Publications by authors named "Bruce A Woda"

67 Publications

Laryngeal mucous membrane plasmacytosis with 15 year follow-up: Case report and literature review.

Leuk Res Rep 2020 27;13:100190. Epub 2019 Nov 27.

Department of Pathology, UMass Memorial Medical Center, Worcester, MA 01605, USA.

Mucous membrane plasmacytosis (MMP) is an uncommon variant of mucositis represented by a polyclonal plasma cell infiltration of mucosal tissue. Various clinical presentations in the upper airway have been reported ranging from erythematous mucosa to fungating masses. Histologic features include mucosal epithelial hyperplasia or psoriasiform changes with a dense submucosal infiltrate of polytypic plasma cells. Molecular studies for immunoglobulin gene rearrangement should be performed in all cases of MMP to rule out clonal neoplastic expansion of plasma cells. We present a case of MMP with over 15 years of clinical follow-up, emphasizing the relatively benign clinical course of this disorder.
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http://dx.doi.org/10.1016/j.lrr.2019.100190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6906643PMC
November 2019

Somatic molecular analysis augments cytologic evaluation of pancreatic cyst fluids as a diagnostic tool.

Oncotarget 2019 Jun 18;10(40):4026-4037. Epub 2019 Jun 18.

University of Massachusetts Medical School, Department of Pathology, Worcester, MA, USA.

Better tools are needed for early diagnosis and classification of pancreatic cystic lesions (PCL) to trigger intervention before neoplastic precursor lesions progress to adenocarcinoma. We evaluated the capacity of molecular analysis to improve the accuracy of cytologic diagnosis for PCL with an emphasis on non-diagnostic/negative specimens. In a span of 7 years, at a tertiary care hospital, 318 PCL endoscopic ultrasound-guided fine needle aspirations (EUS-FNA) were evaluated by cytologic examination and molecular analysis. Mucinous PCL were identified based on a clinical algorithm and 46 surgical resections were used to verify this approach. The mutation allele frequency (MAF) of commonly altered genes (, , , , , , , , and ) was evaluated for their ability to identify and grade mucinous PCL. Cytology showed a diagnostic sensitivity of 43.5% for mucinous PCL due in part to the impact of non-diagnostic (28.8%) and negative (50.5%) specimens. Incorporating an algorithmic approach or molecular analysis markedly increased the accuracy of cytologic evaluation. Detection of mucinous PCL by molecular analysis was 93.3% based on the detection of and/or gene mutations ( = 0.0001). Additional genes provided a marginal improvement in sensitivity but were associated with cyst type (e.g. ) and grade (e.g. ). In the surgical cohort, molecular analysis and the proposed algorithm showed comparable sensitivity (88.9% vs. 100%). Incorporating somatic molecular analysis in the cytologic evaluation of EUS-FNA increases diagnostic accuracy for detection, classification and grading of PCL. This approach has the potential to improve patient management.
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http://dx.doi.org/10.18632/oncotarget.26999DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6592293PMC
June 2019

Next-Generation Sequencing to Detect Deletion of RB1 and ERBB4 Genes in Chromophobe Renal Cell Carcinoma: A Potential Role in Distinguishing Chromophobe Renal Cell Carcinoma from Renal Oncocytoma.

Am J Pathol 2018 04 31;188(4):846-852. Epub 2018 Jan 31.

Department of Pathology, University of Massachusetts Medical School, Worcester, Massachusetts. Electronic address:

Overlapping morphologic, immunohistochemical, and ultrastructural features make it difficult to diagnose chromophobe renal cell carcinoma (ChRCC) and renal oncocytoma (RO). Because ChRCC is a malignant tumor, whereas RO is a tumor with benign behavior, it is important to distinguish these two entities. We aimed to identify genetic markers that distinguish ChRCC from RO by using next-generation sequencing (NGS). NGS for hotspot mutations or gene copy number changes was performed on 12 renal neoplasms, including seven ChRCC and five RO cases. Matched normal tissues from the same patients were used to exclude germline variants. Rare hotspot mutations were found in cancer-critical genes (TP53 and PIK3CA) in ChRCC but not RO. The NGS gene copy number analysis revealed multiple abnormalities. The two most common deletions were tumor-suppressor genes RB1 and ERBB4 in ChRCC but not RO. Fluorescence in situ hybridization was performed on 65 cases (ChRCC, n = 33; RO, n = 32) to verify hemizygous deletion of RB1 (17/33, 52%) or ERBB4 (11/33, 33%) in ChRCC, but not in RO (0/32, 0%). In total, ChRCCs (23/33, 70%) carry either a hemizygous deletion of RB1 or ERBB4. The combined use of RB1 and ERBB4 fluorescence in situ hybridization to detect deletion of these genes may offer a highly sensitive and specific assay to distinguish ChRCC from RO.
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http://dx.doi.org/10.1016/j.ajpath.2017.12.003DOI Listing
April 2018

Phosphorylation of the Mdm2 oncoprotein by the c-Abl tyrosine kinase regulates p53 tumor suppression and the radiosensitivity of mice.

Proc Natl Acad Sci U S A 2016 12 12;113(52):15024-15029. Epub 2016 Dec 12.

Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, MA 01655;

The p53 tumor suppressor acts as a guardian of the genome by preventing the propagation of DNA damage-induced breaks and mutations to subsequent generations of cells. We have previously shown that phosphorylation of the Mdm2 oncoprotein at Ser394 by the ATM kinase is required for robust p53 stabilization and activation in cells treated with ionizing radiation, and that loss of Mdm2 Ser394 phosphorylation leads to spontaneous tumorigenesis and radioresistance in Mdm2 mice. Previous in vitro data indicate that the c-Abl kinase phosphorylates Mdm2 at the neighboring residue (Tyr393) in response to DNA damage to regulate p53-dependent apoptosis. In this present study, we have generated an Mdm2 mutant mouse (Mdm2) to determine whether c-Abl phosphorylation of Mdm2 regulates the p53-mediated DNA damage response or p53 tumor suppression in vivo. The Mdm2 mice develop accelerated spontaneous and oncogene-induced tumors, yet display no defects in p53 stabilization and activity following acute genotoxic stress. Although apoptosis is unaltered in these mice, they recover more rapidly from radiation-induced bone marrow ablation and are more resistant to whole-body radiation-induced lethality. These data reveal an in vivo role for c-Abl phosphorylation of Mdm2 in regulation of p53 tumor suppression and bone marrow failure. However, c-Abl phosphorylation of Mdm2 Tyr393 appears to play a lesser role in governing Mdm2-p53 signaling than ATM phosphorylation of Mdm2 Ser394. Furthermore, the effects of these phosphorylation events on p53 regulation are not additive, as Mdm2 mice and Mdm2 mice display similar phenotypes.
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http://dx.doi.org/10.1073/pnas.1611798114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5206519PMC
December 2016

PD-L1 expression in EBV-negative diffuse large B-cell lymphoma: clinicopathologic features and prognostic implications.

Oncotarget 2016 Sep;7(37):59976-59986

Department of Pathology, UMass Memorial Medical Center and University of Massachusetts Medical School, Worcester, MA, USA.

Programmed cell death ligand 1 (PD-L1) is a cell surface glycoprotein that regulates the cellular immune response and serves as a targetable immune checkpoint molecule. PD-L1 is expressed on tumor cells and the immune microenvironment of several human malignancies, including a subset of aggressive lymphomas. We sought to investigate further the clinical and pathologic features of EBV-negative diffuse large B-cell lymphoma (DLBCL) cases that express PD-L1. Immunohistochemical staining using an anti-PD-L1 monoclonal antibody was performed on DLBCL cases from 86 patients. These patients received standard chemotherapy treatment and were followed for up to 175 months. Overall, 14 cases (16%) were considered positive for PD-L1 in tumor cells. In comparison with PD-L1 negative cases, PD-L1 positive cases had a higher rate of non-GCB type (71% vs. 30%, P=0.0060), and higher Ann Arbor stage (II-IV) (100% vs. 73%, P=0.0327). No significant differences were seen in the immunohistochemical expression of BCL2, MYC, or Ki67. Patients with tumors expressing PD-L1 demonstrated inferior overall survival (OS) upon long term follow up (P=0.0447). Both age/sex-adjusted and multivariate analyses identified PD-L1 as an independent predictor for OS (P=0.0101 and P=0.0424). There was no significant difference, however, in terms of remission rates after first treatment, relapse rates, and progression free survival between the groups. Identification of DLBCL cases that express PD-L1 may serve to select a subset of patients that could further benefit from targeted immunotherapy.
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http://dx.doi.org/10.18632/oncotarget.11045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5312363PMC
September 2016

Immunohistochemical loss of 5-hydroxymethylcytosine expression in acute myeloid leukaemia: relationship to somatic gene mutations affecting epigenetic pathways.

Histopathology 2016 Dec 23;69(6):1055-1065. Epub 2016 Sep 23.

Department of Pathology, University of Massachusetts Memorial Medical Center and University of Massachusetts Medical School, Worcester, MA, USA.

Aims: Genes affecting epigenetic pathways are frequently mutated in myeloid malignancies, including acute myeloid leukaemia (AML). The genes encoding TET2, IDH1 and IDH2 are among the most commonly mutated genes, and cause defective conversion of 5-methylcytosine into 5-hydroxymethylcytosine (5hmC), impairing demethylation of DNA, and presumably serving as driver mutations in leukaemogenesis. The aim of this study was to correlate 5hmC immunohistochemical loss with the mutation status of genes involved in epigenetic pathways in AML.

Methods And Results: Immunohistochemical staining with an anti-5hmC antibody was performed on 41 decalcified, formalin-fixed paraffin-embedded (FFPE) bone marrow biopsies from patients with AML. Archived DNA was subjected to next-generation sequencing for analysis of a panel of genes, including TET2, IDH1, IDH2, WT1 and DNMT3A. TET2, IDH1, IDH2, WT1 and DNMT3A mutations were found in 46% (19/41) of the cases. Ten of 15 cases (67%) with TET2, IDH1, IDH2 or WT1 mutations showed deficient 5hmC staining, whereas nine of 26 cases (35%) without a mutation in these genes showed loss of 5hmC. It is of note that all four cases with TET2 mutations showed deficient 5hmC staining.

Conclusions: Overall, somatic mutations in TET2, IDH1, IDH2, WT1 and DNMT3A were common in our cohort of AML cases. Immunohistochemical staining for 5hmC was lost in the majority of cases harbouring mutations in these genes, reflecting the proposed relationship between dysfunctional epigenetic pathways and leukaemogenesis.
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http://dx.doi.org/10.1111/his.13046DOI Listing
December 2016

Role of Tetrasomy for the Diagnosis of Urothelial Carcinoma Using UroVysion Fluorescent In Situ Hybridization.

Arch Pathol Lab Med 2016 Jun;140(6):552-9

From the Department of Pathology, University of Massachusetts Medical School, Worcester.

Context: -UroVysion fluorescent in situ hybridization (FISH) is routinely used to detect urothelial carcinoma (UC). A positive threshold is defined as chromosome polysomy in 4 or more cells, which also includes tetrasomy, a natural product of cell division.

