and 17 % respectively. Chromosomal microarray analysis using single nucleotide polymorphism microarray (OncoScan) assay showed whole chromosomal gains of chromosomes 8 and 19, whole chromosomal losses of chromosomes 2 and 16, as well as segmental gains of chromosomes 3q25.31q29 (encompassing the PIK3CA gene), 17q21.31q25.3, 20p13q13.33, Xq28, and segmental losses of chromosomes 1q32.2, 6p25.1p21.1, 11q23.1q24.1, 12p11.22, 12p11.22, 14q24.1q32.33, 17p13.3q21.31 (encompassing the TP53 and NF1 genes). The results highlight the need to consider HPV testing in non-squamous cell carcinomas of the oropharynx.
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http://dx.doi.org/10.1016/j.prp.2020.152924DOI Listing
August 2020

Rac2 Regulates the Migration of T Lymphoid Progenitors to the Thymus during Zebrafish Embryogenesis.

J Immunol 2020 05 20;204(9):2447-2454. Epub 2020 Mar 20.

State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, China;

The caudal hematopoietic tissue in zebrafish, the equivalent to the fetal liver in mammals, is an intermediate hematopoietic niche for the maintenance and differentiation of hematopoietic stem and progenitor cells before homing to the thymus and kidney marrow. As one of the ultimate hematopoietic organs, the thymus sustains T lymphopoiesis, which is essential for adaptive immune system. However, the mechanism of prethymic T lymphoid progenitors migrating to the thymus remains elusive. In this study, we identify an Rho GTPase Rac2 as a modulator of T lymphoid progenitor homing to the thymus in zebrafish. -Deficient embryos show the inability of T lymphoid progenitors homing to the thymus because of defective cell-autonomous motility. Mechanistically, we demonstrate that Rac2 regulates homing of T lymphoid progenitor through Pak1-mediated AKT pathway. Taken together, our work reveals an important function of Rac2 in directing T lymphoid progenitor migration to the thymus during zebrafish embryogenesis.
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http://dx.doi.org/10.4049/jimmunol.1901494DOI Listing
May 2020

Unique morphologic and genetic characteristics of acute myeloid leukemia with chromothripsis: a clinicopathologic study from a single institution.

Hum Pathol 2020 04 21;98:22-31. Epub 2020 Feb 21.

Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA. Electronic address:

Chromothripsis is a unique type of genomic instability and is recognized in various cancers. In myeloid neoplasms (MNs), chromothripsis was linked to poor prognosis and specific genetic alterations (complex karyotype, 5q deletions, and loss of TP53). However, the clinicopathologic features of MNs with chromothripsis have not been thoroughly characterized. We identified chromothripsis in 11 cases of MNs (9 acute myeloid leukemia [AML] and 2 myelodysplastic syndrome [MDS] cases) and noted that all chromothripsis-positive AML cases were AML with myelodysplasia-related changes (AML-MRC). We performed a comparative clinicopathologic and genetic characterization of AML-MRC cases with and without chromothripsis. AML-MRC with chromothripsis is associated with lower white blood cell and platelet counts and higher degree of karyotypic complexity. Chromothripsis in AML-MRC most frequently involves chromosomes 8 and 11 with consequent amplification of either MYC or KMT2A. Comparative morphologic assessment of blast morphology revealed unique features characteristic of AML-MRC with chromothripsis: a variable degree of cytoplasmic vacuolization, granulation, and blebbing. These morphologic markers in the context of AML-MRC may prompt additional studies to identify cases with chromothripsis.
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http://dx.doi.org/10.1016/j.humpath.2020.02.003DOI Listing
April 2020

Current concepts in breast cancer genomics: An evidence based review by the CGC breast cancer working group.

Cancer Genet 2020 06 8;244:11-20. Epub 2020 Feb 8.

Mayo Clinic, 200 First Street SW, Rochester, MN 55905, United States.

Background: Genomic abnormalities in breast cancer have been described according to diverse conceptual frameworks, including histologic subtypes, clinical molecular subtypes, intrinsic DNA, RNA, and epigenetic profiles, and activated molecular pathways.

