Publications by authors named "Lawrence M Weiss"

131 Publications

NTRK Fusions and Trk Proteins: What are They and How to Test for Them.

Hum Pathol 2021 Mar 29. Epub 2021 Mar 29.

NeoGenomics Laboratories, Inc.

The NTRK genes include a family of three genes, NTRK1, NTRK2, and NTRK3, which are associated with fusions with a variety of partner genes, leading to upregulation of three proteins, TrkA, TrkB, and TrkC. NTRK fusions occur in a variety of solid tumors: at high incidence in secretory carcinoma of the breast and salivary glands, congenital mesoblastic nephroma, and infantile fibrosarcoma; at intermediate incidence in thyroid carcinoma, particularly post-radiation carcinomas and a subset of aggressive papillary carcinomas, Spitzoid melanocytic neoplasms, pediatric midline gliomas (particularly pontine glioma), and KIT/PDGFRA/RAS negative gastrointestinal stromal sarcomas; and at a low incidence in many other solid tumors. With new FDA-approved treatments available and effective in treating patients whose tumors harbor NTRK fusions, testing for these fusions has become important. A variety of technologies can be used for testing, including FISH, PCR, DNA and RNA-based next generation sequencing, and immunohistochemistry. RNA-based next generation sequencing represents the gold standard for the identification of NTRK fusions, but FISH using break apart probes and DNA-based next generation sequencing also represent adequate approaches. Immunohistochemistry to detect increased levels of Trk protein may be very useful as a screening technology to reduce costs, although it alone does not represent a definitive diagnostic methodology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.humpath.2021.03.007DOI Listing
March 2021

EBV-Associated Lymphoproliferative Disorders: Update in Classification.

Surg Pathol Clin 2019 Sep;12(3):745-770

Department of Pathology and Laboratory Medicine, University of California Irvine (UCI) Medical Center, 101 The City Drive, Orange, CA 92868, USA; NeoGenomics Laboratories, 31 Columbia, Aliso Viejo, CA 92656, USA. Electronic address:

Although about 90% of the world's population is infected by EBV only a small subset of the related infections result in neoplastic transformation. EBV is a versatile oncogenic agent involved in a multitude of hematopoietic, epithelial, and mesenchymal neoplasms, but the precise role of EBV in the pathogenesis of many of the associated lymphoid/histiocytic proliferations remains hypothetical or not completely understood. Additional studies and use of evolving technologies such as high-throughput next-generation sequencing may help address this knowledge gap and may lead to enhanced diagnostic assessment and the development of potential therapeutic interventions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.path.2019.03.002DOI Listing
September 2019

Epstein-Barr virus incidental expression in bone marrow cells: a study of 230 consecutive bone marrow biopsy samples.

Hum Pathol 2019 06 1;88:60-65. Epub 2019 Apr 1.

Department of Pathology and Laboratory Medicine, University of California Irvine (UCI) Medical Center, Orange. Electronic address:

Epstein-Barr virus (EBV) is associated with many neoplastic hematologic conditions, but scattered EBV-positive cells can be detected in lymph nodes of healthy individuals and they usually represent latently infected lymphocytes. The incidence of EBV detection in normal bone marrow samples has not been studied and is largely unknown. The lack of knowledge regarding the true incidence of encountering bystander latent EBV-positive cells in the bone marrow may potentially lead to a diagnostic dilemma when assessing a staging bone marrow for a patient with an EBV-positive B or T/NK-cell lymphoma. The aim of our study was to investigate the rate of detection of EBV expression in bone marrow samples and correlate any positive findings with various clinical parameters including patient's age, sex, clinical history, immune status, and any neoplastic transformation if follow-up data are available. We retrospectively studied 230 consecutive bone marrow biopsies performed in 2013 and found 5 cases (2.17%) with scattered EBV-positive cells by in situ hybridization. The observed scattered EBV-positive cells are largely small in size and likely represent bystander, latently infected cells. The rate of detection of EBV-positive cells in the bone marrow appears to be slightly higher in immunodeficient individuals (3%) than in immunocompetent patients (1%).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.humpath.2018.11.034DOI Listing
June 2019

Immunohistochemical detection of PD-L1 among diverse human neoplasms in a reference laboratory: observations based upon 62,896 cases.

Mod Pathol 2019 07 13;32(7):929-942. Epub 2019 Feb 13.

Department of Pathology, NeoGenomics Laboratories, Aliso Viejo, CA, USA.