Objectives: -To evaluate tetrasomy for UC detection and explore the relation to the surgical diagnosis or patient history.

Design: -The FISH was performed on 1532 urine samples from patients with cytology results and 4 or more years of follow-up. We created separate polysomy and tetrasomy categories and constructed receiver operating curves to determine appropriate thresholds using biopsy (n = 194) as the gold standard. Standard FISH and a novel assay integrating cytomorphology and FISH (Target-FISH) were compared. Matching tissue biopsies of urine samples with 10 or more tetrasomy cells were analyzed.

Results: -No significant threshold was found for tetrasomy cells. Exclusion of tetrasomy from the polysomy category changed the threshold from 8.5 to 4.5 cells, increased specificity (59.2% to 78.9%), but reduced sensitivity (78.9% to 65.9%). In Target-FISH, the same approach yielded a specificity of 93.7% and sensitivity of 65.2%. Similarly, specificity improved significantly for low- and high-grade UC, but sensitivity decreased for low-grade UC. No evidence of UC was observed in 95% (52 of 55) of the patients referred for screening who had 10 or more tetrasomy cells by FISH. Matching biopsies for urines containing 10 or more tetrasomy cells showed few or no tetrasomy cells.

Conclusions: -Tetrasomy is a nonspecific finding frequently encountered in urine FISH and should be excluded from the polysomy classification. Target-FISH is an optimal approach, offering the ability to detect rare tetrasomy tumors.
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http://dx.doi.org/10.5858/arpa.2015-0109-OADOI Listing
June 2016

Mild Microcytic Anemia in an Infant with a Compound Heterozygosity for Hb C (HBB: c.19G > A) and Hb Osu Christiansborg (HBB: c.157G > A).

Hemoglobin 2016 Jun;40(3):208-9

d Department of Pediatrics and Department of Molecular , Cell, and Cancer Biology, University of Massachusetts Medical School , Worcester , Massachusetts , USA.

We report an infant with a compound heterozygosity for Hb C (HBB: c.19G > A) and Hb Osu Christiansborg (HBB: c.157G > A) and a phenotype of mild microcytic anemia with target cell morphology but without overt hemolysis.
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http://dx.doi.org/10.3109/03630269.2016.1165245DOI Listing
June 2016

MYC Immunohistochemistry to Identify MYC-Driven B-Cell Lymphomas in Clinical Practice.

Am J Clin Pathol 2016 Feb 1;145(2):166-79. Epub 2016 Feb 1.

From the Department of Pathology, Brigham and Women's Hospital, Boston, MA

Objectives: Immunohistochemistry with anti-MYC antibody (MYC IHC) detects MYC protein in fixed samples of aggressive B-cell lymphomas and, according to the number of positive staining tumor nuclei, facilitates tumor subclassification, predicts underlying MYC rearrangements, and stratifies patient outcome. We aimed to determine the performance of MYC IHC in clinical practice.

Methods: We reviewed MYC IHC performed on control specimens and 256 aggressive B-cell lymphomas and compared clinically reported IHC scores with experts' review.

Results: Control tissues showed less than 5% variation in daily IHC staining. Reported and expert IHC scores were well correlated (r = 0.86) with an SD of 14.2%. Reported IHC scores 30% or less and 70% or more were accurate (94.5%) compared with experts in categorizing tumors as "MYC IHC-Low" and "MYC IHC-High," respectively, but scores 40% to 60% were not (60.3%). The mean IHC score among lymphomas with MYC rearrangements was 80%, but with a large range of scores (20%-100%). There was no statistically significant association between IHC score and MYC copy number.

Conclusions: Under optimal conditions, clinically reported MYC IHC scores are concordant with expert scores within 15%. MYC IHC does not capture all B-cell lymphomas with MYC rearrangements, however. MYC IHC and MYC fluorescence in situ hybridization are both recommended to identify MYC-driven B-cell lymphomas.
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http://dx.doi.org/10.1093/ajcp/aqv028DOI Listing
February 2016

Hemophagocytic lymphohistiocytosis secondary to T-cell/histiocyte-rich large B-cell lymphoma.

Leuk Res Rep 2014 2;3(2):42-5. Epub 2014 Jun 2.

Department of Pathology UMass Memorial Medical Center and University of Massachusetts Medical School, 1 Innovation Drive, Biotech 3, Worcester, MA 01605, USA.

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening clinical syndrome characterized by dysregulation of the immune system. Impaired function of cytotoxic T cells and natural killer cells is often seen, and T-cell malignancies represent most cases of lymphoma-associated HLH. HLH associated with B-cell lymphoma is rare. We describe a case of a 30-year-old man who presented with fever, splenomegaly, and hyperferritinemia. Bone marrow biopsy revealed T-cell/histiocyte-rich large B-cell lymphoma, a rare, aggressive B-cell malignancy. This case highlights the interplay between a pro-inflammatory cytokine microenvironment and tumor-mediated immune suppression, and addresses the importance of accurately diagnosing these entities for appropriate clinical management.
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http://dx.doi.org/10.1016/j.lrr.2014.05.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4062756PMC
June 2014

IMP3 expression is associated with poor outcome and epigenetic deregulation in intrahepatic cholangiocarcinoma.

Hum Pathol 2014 Jun 6;45(6):1184-91. Epub 2014 Feb 6.