Methods: The Cancer Genomics Consortium (CGC) Breast Cancer Workgroup performed an evidence based literature review to summarize current knowledge of clinically significant genomic alterations in breast cancer using CGC levels of evidence. Targetable or disease-defining alterations were prioritized.

Results: We summarized genomic alterations in breast cancer within a framework of existing clinical tools for diagnosis, risk stratification, and therapeutic management. Using CGC levels of evidence, we catalog copy number profiles, gene expression profiles, and mutations in clinically significant genes. We also describe emerging molecular markers such as methylation profiling and immunotherapy biomarkers.

Conclusion: A summary of currently available information on breast cancer genomics will enhance precision medicine by serving as an interpretive resource for clinical laboratory geneticists, providing a foundation for future practice guidelines, and identifying knowledge gaps to address in future research.
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http://dx.doi.org/10.1016/j.cancergen.2020.02.002DOI Listing
June 2020

FOXM1 regulates leukemia stem cell quiescence and survival in MLL-rearranged AML.

Nat Commun 2020 02 17;11(1):928. Epub 2020 Feb 17.

Division of Hematology/Oncology, UF Health Cancer Center, University of Florida, Gainesville, FL, USA.

FOXM1, a known transcription factor, promotes cell proliferation in a variety of cancer cells. Here we show that Foxm1 is required for survival, quiescence and self-renewal of MLL-AF9 (MA9)-transformed leukemia stem cells (LSCs) in vivo. Mechanistically, Foxm1 upregulation activates the Wnt/β-catenin signaling pathways by directly binding to β-catenin and stabilizing β-catenin protein through inhibiting its degradation, thereby preserving LSC quiescence, and promoting LSC self-renewal in MLL-rearranged AML. More importantly, inhibition of FOXM1 markedly suppresses leukemogenic potential and induces apoptosis of primary LSCs from MLL-rearranged AML patients in vitro and in vivo in xenograft mice. Thus, our study shows a critical role and mechanisms of Foxm1 in MA9-LSCs, and indicates that FOXM1 is a potential therapeutic target for selectively eliminating LSCs in MLL-rearranged AML.
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http://dx.doi.org/10.1038/s41467-020-14590-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7026046PMC
February 2020

Rats provide a superior model of human stress erythropoiesis.

Exp Hematol 2019 10 25;78:21-34.e3. Epub 2019 Sep 25.

Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL. Electronic address:

Mouse models are widely used to study human erythropoiesis in vivo. One important caveat using mouse models is that mice often develop significant extramedullary erythropoiesis with anemia, which could mask important phenotypes. To overcome this drawback in mice, here we established in vitro and in vivo rat models for the studies of stress erythropoiesis. Using flow cytometry-based assays, we can monitor terminal erythropoiesis in rats during fetal and adult erythropoiesis under steady state and stress conditions. We used this system to test rat erythropoiesis under phenylhydrazine (PHZ)-induced hemolytic stress. In contrast to mice, rats did not have an increased proportion of early-stage erythroid precursors during terminal differentiation in the spleen or bone marrow. This could be explained by the abundant bone marrow spaces in rats that allow sufficient erythroid proliferation under stress. Consistently, the extent of splenomegaly in rats after PHZ treatment was significantly lower than that in mice. The level of BMP4, which was significantly increased in mouse spleen after PHZ treatment, remained unchanged in rat spleen. We further demonstrated that the bone marrow c-Kit positive progenitor population underwent a phenotype shift and became more CD71 positive and erythroid skewed with the expression of maturing erythroid markers under stress in rats and humans. In contrast, the phenotype shift to an erythroid-skewed progenitor population in mice occurred mainly in the spleen. Our study establishes rat in vitro and in vivo erythropoiesis models that are more appropriate and superior for the study of human stress erythropoiesis than mouse models.
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http://dx.doi.org/10.1016/j.exphem.2019.09.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6925535PMC
October 2019

Clinical implications of cytogenetic heterogeneity in Philadelphia chromosome positive (Ph+) adult B cell acute lymphoblastic leukemia following tyrosine kinase inhibitors and chemotherapy regimens.