Targeting of the PD1/PD-L1 immune checkpoint pathway has rapidly gained acceptance as a therapeutic strategy for a growing number of malignancies. Testing for expression of PD-L1 in tumor cells and immune cells has been used as a companion or complementary test for drugs targeting the PD1/PD-L1 pathway. We evaluated the results of PD-L1 testing in a large reference lab cohort. Using Food and Drug Administration-approved methods and interpretive instructions for each individual test, 62,896 cases were evaluated for PD-L1 using antibody clone 22C3, 28-8, SP142, or SP263. Case data analyzed included test results and information on tumor location and clinical history. No clinical outcome information was available and no attempt was made to correlate PD-L1 results with any other tests performed. The following numbers of cases were evaluated: 22C3 with tumor proportion score [n = 52585], 22C3 with combined positive score [n = 2631], 28-8 [n = 4191], SP142 [n = 850], and SP263 [n = 70]. In 22C3/tumor proportion score cases, the general results were as follows: negative 33.1% (n = 17,405), (low) expression 33.9% (n = 17,822), and high expression 29.5% (n = 15,486). In cases identified as metastatic, the results were as follows: negative 35.9% (n = 1411), (low) expression 30.8% (n = 1211), and high expression 30.7% (n = 1208). We found broad ranges of expression in tumor types with increasing positivity, as adenocarcinomas were reported as poorly differentiated, whereas squamous cell carcinomas showed more positivity as tumors were described as well-differentiated. The results of many individual tumor types were evaluated and showed, in general, high levels of positive expression. Practical challenges and observations of PD-L1 stain results and interpretation are also discussed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41379-019-0210-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6760643PMC
July 2019

Epstein-Barr virus (EBV)-associated lymphoid proliferations, a 2018 update.

Hum Pathol 2018 09 6;79:18-41. Epub 2018 Jun 6.

Department of Pathology & Laboratory Medicine, University of California Irvine (UCI) Medical Center, Orange, 92868, CA; NeoGenomics Laboratories, Aliso Viejo, 92656, CA.

Epstein-Barr virus (EBV) has been linked to many human neoplasms including hematopoietic, epithelial, and mesenchymal tumors. Since our original review of EBV-associated lymphoproliferative disorders in 2007, many advances and developments have been reported. In this review, we will examine the recent advances in EBV-associated lymphoid/histiocytic proliferations, dividing them into reactive, B cell, T/NK cell, immunodeficiency-related, and histiocytic/dendritic cell proliferations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.humpath.2018.05.020DOI Listing
September 2018

Genomic analysis of follicular dendritic cell sarcoma by molecular inversion probe array reveals tumor suppressor-driven biology.

Mod Pathol 2017 09 16;30(9):1321-1334. Epub 2017 Jun 16.

Department of Pathology, University of Utah, Salt Lake City, UT, USA.

Follicular dendritic cell sarcoma is a rare malignant neoplasm of dendritic cell origin that is currently poorly characterized by genetic studies. To investigate whether recurrent genomic alterations may underlie the biology of follicular dendritic cell sarcoma and to identify potential contributory regions and genes, molecular inversion probe array analysis was performed on 14 independent formalin-fixed, paraffin-embedded samples. Abnormal genomic profiles were observed in 11 out of 14 (79%) cases. The majority showed extensive genomic complexity that was predominantly represented by hemizygous losses affecting multiple chromosomes. Alterations of chromosomal regions 1p (55%), 2p (55%), 3p (82%), 3q (45%), 6q (55%), 7q (73%), 8p (45%), 9p (64%), 11q (64%), 13q (91%), 14q (82%), 15q (64%), 17p (55%), 18q (64%), and 22q (55%) were recurrent across the 11 samples showing abnormal genomic profiles. Many recurrent genomic alterations in follicular dendritic cell sarcoma overlap deletions that are frequently observed across human cancers, suggesting selection, or an active role for these alterations in follicular dendritic cell sarcoma pathogenesis. In support of a tumor suppressor-driven biology, homozygous deletions involving tumor suppressor genes CDKN2A, RB1, BIRC3, and CYLD were also observed. Neither recurrent gains nor amplifications were observed. This genomic characterization provides new information regarding follicular dendritic cell sarcoma biology that may improve understanding about the underlying pathophysiology, provide better prognostication, and identify potential therapeutic markers for this rare disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/modpathol.2017.34DOI Listing
September 2017

Fibrin-associated EBV-positive Large B-Cell Lymphoma: An Indolent Neoplasm With Features Distinct From Diffuse Large B-Cell Lymphoma Associated With Chronic Inflammation.