Liver Transplantation Center of the First Affiliated Hospital, Nanjing Medical University and The Key Laboratory of Living Donor Liver Transplantation, Ministry of Health, Nanjing 210029, China. Electronic address:

IMP3 is a fetal protein not expressed in normal adult tissues. IMP3 is an oncoprotein and a useful biomarker for a variety of malignancies and is associated with reduced overall survival of a number of them. IMP3 expression and its prognostic value for patients with intrahepatic cholangiocarcinoma (ICC) have not been well investigated. The molecular mechanism underlying IMP3 expression in human cancer cells remains to be elucidated. Here we investigated IMP3 expression in ICC and adjacent nonneoplastic liver in 72 unifocal primary ICCs from a single institute by immunohistochemistry, immunoblotting, and real-time polymerase chain reaction. IMP3 was specifically expressed in cancer cells but not in the surrounding normal tissue, and 59 (82%) of 72 ICCs were IMP3 positive by immunohistochemistry. Among 35 cases with lymphovascular invasion, 26 (74%) showed IMP3 positivity in lymph node metastases. IMP3 expression was significantly correlated with tumor size, pathological grade, metastasis, and clinical stage. Kaplan-Meier analysis demonstrated an inverse correlation between IMP3 expression and overall survival rate. Multivariate analysis revealed that IMP3 was the only risk factor associated with survival. To further explore the mechanism of IMP3 expression in cancers, we identified 2 CpG islands at IMP3 proximal promoter. Interestingly, the IMP3 promoter was almost completely demethylated in ICCs in contrast to densely methylated promoter in normal liver tissues. IMP3 expression is a useful biomarker for ICCs and can provide an independent prognostic value for patients with ICC. To our knoweldge, this is the first direct evidence of epigenetic deregulation of IMP3 in human cancer.
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http://dx.doi.org/10.1016/j.humpath.2014.01.016DOI Listing
June 2014

Oncofetal protein IMP3, a new cancer biomarker.

Adv Anat Pathol 2014 May;21(3):191-200

Department of Pathology, University of Massachusetts Medical School, Worcester, MA.

IMP3 is a member of a family of RNA-binding proteins that consists of IMP1, IMP2 and IMP3. These proteins contain 2 RNA recognition motifs and 4 K-homology domains that allow them to bind RNAs strongly and specifically. IMP3 is an oncofetal protein involved in embryogenesis and its expression is associated with a number of malignant neoplasms. IMP3 is associated with aggressive and advanced cancers and is specifically expressed in malignant tumors but is not found in adjacent benign tissues. Moreover, in vitro studies have shown that IMP3 promotes tumor cell proliferation, adhesion, and invasion. This review focuses on the studies of IMP3 expression in different cancers and emphasizes the potential utility of IMP3 in routine surgical pathology practice. We also discuss IMP3 as a prognostic biomarker for cancer patients' outcomes.
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http://dx.doi.org/10.1097/PAP.0000000000000021DOI Listing
May 2014

MYC protein expression is detected in plasma cell myeloma but not in monoclonal gammopathy of undetermined significance (MGUS).

Am J Surg Pathol 2014 Jun;38(6):776-83

Departments of *Pathology †Medicine, Division of Hematology/Oncology, UMass Memorial Medical Center and University of Massachusetts Medical School, Worcester ‡Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.

It has been recognized that monoclonal gammopathy of undetermined significance (MGUS) precedes a diagnosis of plasma cell myeloma in most patients. Recent gene expression array analysis has revealed that an MYC activation signature is detected in plasma cell myeloma but not in MGUS. In this study, we performed immunohistochemical studies using membrane CD138 and nuclear MYC double staining on bone marrow biopsies from patients who met the diagnostic criteria of plasma cell myeloma or MGUS. Our study demonstrated nuclear MYC expression in CD138-positive plasma cells in 22 of 26 (84%) plasma cell myeloma samples and in none of the 29 bone marrow samples from patients with MGUS. In addition, our data on the follow-up biopsies from plasma cell myeloma patients with high MYC expression demonstrated that evaluation of MYC expression in plasma cells can be useful in detecting residual disease. We also demonstrated that plasma cells gained MYC expression in 5 of 8 patients (62.5%) when progressing from MGUS to plasma cell myeloma. Analysis of additional lymphomas with plasmacytic differentiation, including lymphoplasmacytic lymphoma, marginal zone lymphoma, and plasmablastic lymphoma, reveals that MYC detection can be a useful tool in the diagnosis of plasma cell myeloma.
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http://dx.doi.org/10.1097/PAS.0000000000000213DOI Listing
June 2014

Five important advances in hematopathology.

Arch Pathol Lab Med 2014 Mar;138(3):410-9

From the Department of Pathology, UMass Memorial Medical Center, Worcester, Massachusetts.

Context: Hematopathology is a dynamic field that has always been on the frontier of clinical research within the scope of pathology. Several recent developments in hematopathology will likely affect its practice clinically.

Objective: To review 5 important recent advances in hematopathology: (1) detection and prognostic implication of MYC in diffuse large B-cell lymphomas, (2) determining origin and prognosis through immunoglobulin gene usage in mature B-cell neoplasms, (3)detecting minimal residual disease in multiple myeloma, (4) using genome-wide analysis in myelodysplastic syndromes, and (5) employing whole-genome sequencing in acute myeloid leukemias.

Data Sources: Literature review and the authors' experiences in an academic center.

Conclusions: These advances will bring hematopathology into a new molecular era and help us to better understand the molecular, pathologic mechanisms of lymphomas, leukemias, myelomas, and myelodysplastic syndromes. They will help us to identify diagnostic and prognostic markers and eventually provide new therapeutic targets and treatments for these diseases.
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http://dx.doi.org/10.5858/ARPA.2012-0645-RADOI Listing
March 2014

Loss of 5-hydroxymethylcytosine correlates with increasing morphologic dysplasia in melanocytic tumors.