Leuk Res 2019 09 27;84:106176. Epub 2019 Jun 27.

Departments of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States; Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, United States. Electronic address:

We retrospectively studied a cohort of 144 adults with Philadelphia chromosome/BCR-ABL1 positive B acute lymphoblastic leukemia (Ph + B-ALL) to assess the clinical implications of cytogenetic heterogeneity in this disease. The study group included 85 men and 59 women that were sorted into 6 subgroups based on karyotypic findings in the stemline as follows: 32 patients with t(9;22) as a sole aberration, 23 with t(9;22) plus 1 additional chromosomal abnormality (ACA), 26 with t(9;22) as part of a complex karyotype, 18 showing a variant-/complex- t(9;22), 30 with t(9;22) as the stemline with ACAs in the sideline(s), and 15 patients who had the t(9;22) and hyperdiploidy. In 89 patients 1 clone was identified; 41 had 2 clones and 14 had ≥ 3 clone(s). The median overall survival (OS) was 25.6 months and the median relapse-free survival (RFS) was 20.6 months. Patients with variant-/complex- t(9;22) had poorer OS and RFS when compared with all other subgroups combined (P = 0.0018 and P = 0.0049, respectively). In addition, patients with ≥ 2 clones had worse OS and RFS than patients with 1 clone (P = 0.0179 and P = 0.0429, respectively). Multivariate analysis confirmed that variant-/complex-t(9;22) and clone number are independent risk factors. We suggest that conventional chromosomal analysis is of clinical importance for risk stratification of B-ALL patients.
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http://dx.doi.org/10.1016/j.leukres.2019.106176DOI Listing
September 2019

Data on rearrangement-driven chromosomal aberrations in myeloid malignancies.

Data Brief 2019 Jun 23;24:104025. Epub 2019 May 23.

Department of Hematopathology, School of Health Professions, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Data in this article presents the results of conventional cytogenetics and fluorescence in situ hybridization (FISH) analyses in 129 patients with confirmed rearrangement (https://doi.org/10.1016/j.cancergen.2019.03.002) [1]. Generally, the rearrangement has arisen through translocation, inversion, and insertion and/or unknown mechanism. In addition to the typical chromosomal aberrations, inv(3)(q21q26.2) and t(3; 3)(q21; q26.6) [2-4], over 50% of cases presented here exhibit a wide spectrum of rearrangement-driven, atypical chromosomal aberrations, including inv(3) with breakpoint other than 3q21; t(1; 3); t(2; 3); t(3; 6); t(3; 8); t(3; 12); t(3; 17); t(3; 21) as well as an insertion of 3q26.2 into different chromosomes. These cases are thoroughly characterized by karyotyping, interphase-, metaphase-, map-back FISH and whole chromosomal painting (WCP) analyses.
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http://dx.doi.org/10.1016/j.dib.2019.104025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6545385PMC
June 2019

An integrative approach reveals genetic complexity and epigenetic perturbation in acute promyelocytic leukemia: a single institution experience.

Hum Pathol 2019 09 21;91:1-10. Epub 2019 May 21.

Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA. Electronic address:

Acute promyelocytic leukemia (APL) is a distinct type of acute myeloid leukemia that is defined by the presence of the translocations that mostly involve the RARA gene. The most frequent translocation is the t(15;17), which fuses the RARA gene with the PML gene. Previous studies have shown that other cooperative mutations are required for the development of APL after the initiating event of the t(15;17). In this study, we combined cytogenetics with next-generation sequencing and single-nucleotide polymorphism array to study the genetic complexity in 20 APL cases diagnosed in our institution. All but 3 cases had additional genetic aberrations. Our study demonstrated that somatic mutations are frequent events in APL. In addition to the previously reported recurrent cooperative mutations in the FLT3, WT1, and RAS genes, we identified mutations in several epigenetic modifiers, including TET2, EZH2, and DNMT3A, co-occurring with either FLT3 or WT1 mutations. Mutations of the WT1 gene and chromosome 11p copy neutral loss of heterozygosity affecting WT1 are present in a third of the cases in our series. Two-thirds of APL cases in our study demonstrated a global reduction but focal accumulation of H3K27 methylase (H3K27me) expression, indicating a disorganized chromatin methylation pattern with generally more accessible chromatin status. Our study confirmed genetic complexity of APL and revealed that epigenetic aberrations are more common than previously expected. Although epigenetic modulation is not a common treatment strategy in APL, targeting this pathway may have some clinical utility in refractory or relapsed APL cases.
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http://dx.doi.org/10.1016/j.humpath.2019.05.008DOI Listing
September 2019