Am J Surg Pathol 2017 Mar;41(3):299-312

*Department of Pathology, University of Michigan School of Medicine, Ann Arbor, MI †Department of Pathology, The James Homer Wright Pathology Laboratories of the Massachusetts General Hospital, Harvard Medical School, Boston ‡‡Department of Pathology, North Shore Medical Center, Salem, MA ‡Department of Anatomical Pathology, St Vincent's Hospital, Melbourne, Vic., Australia §Institut Universitaire de Pathologie, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland ∥Department of Laboratory Medicine, University of Washington, Seattle, WA ¶Department of Pathology, Samsung Medical Center, Sungkyunkwan University, Seoul, Republic of Korea #Herbert Wertheim College of Medicine, Florida International University, Miami, FL **Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN ††Department of Pathology, Holmes Regional Medical Center, Melbourne, FL §§NeoGenomics Laboratories, Aliso Viejo, CA ∥∥Department of Pathology, Johns Hopkins University School of Medicine, Baltimore ¶¶Laboratory of Pathology, Hematopathology Section, National Cancer Institute, National Institutes of Health, Bethesda, MD.

Incidental cases of localized fibrin-associated Epstein-Barr virus (EBV)+ large B-cell proliferations have been described at unusual anatomic sites and have been included in the category of diffuse large B-cell lymphoma associated with chronic inflammation (DLBCL-CI) in the WHO Classification. We describe 12 cases and review the literature to define their clinicopathologic spectrum and compare features with typical cases of DLBCL-CI. Median age was 55.5 years with a M:F ratio of 3. In all 12 cases, the lymphoma was an incidental microscopic finding involving atrial myxomas (n=3), thrombi associated with endovascular grafts (n=3), chronic hematomas (n=2), and pseudocysts (n=4). All cases tested were nongerminal center B-cell origin, type III EBV latency, and were negative for MYC rearrangements and alternative lengthening of telomeres by FISH. Most showed high CD30, Ki67, and PD-L1, and low to moderate MYC and p53 expression. Among 11 patients with detailed follow-up, 6 were treated surgically, 3 with cardiac or vascular lesions had persistent/recurrent disease at intravascular sites, and 4 died of causes not directly attributable to lymphoma. Reports of previously published fibrin-associated cases showed similar features, whereas traditional DLBCL-CI cases with a mass lesion had significantly higher lymphoma-associated mortality. Fibrin-associated EBV+ large B-cell lymphoma is clinicopathologically distinct from DLBCL-CI, warranting separate classification. Most cases, particularly those associated with pseudocysts, behave indolently with the potential for cure by surgery alone and may represent a form of EBV+ lymphoproliferative disease rather than lymphoma. However, primary cardiac or vascular disease may have a higher risk of recurrence despite systemic chemotherapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/PAS.0000000000000775DOI Listing
March 2017

Revised classification of histiocytoses and neoplasms of the macrophage-dendritic cell lineages.

Blood 2016 06 10;127(22):2672-81. Epub 2016 Mar 10.

Clarient Pathology Services, Aliso Viejo, CA.

The histiocytoses are rare disorders characterized by the accumulation of macrophage, dendritic cell, or monocyte-derived cells in various tissues and organs of children and adults. More than 100 different subtypes have been described, with a wide range of clinical manifestations, presentations, and histologies. Since the first classification in 1987, a number of new findings regarding the cellular origins, molecular pathology, and clinical features of histiocytic disorders have been identified. We propose herein a revision of the classification of histiocytoses based on histology, phenotype, molecular alterations, and clinical and imaging characteristics. This revised classification system consists of 5 groups of diseases: (1) Langerhans-related, (2) cutaneous and mucocutaneous, and (3) malignant histiocytoses as well as (4) Rosai-Dorfman disease and (5) hemophagocytic lymphohistiocytosis and macrophage activation syndrome. Herein, we provide guidelines and recommendations for diagnoses of these disorders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood-2016-01-690636DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5161007PMC
June 2016

Distinguishing Classical Hodgkin Lymphoma, Gray Zone Lymphoma, and Large B-cell Lymphoma: A Proposed Scoring System.

Appl Immunohistochem Mol Morphol 2016 09;24(8):535-40

*Clarient Pathology Services, Aliso Viejo, CA †MD Anderson Cancer Center/University of Texas, Houston, TX ‡Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC.