Mod Pathol 2014 Jul 3;27(7):936-44. Epub 2014 Jan 3.

Program in Dermatopathology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

DNA methylation is the most well-studied epigenetic modification in cancer biology. 5-hydroxymethylcytosine is an epigenetic mark that can be converted from 5-methylcytosine by the ten-eleven translocation gene family. We recently reported the loss of 5-hydroxymethylcytosine in melanoma compared with benign nevi and suggested that loss of this epigenetic marker is correlated with tumor virulence based on its association with a worse prognosis. In this study, we further characterize the immunoreactivity patterns of 5-hydroxymethylcytosine in the full spectrum of melanocytic lesions to further validate the potential practical application of this epigenetic marker. One hundred and seventy-five cases were evaluated: 18 benign nevi, 20 dysplastic nevi (10 low-grade and 10 high-grade lesions), 10 atypical Spitz nevi, 20 borderline tumors, 5 melanomas arising within nevi, and 102 primary melanomas. Progressive loss of 5-hydroxymethylcytosine from benign dermal nevi to high-grade dysplastic nevi to borderline melanocytic neoplasms to melanoma was observed. In addition, an analysis of the relationship of nuclear diameter with 5-hydroxymethylcytosine staining intensity within lesional cells revealed a significant correlation between larger nuclear diameter and decreased levels of 5-hydroxymethylcytosine. Furthermore, borderline lesions uniquely exhibited a diverse spectrum of staining of each individual case. This study further substantiates the association of 5-hydroxymethylcytosine loss with dysplastic cytomorphologic features and tumor progression and supports the classification of borderline lesions as a biologically distinct category of melanocytic lesions.
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http://dx.doi.org/10.1038/modpathol.2013.224DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4077910PMC
July 2014

Advances in understanding the pathogenesis of HLH.

Br J Haematol 2013 Jun 12;161(5):609-22. Epub 2013 Apr 12.

Division of Pediatric Hematology and Oncology, University of Massachusetts Medical Center, Worcester, MA 01655, USA.

Haemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory disorder resulting from immune dysfunction reflecting either primary immune deficiency or acquired failure of normal immune homeostasis. Familial HLH includes autosomal recessive and X-linked disorders characterized by uncontrolled activation of T cells and macrophages and overproduction of inflammatory cytokines, secondary to defects in genes encoding proteins involved in granule-dependent cytolytic pathways. In older children and adults, HLH is associated more often with infections, malignancies, autoimmune diseases, and acquired immune deficiencies. HLH, macrophage activation syndrome, sepsis, and systemic inflammatory response syndrome are different clinical entities that probably represent a common immunopathological state, termed cytokine storm. These conditions may be clinically indistinguishable; all include massive inflammatory response, elevated serum cytokine levels, multi-organ involvement, haemophagocytic macrophages, and often death. Tissues of haematopoietic and lymphoid function are directly involved; other organs are secondarily damaged by circulating cytokines and chemokines. Haemophagocytic disorders are now increasingly diagnosed in the context of severe inflammatory reactions to viruses, malignancies and systemic connective tissue diseases. Many of these cases may reflect underlying genetic predispositions to HLH. The detection of gene defects has contributed considerably to our understanding of HLH, but the mechanisms leading to acquired HLH have yet to be fully determined.
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http://dx.doi.org/10.1111/bjh.12293DOI Listing
June 2013

Transformation of follicular lymphoma to Epstein-Barr virus-related Hodgkin-like lymphoma.

J Clin Oncol 2013 Feb 7;31(5):e53-6. Epub 2013 Jan 7.

Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

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http://dx.doi.org/10.1200/JCO.2012.43.2377DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3565184PMC
February 2013

Loss of 5-hydroxymethylcytosine is an epigenetic hallmark of melanoma.

Cell 2012 Sep;150(6):1135-46

Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.

DNA methylation at the 5 position of cytosine (5-mC) is a key epigenetic mark that is critical for various biological and pathological processes. 5-mC can be converted to 5-hydroxymethylcytosine (5-hmC) by the ten-eleven translocation (TET) family of DNA hydroxylases. Here, we report that "loss of 5-hmC" is an epigenetic hallmark of melanoma, with diagnostic and prognostic implications. Genome-wide mapping of 5-hmC reveals loss of the 5-hmC landscape in the melanoma epigenome. We show that downregulation of isocitrate dehydrogenase 2 (IDH2) and TET family enzymes is likely one of the mechanisms underlying 5-hmC loss in melanoma. Rebuilding the 5-hmC landscape in melanoma cells by reintroducing active TET2 or IDH2 suppresses melanoma growth and increases tumor-free survival in animal models. Thus, our study reveals a critical function of 5-hmC in melanoma development and directly links the IDH and TET activity-dependent epigenetic pathway to 5-hmC-mediated suppression of melanoma progression, suggesting a new strategy for epigenetic cancer therapy.
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http://dx.doi.org/10.1016/j.cell.2012.07.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3770275PMC
September 2012

ATM phosphorylation of Mdm2 Ser394 regulates the amplitude and duration of the DNA damage response in mice.

Cancer Cell 2012 May;21(5):668-79

Department of Cell Biology, University of Massachusetts Medical School, Worcester, MA 01655, USA.