Deciphering the complexities of MECOM rearrangement-driven chromosomal aberrations.

Cancer Genet 2019 04 11;233-234:21-31. Epub 2019 Mar 11.

Department of Hematopathology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, United States.

MECOM rearrangement is associated with rapid disease progression and poor prognosis in myeloid neoplasms. Previous studies were often based on 3q26.2 abnormalities without confirmation of MECOM status. The frequency of MECOM rearrangement and attribution of various chromosomal aberrations remain poorly characterized. This study presented 129 cases with confirmed MECOM rearrangement by karyotyping and multiple FISH methodologies. MECOM rearrangement arose through translocation (49.6%, n = 64), inversion (40.3%, n = 52), insertion (5.4%, n = 7) or unknown mechanism(s) (4.7%, n = 6). The classic inv(3)(q21q26.2) was dominant (n = 50) in inversion-driven MECOM rearrangement; and 3 of them also had double inv(3). For translocation-driven MECOM rearrangement, t(3;21) was most common (n = 15), followed by t(2;3) (n = 13), t(3;12) (n = 10), t(3;3) (n = 9), t(3;8) (n = 6), t(3;6) and t(3;17) (n = 4 each), t(1;3) and t(3;?) (n = 1 each). Cases with t(3;3)-, t(3;12)-, and insertion-driven MECOM rearrangement were prone to exhibit a complex karyotype, while cases with t(2;3)-, t(3;21)- and insertion-driven MECOM rearrangement were prone to have an "unbalanced" MECOM FISH signal pattern, likely caused by uncommon breakpoint(s) within the target of 5'MECOM probe. Therefore, atypical chromosomal aberrations and/or mechanisms are involved in MECOM rearrangement. Confirmation/exclusion of MECOM rearrangement is necessary in all cases with a 3q26.2 abnormality. (Word count: 190).
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http://dx.doi.org/10.1016/j.cancergen.2019.03.002DOI Listing
April 2019

Rare myeloid sarcoma with KMT2A (MLL)-ELL fusion presenting as a vaginal wall mass.

Diagn Pathol 2019 Mar 28;14(1):26. Epub 2019 Mar 28.

Department of Pathology, Northwestern University Feinberg School of Medicine, 303 East Chicago Avenue, ward 3-140, Chicago, IL, 60611, USA.

Backgroud: Myeloid sarcoma (MS) is a rare neoplasm of immature myeloid precursors that form tumor mass outside the bone marrow. The diagnosis of de novo MS can be challenging, particularly in patients with no prior history of hematologic malignancies or when MS involves unusual anatomic sites.

Case Presentation: The patient was a 53-year-old woman with a history of uterine fibroids and vaginal bleeding for many years who presented with a vaginal wall mass. The tumor had histologic and phenotypic features of histiocytic sarcoma, however, overlapping with a possible extramedullary MS. Using a comprehensive genomic profiling, we were able to identify recurrent chromosomal aberrations associated with MS including a rare KMT2A-ELL fusion, losses of chromosomes 1p, 9, 10, 15, 18, and gain of chromosome 1q and mutations in FLT3 and PTPN11, and achived the final diagnosis of a de novo MS. The patient received standard treatment for acute myeloid leukemia regimen with stem cell transplantation and achieved complete remission.