Background: The diagnosis of "B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma" represents an indeterminate or equivocal decision in relation to management because there remain differences in the management of Hodgkin and non-Hodgkin lymphomas. We developed a scoring system for this group of lymphomas using markers that are traditionally associated with diagnosis of classical Hodgkin lymphoma (CHL) and immunophenotypic markers associated with the "B-cell program" expressed in normal B cells.

Materials And Methods: This system emphasized known criteria used to diagnose CHL that are rare in B-cell lymphoma (BCL) [CD15+, CD45-, CD20- or weak/variable, PAX5+ (weak or moderate), CD79a-, OCT-2-/BOB.1- or OCT-2+/BOB.1- or OCT-2-/BOB.1+, EBV+] versus findings that are common in BCL in contrast to CHL (CD15-, CD45+, CD20+ strong, PAX5+ strong, CD79a+, OCT-2+/BOB.1+, EBV-). After a preliminary test trial, MUM1 staining was also added. Results associated with CHL were assigned a score of +1 and score associated with BCL were assigned a score of -1. In the final grading system, a maximum score of +6 is possible for CHL and -6 for BCL.

Results: An initial series of 38 cases was evaluated using a proprietary system that allows analysis of multiple stains on individual cells in a single section. An additional 23 cases were evaluated with results blinded until after scoring was performed. In general there was high concordance among cases originally diagnosed as CHL with high scores (score +4 to +6). Cases originally diagnosed as gray zone lymphomas exhibited a broader range of scores (+3 to -4). Cases of BCLs had low scores (-3 to -6).

Conclusions: The primary goal of this study was to create a scoring system that allows a cumulative quantitative measure of immunohistochemical markers, based on expected results to compare cases that might have overlapping features. In most cases, scores that trend to one extreme or another are likely representative of CHL or BCL and do not lie in the gray zone. This scoring system allows for practical resolution of many borderline cases and provide some guidance in difficult cases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/PAI.0000000000000236DOI Listing
September 2016

Cytotoxic Molecule-positive Epstein-Barr Virus-associated Peripheral T-cell Lymphoma in a 20-Month-old Child: A Case Report and Review of the Literature.

J Pediatr Hematol Oncol 2015 Nov;37(8):e475-80

*Department of Pathology and Laboratory Medicine †Pediatric Hematology and Oncology, Loma Linda University Medical Center, Loma Linda ‡Clarient Diagnostic Inc., Aliso Viejo, CA.

Peripheral T-cell lymphoma (PTCL) is rare in children. Expression of cytotoxic molecules (CM) in nodal PTCL has unique clinicopathologic features, including an Epstein-Barr virus (EBV) association. However, CM+, EBV-associated PTCL is extremely rare in the childhood, with only 1 study having been reported to date, including both pediatric and adult patients. We report a case of CM+ PTCL in a 20-month-old boy with left neck lymphadenopathy as well as multiple visceral lesions. A biopsied lymph node was diffusely infiltrated by atypical lymphoid cells with a CD4/CD8, granzyme B+, perforin+, and TIA-1+ phenotype, and EBV positivity by in situ hybridization. Rearrangements of the TCR γ-chain and β-chain genes were demonstrated by polymerase chain reaction. Ancillary genetic studies detected trisomy 2, trisomy 10, a structurally abnormal 6p, and additional copies of the IRF4 gene. Multiple bone marrow biopsies failed to show any evidence of tumor, histiocytic hyperplasia, or hemophagocytosis. This lesion was therefore diagnosed as "CM+, EBV-associated high-grade peripheral T-cell lymphoma." After 5 cycles of chemotherapy, the patient was in remission 8 months following initial diagnosis. To our knowledge, this represents the youngest child with this rare tumor in the published literature, and showing an unusually favorable initial response to therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/MPH.0000000000000368DOI Listing
November 2015

Piwi-Interacting RNAs (piRNAs) Are Dysregulated in Renal Cell Carcinoma and Associated with Tumor Metastasis and Cancer-Specific Survival.

Mol Med 2015 May 13;21:381-8. Epub 2015 May 13.

Department of Pathology, City of Hope National Medical Center and Beckman Research Institute, Duarte, California, United States of America.