DNA damage induced by ionizing radiation activates the ATM kinase, which subsequently stabilizes and activates the p53 tumor suppressor protein. Although phosphorylation of p53 by ATM was found previously to modulate p53 levels and transcriptional activities in vivo, it does not appear to be a major regulator of p53 stability. We have utilized mice bearing altered Mdm2 alleles to demonstrate that ATM phosphorylation of Mdm2 serine 394 is required for robust p53 stabilization and activation after DNA damage. In addition, we demonstrate that dephosphorylation of Mdm2 Ser394 regulates attenuation of the p53-mediated response to DNA damage. Therefore, the phosphorylation status of Mdm2 Ser394 governs p53 protein levels and functions in cells undergoing DNA damage.
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http://dx.doi.org/10.1016/j.ccr.2012.04.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3360886PMC
May 2012

Post transplant lymphoproliferative disorders: risk, classification, and therapeutic recommendations.

Curr Treat Options Oncol 2012 Mar;13(1):122-36

The University of Massachusetts Medical School, Worcester, MA, USA.

Opinion Statement: Post transplant lymphoproliferative disorder (PTLD) is a heterogeneous disease that may occur in recipients of solid organ transplants (SOT) and hematopoietic stem cell transplant. The risk of lymphoma is increased 20-120% compared with the general population with risk dependent in part on level of immune suppression. In addition, recent data have emerged, including HLA and cytokine gene polymorphisms, regarding genetic susceptibility to PTLD. Based on morphologic, immunophenotypic, and molecular criteria, PLTD are classified into 4 pathologic categories: early lesions, polymorphic, monomorphic, and classical Hodgkin lymphoma. Evaluation by expert hematopathology is critical in establishing the diagnosis. The aim of therapy for most patients is cure with the concurrent goal of preservation of allograft function. Given the pathologic and clinical heterogeneity of PTLD, treatment is often individualized. A mainstay of therapy remains reduction of immune suppression (RI) with the level of reduction being dependent on several factors (e.g., history of rejection, current dosing, and type of allograft). Outside of early lesions and/or low tumor burden, however, RI alone is associated with cure in a minority of subjects. We approach most newly-diagnosed polymorphic and monomorphic PTLDs similarly using frontline single-agent rituximab (4 weeks followed by abbreviated maintenance) in conjunction with RI. Frontline combination chemotherapy may be warranted for patients with high tumor burden in need of prompt response or following failure of RI and/or rituximab. Due to chemotherapy-related complications in PTLD, especially infectious, we advocate comprehensive supportive care measures. Surgery or radiation may be considered for select patients with early-stage disease. For PTLD subjects with primary CNS lymphoma, we utilize therapeutic paradigms similar to immunocompetent CNS lymphoma using high-dose methotrexate-based therapy with concurrent rituximab therapy and sequential high-dose cytarabine. Finally, novel therapeutic strategies, especially adoptive immunotherapy, should continued to be explored.
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http://dx.doi.org/10.1007/s11864-011-0177-xDOI Listing
March 2012

IMP3, a new biomarker to predict progression of cervical intraepithelial neoplasia into invasive cancer.

Am J Surg Pathol 2011 Nov;35(11):1638-45

Department of Pathology, Division of Preventive and Behavioral Medicine, University of Massachusetts Medical Center, Worcester, USA.

The expression of IMP3, an oncofetal protein, has been strongly associated with aggressive cancers. In this study, we investigated whether IMP3 can serve as a biomarker to predict invasive squamous cell carcinoma (SCC) in patients with cervical intraepithelial neoplasia (CIN) II and III. A total of 1249 patients with no dysplasia, CINs, or invasive SCC were studied for IMP3 expression. The 710 patients with CIN II and III in their cervical biopsies were further evaluated for invasive cancer-free survival analysis. The role of IMP3 in the regulation of cell proliferation and migration of HeLa cervical cancer cells was examined by modification of IMP3 expression with small interference RNA. Compared with CIN I or cervical tissues without dysplasia, IMP3 expression was significantly increased not only in invasive SCC but also most importantly in a subset of CIN III cases with concurrent invasive SCC. Importantly, invasive cancer was found only in patients with IMP3-positive CIN II and III, whereas no invasive cancer was detected in patients with IMP3-negative CIN II and III in their follow-up resections (P<0.0001). Reduction of IMP3 expression in cervical cancer cells significantly reduced cell migration without altering cell proliferation. IMP3 plays a critical role in the development of invasive SCC from cervical dysplasia. IMP3 can be used at the time of initial diagnosis of CIN to identify a group of patients with an increased chance of developing invasive cancer.
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http://dx.doi.org/10.1097/PAS.0b013e31823272d4DOI Listing
November 2011

The oncofetal protein IMP3: a novel molecular marker to predict aggressive meningioma.

Arch Pathol Lab Med 2011 Aug;135(8):1032-6

Department of Pathology, University of Massachusetts Medical Center, Worcester, USA.

Context: One of the major clinical challenges is to predict recurrence of meningioma. Recently, we have found that IMP3, an oncofetal RNA-binding protein, is a biomarker to predict aggressive tumors.

Objective: To investigate whether IMP3 can be used as a new biomarker to predict the recurrence and overall survival of patients with meningiomas.

Design: One hundred seven patients with primary meningiomas were investigated for expression of IMP3 by immunohistochemistry and whether expression of this molecule correlated with tumor recurrence and overall survival.

Results: Tumor recurrence was found in 13 of 107 patients with primary meningioma. Seven of 107 patients (6.5%) with primary meningiomas expressed IMP3. Kaplan-Meier plots and log-rank tests showed that patients with IMP3-positive tumors had a much higher recurrence rate (P = .004) and a poorer overall survival (P < .001) than did patients with IMP3-negative tumors. The 5-year recurrence-free and overall survival rates were 0% and 36% in IMP3-positive patients versus 89% and 94% in IMP3-negative patients, respectively. Multivariable analysis of IMP3 status (positive versus negative) in primary tumors showed a hazard ratio of 17.89 for recurrence (P = .01), which was much higher than hazard ratios associated with all other known risk factors including higher tumor grades and Ki-67 labeling index.