Conclusion: Our case illustrates the clinical utility of comprehensive genomic profiling in assisting the diagnosis or differential diagnosis of challenging MS or histiocytic sarcoma cases, and in providing important information in tumor biology for appropriate clinical management.
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http://dx.doi.org/10.1186/s13000-019-0804-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6440110PMC
March 2019

Assessing genome-wide copy number aberrations and copy-neutral loss-of-heterozygosity as best practice: An evidence-based review from the Cancer Genomics Consortium working group for plasma cell disorders.

Cancer Genet 2018 12 5;228-229:184-196. Epub 2018 Oct 5.

Fred Hutchinson Cancer Research Center and University of Washington, Seattle, WA, USA. Electronic address:

Background: Plasma cell neoplasms (PCNs) encompass a spectrum of disorders including monoclonal gammopathy of undetermined significance, smoldering myeloma, plasma cell myeloma, and plasma cell leukemia. Molecular subtypes have been defined by recurrent cytogenetic abnormalities and somatic mutations that are prognostic and predictive. Karyotype and fluorescence in situ hybridization (FISH) have historically been used to guide management; however, new technologies and markers raise the need to reassess current testing algorithms.

Methods: We convened a panel of representatives from international clinical laboratories to capture current state-of-the-art testing from published reports and to put forward recommendations for cytogenomic testing of plasma cell neoplasms. We reviewed 65 papers applying FISH, chromosomal microarray (CMA), next-generation sequencing, and gene expression profiling for plasma cell neoplasm diagnosis and prognosis. We also performed a survey of our peers to capture current laboratory practice employed outside our working group.

Results: Plasma cell enrichment is widely used prior to FISH testing, most commonly by magnetic bead selection. A variety of strategies for direct, short- and long-term cell culture are employed to ensure clonal representation for karyotyping. Testing of clinically-informative 1p/1q, del(13q) and del(17p) are common using karyotype, FISH and, increasingly, CMA testing. FISH for a variety of clinically-informative balanced IGH rearrangements is prevalent. Literature review found that CMA analysis can detect abnormalities in 85-100% of patients with PCNs; more specifically, in 5-53% (median 14%) of cases otherwise normal by FISH and cytogenetics. CMA results in plasma cell neoplasms are usually complex, with alteration counts ranging from 1 to 74 (median 10-20), primarily affecting loci not covered by FISH testing. Emerging biomarkers include structural alterations of MYC as well as somatic mutations of KRAS, NRAS, BRAF, and TP53. Together, these may be measured in a comprehensive manner by a combination of newer technologies including CMA and next-generation sequencing (NGS). Our survey suggests most laboratories have, or are soon to have, clinical CMA platforms, with a desire to move to NGS assays in the future.

Conclusion: We present an overview of current practices in plasma cell neoplasm testing as well as an algorithm for integrated FISH and CMA testing to guide treatment of this disease.
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http://dx.doi.org/10.1016/j.cancergen.2018.07.002DOI Listing
December 2018

KRAS mutation in secondary malignant histiocytosis arising from low grade follicular lymphoma.

Diagn Pathol 2018 Oct 15;13(1):78. Epub 2018 Oct 15.

Department of Pathology, Northwestern University Feinberg School of Medicine, 251 E Huron Street, Chicago, IL, 60611, USA.

Background: Transformation of follicular lymphoma most typically occurs as diffuse large B-cell lymphoma, however other forms of transformation such as classic Hodgkin lymphoma and lymphoblastic transformation can occur. Secondary malignant histiocytosis also represents a rare form of transformation, which is thought to occur due to a process of transdifferentiation whereby the lymphoma cells exhibit lineage plasticity and lose all evidence of B-cell phenotype and instead acquire the phenotype of a histiocytic neoplasm. Little is known about the underlying genetic alterations that occur during this unusual process. Comparative genetic analysis of pre- and post-transformation/transdifferentiation would be one tool by which we could better understand how this phenomenon occurs.