Piwi-interacting RNAs (piRNAs) are a distinct group of small noncoding RNAs (sncRNAs) that silence transposable genetic elements to protect genome integrity. Because of their limited expression in gonads and sequence diversity, piRNAs remain the most mysterious class of small RNAs. Studies have shown piRNAs are present in somatic cells and dysregulated in gastric, breast and liver cancers. By deep sequencing 24 frozen benign kidney and clear cell renal cell carcinoma (ccRCC) specimens and using the publically available piRNA database, we found 26,991 piRNAs present in human kidney tissue. Among 920 piRNAs that had at least two copies in one specimen, 19 were differentially expressed in benign kidney and ccRCC tissues, and 46 were associated with metastasis. Among the metastasis-related piRNAs, we found three piRNAs (piR-32051, piR-39894 and piR-43607) to be derived from the same piRNA cluster at chromosome 17. We confirmed the three selected piRNAs not to be miRNAs or miRNA-like sncRNAs. We further validated the aberrant expression of the three piRNAs in a 68-case formalin-fixed and paraffin-embedded (FFPE) ccRCC tissue cohort and showed the up-regulation of the three piRNAs to be highly associated with ccRCC metastasis, late clinical stage and poor cancer-specific survival.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2119/molmed.2014.00203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4534471PMC
May 2015

Distinctive immunohistochemical staining in littoral cell angioma using ERG and WT-1.

Ann Diagn Pathol 2015 Jun 5;19(3):143-5. Epub 2015 Mar 5.

Clarient Pathology Services, Aliso Viejo, CA. Electronic address:

Littoral cell angioma (LCA) is a rare vascular tumor of the spleen. It has an immunohistochemical staining pattern that is somewhat distinctive but can still be occasionally confused with other vascular and stromal proliferations in the spleen. In this study, LCA was evaluated using Ets-related gene (ERG) and Wilms tumor-1 (WT-1), relatively recently described vascular markers. In addition, other vascular lesions including normal spleen, hemangiomas, hamartoma, peliosis, and sclerosing angiomatoid nodular transformation were evaluated using these stains. In LCA, ERG stains the endothelial cells of the tumor as expected. ERG also was uniformly positive in vascular elements of other lesions except peliosis. However, in contrast to most other vascular elements, LCA was negative for WT-1 staining. This staining pattern may prove useful in diagnosing LCA and may provide insight into the derivation of the distinctive tumor.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.anndiagpath.2015.02.007DOI Listing
June 2015

Evidence of BRAF V600E in indeterminate cell tumor and interdigitating dendritic cell sarcoma.

Ann Diagn Pathol 2015 Jun 5;19(3):113-6. Epub 2015 Mar 5.

Clarient Pathology Services, Aliso Viejo, CA.

BRAF V600E mutations have been reported in several histiocytic and dendritic cell neoplasms. In this case series, we report BRAF V600E-positive histiocytic and dendritic cell neoplasms in association with lymphomas and lymphoid proliferations. This is a review of cases with immunohistochemistry for BRAF V600E, with additional immunohistochemistry to categorize tumors. We report the first case of BRAF V600E-positive indeterminate cell tumor in association with angioimmunoblastic T-cell lymphoma. We also report a case of BRAF V600E-positive interdigitating dendritic cell sarcoma in a patient with positive B-cell polymerase chain reaction. It is unclear if these neoplasms developed as transdifferentiation of lymphoid neoplasms or if they developed independently. These cases illustrate the expanding spectrum of BRAF V600E-positive histiocytic and dendritic cell tumors and suggest that attention should be paid to lymphomas for possible coincident presentation of these disorders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.anndiagpath.2015.02.008DOI Listing
June 2015

Best practices in diagnostic immunohistochemistry: workup of cutaneous lymphoid lesions in the diagnosis of primary cutaneous lymphoma.

Arch Pathol Lab Med 2015 Mar;139(3):338-50

From the Department of Pathology, Beth Israel Deaconess Medical Center, and Harvard Medical School, Boston, Massachusetts (Dr Dewar); the Department of Pathology, University of Michigan, Ann Arbor (Dr Andea); the Department of Pathology and Dermatology, Northwestern University, Chicago, Illinois (Dr Guitart); the Department of Pathology, Stanford University Medical Center, Stanford, California (Dr Arber); and the Department of Hematopathology, Clarient Pathology Services, Inc, Aliso Viejo, California (Dr Weiss).

Context: Primary cutaneous lymphoma is a common extranodal non-Hodgkin lymphoma. These lesions share common features with their nodal counterparts, but also have differences in morphology, unique clinical presentations, and immunohistochemical features.