Conclusions: IMP3 is a potential independent prognostic biomarker that can be used at the time of initial diagnosis of meningioma to identify patients who have a high risk of developing a recurrence.
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http://dx.doi.org/10.5858/2009-0652-OAR2DOI Listing
August 2011

Oncofetal protein IMP3, a new diagnostic biomarker to distinguish malignant mesothelioma from reactive mesothelial proliferation.

Am J Surg Pathol 2011 Jun;35(6):878-82

Department of Pathology, University of Massachusetts Medical Center, One Innovation Drive, Worcester, MA 01605, USA.

The distinction of malignant mesothelioma from reactive mesothelial proliferation remains to be a major challenge for surgical pathologists. In this study, we investigated whether insulin-like growth factor II messenger ribonucleic acid-binding protein 3 (IMP3), an oncofetal protein, can be used as a biomarker to distinguish between malignant and reactive mesothelial cells. A total of 109 cases (mesothelioma, n=45; reactive mesothelial proliferation, n=64) were examined by immunohistochemistry for IMP3 expression. IMP3 showed strong cytoplasmic staining in 33 of 45 (73%) mesothelioma cases. In contrast, the expression of IMP3 was undetectable in all (64 cases) benign reactive mesothelial proliferations. Among the IMP3-positive mesotheliomas, 27 (82%) exhibited diffuse IMP3 expression. The vast majority of IMP3-positive subtypes of mesotheliomas showed IMP3 expression in >50% of malignant cells, as this diffuse staining pattern occurred in 17 (81%) cases of epithelial, 4 (100%) cases of sarcomatoid, and 6 (75%) cases of mixed types of mesothelioma. In addition, 2 cases, which were initially diagnosed as atypical mesothelial proliferations and later confirmed to be mesotheliomas, showed diffuse IMP3 expression. Our findings suggest that IMP3 is a new positive biomarker for malignant mesothelioma. IMP3 immunohistochemical staining can be used as an adjunct tool in the distinction of malignant mesothelioma from reactive mesothelial proliferations.
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http://dx.doi.org/10.1097/PAS.0b013e318218985bDOI Listing
June 2011

IMP2 expression distinguishes endometrioid from serous endometrial adenocarcinomas.

Am J Surg Pathol 2011 Jun;35(6):868-72

Department of Pathology, University of Massachusetts Medical Center, One Innovation Drive, Worcester, MA 01605, USA.

Among various endometrial adenocarcinomas, endometrioid carcinoma can be very difficult to separate from serous carcinomas. Various biomarkers have been studied with proven value, including p53, Ki-67, and p16. In this study, we present data on another biomarker, IMP2, which we believe is sensitive and specific. Using 320 endometrial biopsy cases, we demonstrate that IMP2 is normally expressed in all proliferative and inactive endometrial glandular cells. The pattern of such expression is unchanged in serous carcinomas. IMP2 expression is, however, lost in all cases of endometrioid carcinomas by at least 25% to >95% of tumor cell populations. Therefore, loss of IMP2 expression can differentiate endometrioid from serous carcinomas. Such finding of IMP2 expression remained the same in mixed endometrioid and serous carcinomas; IMP2 expression is lost in all endometrioid components by at least 25% of tumor cell population, whereas it remained diffuse and strong in all serous components of carcinomas.
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http://dx.doi.org/10.1097/PAS.0b013e318219c6f9DOI Listing
June 2011

Anaplastic lymphoma kinase-positive large B-cell lymphoma with complex karyotype and novel ALK gene rearrangements.

Hum Pathol 2011 Oct 15;42(10):1562-7. Epub 2011 Apr 15.

Department of Pathology and Department of Hospital Laboratories, UMass Memorial Medical Center and University of Massachusetts Medical School, Worcester, MA 01605, USA.

Anaplastic lymphoma kinase-positive large B-cell lymphoma is a rare non-Hodgkin lymphoma that exhibits a characteristic immunoblastic/plasmablastic morphology and is frequently associated with t(2;17)(p23;q23) and expression of Clathrin-anaplastic lymphoma kinase fusion protein. Here, we report a refractory anaplastic lymphoma kinase-positive large B-cell lymphoma in a 49-year-old human immunodeficiency virus-positive man. The neoplastic cells expressed CD138, epithelial membrane antigen, CD45, and perforin, and showed a strong granular cytoplasmic anaplastic lymphoma kinase staining pattern. Conventional chromosome analysis revealed a clone with multiple anomalies and a chromosome count of 76 to 79. Fluorescence in situ hybridization studies showed 5 copies of the ALK gene with 2 intact signals and 3 signals resulting from 2 independent, previously unreported, rearrangements. One rearrangement, seen in 2 copies, involved translocation of ALK sequences to chromosome Xq21. The second rearrangement involved translocation of ALK sequences to chromosome 12q24.1. This case broadens the cytogenetic alterations in anaplastic lymphoma kinase-positive large B-cell lymphoma, and it also demonstrates the high genetic instability of this tumor.
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http://dx.doi.org/10.1016/j.humpath.2011.01.012DOI Listing
October 2011

High-level CD34 expression on megakaryocytes independently predicts an adverse outcome in patients with myelodysplastic syndromes.

Leuk Res 2011 Jun 1;35(6):766-70. Epub 2011 Mar 1.

Department of Pathology, University of Massachusetts Medical Center, Worcester, MA 01605, USA.