Case Presentation: Here we report the clinical, immunophenotypic and genetic features of a rare case of secondary malignant histiocytosis, Langerhans cell-type (Langerhans cell sarcoma) arising from a previous low grade follicular lymphoma. FISH analysis confirmed the presence of IgH/BCL2 rearrangement in both the low grade follicular lymphoma (FL) and transformed Langerhans cells sarcoma (LCS) samples, demonstrating a clonal relationship. Comparative whole exome sequencing was then performed, which identified a KRAS p.G13D mutation in the LCS that was not present in the FL.

Conclusions: This report highlights genetic alterations, in particular an acquired somatic KRAS mutation, that may occur during transdifferentiation, with additional significance of KRAS mutation as a possible therapeutic target in cases which otherwise would have limited treatment options.
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http://dx.doi.org/10.1186/s13000-018-0758-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6190545PMC
October 2018

Hydropic leiomyoma: a distinct variant of leiomyoma closely related to HMGA2 overexpression.

Hum Pathol 2019 02 5;84:164-172. Epub 2018 Oct 5.

Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA. Electronic address:

Hydropic leiomyoma (HLM) is a variant of uterine leiomyoma with characteristic features of zonal distributions of edema, increased vascularity, and tumor cells arranged in nodules or cords. Diagnostic difficulty and patient management are further complicated by a lack of studies and unknown cause of the disease. To study this tumor's nature, 24 HLM cases were selected for analysis of cytohistologic features, immunohistochemical profile (HMGA2, FH, CD34, pAKT, p16, ER, SMA, and Ki-67), and molecular alterations of HMGA2 by fluorescence in situ hybridization and MED12 mutations. HLM showed large tumor size (average 14.4 cm) and unique histology, characterized by edematous areas of tumor cells with mostly round-oval nuclei, arranged in cords and/or with perinodular growth around vessels, and increased thick-walled vessels (average 17 vessels/10× medium-power field). Immunohistochemistry revealed that 76% (18/24) of HLMs had HMGA2 overexpression, 32% (6/19) of which harbored HMGA2 rearrangement detected by fluorescence in situ hybridization. Thick-walled vessels in HLM were composed of mostly HMGA2-positive tumor cells, and HLM with HMGA2 overexpression also showed CD34-positive tumor vessel-supporting pericytes. In contrast to usual-type leiomyoma with a high frequency of MED12 mutations, no MED12 mutations were found in any HLM. HLM showed increased pAKT activity, indicating a strong contribution of AKT pathway signaling in HLM promoting tumor growth. Our findings suggest that HLM is a distinct variant of uterine smooth muscle tumor likely driven by HMGA2 overexpression.
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http://dx.doi.org/10.1016/j.humpath.2018.09.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6408288PMC
February 2019

Genomic aberrations involving 12p/ETV6 are highly prevalent in blastic plasmacytoid dendritic cell neoplasms and might represent early clonal events.

Leuk Res 2018 10 17;73:86-94. Epub 2018 Sep 17.

Department of Hematopathology, The University of Texas MD Anderson Cancer Center, United States.

Background: Chromosomal aberrations at the ETV6 gene locus on 12p13.2 are common in bone marrow samples involved by blastic plasmacytoid dendritic cell neoplasm (BPDCN). However, their pathogenic role, incidence in cutaneous BPDCN lesions, and clinical significance have not been assessed systematically.

Results: The study group included 30 BPDCN patients, 25 men and 5 women, with a median age of 64 years. Conventional cytogenetic analysis demonstrated karyotypic aberrancies in 15 cases, of which 8 had chromosomal lesions involving 12p. In addition, 2 cases with normal diploid karyotype had cryptic 12p/ETV6 deletion by ETV6 FISH test. Notably, 2 bone marrow samples with ETV6 rearrangement had no detectable BPDCN involvement, but otherwise dynamic changes in the detection of 12p/ETV6 aberrations correlated with the presence of morphologically and/or immunophenotypically detectable disease. Tissue specimens from 6 patients with cutaneous BPDCN all tested positive for homozygous or heterozygous ETV6 deletions.