Objective: To review the 2008 World Health Organization (WHO) and 2005 consensus WHO-EORTC (European Organisation for Research and Treatment of Cancer) classifications, and address the immunohistochemical findings in the most common primary cutaneous T- and B-cell lymphomas. Since clonality testing is commonly used as an ancillary test in the evaluation of cutaneous lymphoma, a brief section in the use and pitfalls of clonality testing is included.

Data Sources: The WHO and EORTC classification publications and the relevant recent literature were used to compile appropriate and practical guidelines in this review.

Conclusions: The practice of dermatopathology and hematopathology varies widely. Thus, while this review provides an overview and guideline for the workup of lymphoid lesions of the skin, the practitioner should understand the importance of clinical correlation as well as appropriate utility of available resources (such as clonality testing) in arriving at a diagnosis in cutaneous lymphoid lesions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.5858/arpa.2014-0018-CPDOI Listing
March 2015

Practical Applications in Immunohistochemistry: Evaluation of Diffuse Large B-Cell Lymphoma and Related Large B-Cell Lymphomas.

Arch Pathol Lab Med 2015 Sep 2;139(9):1094-107. Epub 2015 Jan 2.

From Clarient Diagnostic Services, Aliso Viejo, California (Drs O'Malley and Weiss); and Joint Pathology Center, Silver Spring, Maryland (Dr Auerbach).

Context: Diffuse large B-cell lymphoma is the most commonly diagnosed subtype of lymphoma worldwide. The current World Health Organization (WHO) classification includes several subtypes, based on a combination of clinical, immunohistochemical, and genetic differences. Immunohistochemical staining is essential in evaluating diffuse large B-cell lymphoma and many related large B-cell lymphomas and aggressive B-cell lymphomas.

Objective: To address different immunohistochemical features used for identification, subclassification, prognosis and in some cases, therapy, of diffuse large B-cell lymphoma and related lymphomas.

Data Sources: The information outlined in this review article is based on our experiences with routine cases, on the current WHO classification of hematopoietic and lymphoid tumors, and on a review of English-language articles published throughout 2014.

Conclusions: Features and diagnostic criteria of diffuse large B-cell lymphoma, aggressive variants of B-cell lymphomas, including Burkitt lymphoma and "double-hit" lymphomas, are discussed. Identification of cell of origin (germinal center type versus activated B-cell type) is discussed at length. Finally, practical approaches for diagnosis are discussed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.5858/arpa.2014-0451-CPDOI Listing
September 2015

BRAF V600E mutation-specific immunohistochemistry is a rare finding in dendritic cell- and histiocyte-derived tumors.

Leuk Lymphoma 2015 Apr 10;56(4):1132-3. Epub 2014 Nov 10.

Department of Pathology and Laboratory Medicine, University of North Carolina , Wilmington, NC , USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3109/10428194.2014.946028DOI Listing
April 2015

Cytotoxic T-cell and NK-cell lymphomas: current questions and controversies.

Am J Surg Pathol 2014 Oct;38(10):e60-71

*Department of Pathology, Division of Hematopathology, University of Pittsburgh School of Medicine, Pittsburgh, PA †National Cancer Institute, Bethesda, MD #Massachusetts General Hospital, Harvard Medical School, Boston, MA ††Clarient Diagnostic Services Inc., A GE Healthcare Company, Aliso Viejo, CA ‡IUC-T-Oncopole, Toulouse, France ¶Department of Pathology, Inserm U955, Hôpital Henri Mondor, Université Paris-Est, Créteil, France §Queen Elizabeth Hospital, Hong Kong, SAR China ∥Institute of Pathology, University Hospital of Lausanne (CHUV), Lausanne, Switzerland **St Orsola Policlinic, Bologna University School of Medicine, Bologna, Italy.

The cytotoxic T-cell and natural killer (NK)-cell lymphomas and related disorders are important but relatively rare lymphoid neoplasms that frequently are a challenge for practicing pathologists. This selective review, based on a meeting of the International Lymphoma Study Group, briefly reviews T-cell and NK-cell development and addresses questions related to the importance of precise cell lineage (αβ-type T cell, γδ T cell, or NK cell), the implications of Epstein-Barr virus infection, the significance of anatomic location including nodal disease, and the question of further categorization of enteropathy-associated T-cell lymphomas. Finally, developments subsequent to the 2008 World Health Organization Classification, including the recognition of indolent NK-cell and T-cell disorders of the gastrointestinal tract are presented.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/PAS.0000000000000295DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6329302PMC
October 2014

A single slide multiplex assay for the evaluation of classical Hodgkin lymphoma.