Expression of CD34 on mature-appearing megakaryocytes can be seen in various intrinsic bone marrow (BM) disorders as well as reactive bone marrows. In this study we investigate the clinical significance of CD34+ megakaryocytes in myelodysplastic syndromes (MDSs). Expression of CD34 on megakaryocytes was assessed on BM biopsies obtained from 202 patients with MDS. High-level (≥20%) CD34 expression on megakaryocytes was found in BM of 29 patients (14%). The expression of CD34 on megakaryocytes is correlated with severe cytopenia, higher numbers of myeloblasts, more frequent and higher risk cytogenetic abnormalities, and a shorter overall survival. Multivariate analysis indicated that the expression of CD34 on megakaryocytes could be a strong and an independent poor prognostic factor in MDS, with a hazard ratio of 2.53.
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http://dx.doi.org/10.1016/j.leukres.2011.01.009DOI Listing
June 2011

Infection with viruses from several families triggers autoimmune diabetes in LEW*1WR1 rats: prevention of diabetes by maternal immunization.

Diabetes 2010 Jan 30;59(1):110-8. Epub 2009 Sep 30.

BioMedical Research Models, Worcester, Massachusetts, USA.

Objective: The contribution of antecedent viral infection to the development of type 1 diabetes in humans is controversial. Using a newer rat model of the disease, we sought to 1) identify viruses capable of modulating diabetes penetrance, 2) identify conditions that increase or decrease the diabetogenicity of infection, and 3) determine whether maternal immunization would prevent diabetes.

Research Design And Methods: About 2% of LEW*1WR1 rats develop spontaneous autoimmune diabetes, but disease penetrance is much higher if weanling rats are exposed to environmental perturbants including Kilham rat virus (KRV). We compared KRV with other viruses for diabetogenic activity.

Results: Both KRV and rat cytomegalovirus (RCMV) induced diabetes in up to 60% of LEW*1WR1 rats, whereas H-1, vaccinia, and Coxsackie B4 viruses did not. Simultaneous inoculation of KRV and RCMV induced diabetes in 100% of animals. Pretreatment of rats with an activator of innate immunity increased the diabetogenicity of KRV but not RCMV and was associated with a moderate rate of diabetes after Coxsackie B4 and vaccinia virus infection. Inoculation of LEW*1WR1 dams with both KRV and RCMV prior to pregnancy protected weanling progeny from virus-induced diabetes in a virus-specific manner.

Conclusions: Exposure to viruses can affect the penetrance of autoimmune diabetes in genetically susceptible animals. The diabetogenicity of infection is virus specific and is modified by immunomodulation prior to inoculation. Maternal immunization protects weanlings from virus-induced diabetes, suggesting that modification of immune responses to infection could provide a means of preventing islet autoimmunity.
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http://dx.doi.org/10.2337/db09-0255DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2797911PMC
January 2010

Chronic basophilic leukemia: a rare form of chronic myeloproliferative neoplasm.

Hum Pathol 2009 Aug 8;40(8):1194-9. Epub 2009 May 8.

Department of Pathology, University of Massachusetts Medical Center, Worcester, MA 01605, USA.

Chronic basophilic leukemia is a rare and poorly characterized entity. Only a limited number of cases have been described. Herein, we report a patient who presented with fatigue, weight loss, leukocytosis, persistent prominent basophilia, and mild eosinophilia. The bone marrow showed features characteristic of a myeloproliferative neoplasm with a marked increase in maturing basophils. The basophils exhibited nuclear hypersegmentation, abnormal granulation, and abnormally low CD38 expression. Conventional karyotyping revealed a t(5;12)(q31;p13). ETV6 but not PDGFRB rearrangement was detected by fluorescence in situ hybridization.
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http://dx.doi.org/10.1016/j.humpath.2009.02.011DOI Listing
August 2009

The utility of flow cytometric immunophenotyping in cytopenic patients with a non-diagnostic bone marrow: a prospective study.

Leuk Res 2009 Aug 18;33(8):1039-46. Epub 2009 Feb 18.

Department of Pathology, UMass Memorial Medical Center, University of Massachusetts School of Medicine, Worcester, MA, USA.

Cytopenia is a common problem in hematology outpatient clinics and among hospitalized patients. A bone marrow (BM) aspirate and biopsy are often performed to rule out an infiltrative versus intrinsic BM process, such as myelodysplastic syndrome (MDS). We have previously described a flow cytometric (FCM) assay useful in diagnosing MDS and demonstrated its good correlation with "gold standard" morphologic and cytogenetic criteria. In this study, we prospectively tested the utility of the FCM assay in 102 cytopenic patients with BMs showing neither diagnostic morphological dysplasia nor abnormal cytogenetics. FCM, following our published criteria, was positive in 22 cases (21.6%), intermediate in 11 cases (10.8%) and negative in 69 cases (67.6%). With a median follow-up period of 11 months (range, 4-24 months), 12 (11.8%) patients were proven to have or/develop MDS or related BM diseases (group-1); 61 (59.8%) patients had their cytopenia(s) attributed to various medical causes (group-2). In the remaining 29 patients, the causes of cytopenia(s) were not found, and some had the features consistent with the recently defined clinical entity -- idiopathic cytopenia of uncertain significance. A positive FCM result was significantly more prevalent (9/12, 75%) in group-1 patients; while a negative FCM result was significantly more frequent in group-2 patients (4/61, 7%) (p<0.0001) with a positive predictive value of 69% and a negative predictive value of 95%. We conclude that FCM analysis of myelomonocytic maturation has diagnostic utility in cytopenic patients who have an inconclusive BM examination by morphologic and cytogenetic evaluation, and may therefore be a useful adjunct in clinical management of these patients.
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http://dx.doi.org/10.1016/j.leukres.2009.01.012DOI Listing
August 2009