Conclusion: We demonstrate that monoallelic and biallelic 12p/ETV6 deletions are highly prevalent in BPDCN, and their detection is enhanced by the use of FISH and aCGH. In addition, 12p/ETV6 may be present in the bone marrow of BPDCN patients in the absence of detectable disease suggesting that such alterations might represent an early pathogenic event.
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http://dx.doi.org/10.1016/j.leukres.2018.09.006DOI Listing
October 2018

PD-1 is highly expressed by neoplastic B-cells in Richter transformation.

Br J Haematol 2019 04 20;185(2):370-373. Epub 2018 Jul 20.

Department of Pathology, Northwestern University Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.

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http://dx.doi.org/10.1111/bjh.15514DOI Listing
April 2019

Clinicopathologic and molecular features in hairy cell leukemia-variant: single institutional experience.

Mod Pathol 2018 11 28;31(11):1717-1732. Epub 2018 Jun 28.

Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Hairy cell leukemia-variant is rare. Only a small number of cases have been reported in the literature with little cytogenetic or molecular data available. In this study, we describe the clinicopathologic and genetic features of 23 patients with hairy cell leukemia-variant (16 men and 7 women) with a median age of 70 years. Most patients had splenomegaly (90%), leukocytosis (77%), and lymphocytosis (82%); no patients had monocytopenia. Histologically, the bone marrow biopsy specimens showed a mixed pattern of predominantly interstitial and lesser intrasinusoidal infiltration by leukemic cells. In bone marrow aspirate smears most cells had villous cytoplasmic features and a small nucleolus. We describe unusual sites of hairy cell leukemia-variant involvement in 4 patients, including brain, omentum, terminal ileum, and skin at the time of initial presentation. Immunophenotyping showed monotypic B-cells positive for pan B-cell antigens, CD11c, and CD103, and negative for CD25 and annexin A1. Conventional cytogenetic or fluorescence in situ hybridization analysis showed deletions of 17p13/TP53 and 11q22/ATM gene in 5/12 (42%) and 2/9 (22%) cases, respectively. Sequencing of the variable region of IGVH showed mutations (>2% deviation from germline) in 40% of the cases assessed. MAP2K1 mutation (p.C121S) was seen in 1 of 14 (7%) patients tested. No BRAF V600E mutations were detected. The patients were treated in a heterogeneous manner, but most often with therapies designed for classical hairy cell leukemia and the 5-year overall survival was 84%. In summary, hairy cell leukemia-variant exhibits a heterogeneous spectrum of clinical, morphologic, immunophenotypic, and genetic features that may overlap with classic hairy cell leukemia and other hairy cell-like B-cell neoplasms. A subset of patients can have an aggressive clinical course. In our experience MAP2K1 mutations are uncommon in this disease.
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http://dx.doi.org/10.1038/s41379-018-0093-8DOI Listing
November 2018

Isolated orbital mass as the primary presentation of a triple-hit lymphoma transformed from a systemic follicular lymphoma.

Am J Ophthalmol Case Rep 2018 Jun 24;10:156-158. Epub 2018 Feb 24.

Department of Pathology, Northwestern Memorial Hospital, 251 E. Huron, Chicago, IL 60611, USA.

Purpose: Triple-hit lymphoma is a highly aggressive B-cell lymphoma. We report a case of triple-hit lymphoma transformed from systemic follicular lymphoma (FL) after 9-year remission and presented primarily as an isolated orbital mass without systemic symptoms or lymphadenopathy.

Observations: A 58-year-old female presented with intermittent vertical binocular diplopia, left upper eyelid swelling and pain and was found to have a 2.9 cm orbital mass. Histological section revealed a CD10-positive large B-cell lymphoma, consistent with transformation of FL. Fluorescent hybridization (FISH) analysis demonstrated rearrangements involving and genes, indicating a high grade, triple-hit lymphoma.

Conclusions And Importance: Triple-hit lymphoma transformed from a low-grade lymphoma may initially present as an isolated orbital mass without systemic evidence of transformation. Early recognition of double or triple-hit lymphomas is important since these patients require aggressive chemotherapy.
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http://dx.doi.org/10.1016/j.ajoc.2018.02.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5956659PMC
June 2018