Am J Surg Pathol 2014 Sep;38(9):1193-202

*Clarient Diagnostic Services Inc., a GE Healthcare Company †Clarient Pathology Services Inc., Aliso Viejo, CA.

Classical Hodgkin lymphoma can be diagnosed with confidence in the majority of cases, but there is a significant subset that remains a diagnostic challenge. The authors have investigated the utility of a novel hyperplexing technology, MultiOmyx™, which may be applied to stain with >60 antibodies on single tissue sections from formalin-fixed paraffin-embedded tissue as an aid to the diagnosis of classical Hodgkin lymphoma. The multiplexing protocol included CD30, CD15, PAX-5, CD20, CD79a, CD45, BOB.1, OCT-2, and CD3 antibodies. The technology showed a high degree of sensitivity, specificity, and precision. Comparison studies with routine hematoxylin and eosin and immunohistochemical assessment of hematopathology cases in which classical Hodgkin lymphoma was included in the differential diagnosis showed concordance in 54 of 56 cases, with the 2 discordant cases illustrating the potential of this multiplexed immunofluorescence technology to improve on traditional immunohistochemistry for classical Hodgkin lymphoma diagnosis. This technology is practical for routine diagnosis and may be particularly useful in cases in which the sample size is limited, few Hodgkin-like cells are present, or in CD30-positive lymphoma cases with difficult morphology. MultiOmyx may potentially benefit other areas of research and diagnostic pathology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/PAS.0000000000000242DOI Listing
September 2014

Merkel cell carcinoma of lymph node with unknown primary has a significantly lower association with Merkel cell polyomavirus than its cutaneous counterpart.

Mod Pathol 2014 Sep 10;27(9):1182-92. Epub 2014 Jan 10.

Department of Pathology, City of Hope National Medical Center, Duarte, CA, USA.

Rare cases of Merkel cell carcinoma have been encountered in lymph nodes with unknown extranodal primary, which exhibit similar morphologic and immunophenotypic features to those in primary cutaneous Merkel cell carcinomas. However, it is uncertain whether the nodal Merkel cell carcinoma is a primary tumor of the lymph node or represents a metastasis from an occult or regressed extranodal lesion. To establish an accurate diagnosis of the nodal Merkel cell carcinoma can be challenging because of significant morphologic mimics, including lymphoblastic lymphoma and metastatic small cell carcinoma. Moreover, there is no consensus for a diagnostic term, and many different terms have been used, which can be confusing and may not fully reflect the nature of nodal Merkel cell carcinoma. In this study, we investigated the detailed clinicopathologic features of 22 nodal Merkel cell carcinomas, with comparison to 763 primary cutaneous cases retrieved from the literature. Overall, the nodal and cutaneous Merkel cell carcinomas shared similar clinical presentations, morphologic spectrum, and immunophenotype; both were mostly seen in elderly male with a typical neuroendocrine morphology. Most of cases expressed CK20, synaptophysin, and chromogranin A; and PAX5 and TdT were also positive in majority of cases. However, nodal Merkel cell carcinomas had a significantly lower association with Merkel cell polyomavirus than cutaneous cases (31% vs 76%, P=0.001). Therefore, these two entities may arise from overlapping but not identical biological pathways. We also recommend the use of the diagnostic term 'Merkel cell carcinoma of lymph node' to replace many other names used.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/modpathol.2013.250DOI Listing
September 2014

The genetics of interdigitating dendritic cell sarcoma share some changes with Langerhans cell histiocytosis in select cases.

Ann Diagn Pathol 2014 Feb 29;18(1):18-20. Epub 2013 Oct 29.

Clarient/GE Healthcare, Aliso Viejo, CA; MD Anderson Cancer Center/University of Texas, Houston, TX. Electronic address:

Histiocytic disorders have been noted to have evidence of transdifferentiation; examples of cases with combinations of different lineages have been shown. In our index case, we identified interdigitating dendritic cell (IDC) differentiation in a case of Langerhans cell histiocytosis (LCH). Little is currently known about the genetics of IDC sarcoma (IDCS) because they are exceedingly rare. Using array comparative genomic hybridization (aCGH), we evaluated 4 cases of IDCS and compared them with our index case, as well as genetic abnormalities previously found in LCH. Four cases of paraffin-embedded samples of IDCS and 1 case of LCH with IDC differentiation were evaluated using aCGH. Array CGH results showed no abnormalities in a case of LCH with interdigitating cell differentiation. In 3 of 4 cases of IDCS, genetic abnormalities were identified; 1 case had no identifiable abnormalities. Interdigitating dendritic cell sarcoma case 1 had gains of 3q and 13q; IDCS case 2 had trisomy 12; IDCS case 3 had deletions of 7p, 12p, 16p, 18q, 19q, and 22q; and IDCS case 4 had no detectable abnormalities. Our index case, LCH with IDC differentiation, showed no abnormalities by aCGH. A number of LCH cases do not have detectable genetic abnormalities. In contrast, 3 of 4 cases of IDCS evaluated had identifiable abnormalities by aCGH. Furthermore, 2 of these shared abnormalities, albeit of large genetic regions, with published abnormalities seen in LCH. No recurrent abnormalities were identified in the IDCS cases. However, the possibility of a relationship between IDCS and LCH cannot be entirely excluded by these results.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.anndiagpath.2013.10.003DOI Listing
February 2014

Atypical Phenotypes in Classical Hodgkin Lymphoma.

Authors:
Lawrence M Weiss

Surg Pathol Clin 2013 Dec;6(4):729-42

Clarient Diagnostic Services, Inc, 31 Columbia, Aliso Viejo, CA 92656, USA. Electronic address:

Classical Hodgkin lymphoma has a characteristic immunophenotype in most cases, with expression of CD30, CD15, and PAX-5, and absence of CD45 and T-lineage markers. However, in a significant subset of cases, atypical staining patterns may be seen for one or more antigens, particularly negative staining for CD15 or staining for one or more B-lineage markers, such as CD20, CD79a, OCT-2, or BOB.1. The greatest pitfall is in the misinterpretation of other cells, such as immunoblasts or histiocytes, as Hodgkin cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.path.2013.08.011DOI Listing
December 2013

Characterization of bone marrow mast cells in acute myeloid leukemia with t(8;21) (q22;q22); RUNX1-RUNX1T1.

Leuk Res 2013 Nov 1;37(11):1572-5. Epub 2013 Sep 1.

Department of Pathology and Laboratory Medicine, UCLA David Geffen School of Medicine, Los Angeles, CA, United States.

Mast cells are often increased in AML with t(8;21). We analyzed characteristics of mast cells to elucidate their relationship with leukemic blasts. In 31 cases in which the results of KIT mutation analysis were available, five cases showed mutations. None of the cases positive for KIT mutation showed increased mast cells. In five cases with increased mast cells in which targeted-FISH analysis was performed for RUNX1-RUNX1T1, fusion signals demonstrated the translocation in mast cells in all cases. These findings confirm the shared origin between mast cells and leukemic blasts in AML with t(8;21).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.leukres.2013.08.010DOI Listing
November 2013

Molecular characteristics of diffuse large B-cell lymphoma in human immunodeficiency virus-infected and -uninfected patients in the pre-highly active antiretroviral therapy and pre-rituximab era.

Leuk Lymphoma 2014 Mar 29;55(3):551-7. Epub 2013 Jul 29.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS , Rockville, MD , USA.

Human immunodeficiency virus (HIV) infection substantially elevates diffuse large B-cell lymphoma (DLBCL) risk, but its impact on the distinct DLBCL subtypes defined by cell of origin is unclear. We compared DLBCL molecular characteristics and prognosis in 51 HIV-infected and 116 HIV-uninfected cases diagnosed during 1977-2003. Using immunohistochemistry to classify cell of origin based on the Tally algorithm, activated B-cell (ABC)-DLBCL was substantially more common in HIV-infected (83%) than in HIV-uninfected (54%) cases (p < 0.001). Epstein-Barr virus (EBV) was detected in 63% of DLBCLs in HIV-infected cases, occurring almost exclusively in ABC-DLBCL (74% vs. 13% of germinal center B-cell [GCB]-DLBCL, p = 0.002), but was rarely detected in DLBCLs among HIV-uninfected cases (3%). Among HIV-uninfected cases, MYC/IgH [t(8;14)(q24;q32)] and IgH/BCL2 [t(14;18)(q32;q21)] translocations were significantly more common and BCL6/IgH [t(3;14)(q27;q32)] significantly less common in GCB-DLBCL than in ABC-DLBCL (p = 0.010, < 0.001 and = 0.039, respectively). Among HIV-infected cases, translocations other than MYC/IgH [t(8;14)(q24;q32)] (21%) were rare (≤ 6%) and unrelated to cell of origin. ABC-DLBCL was associated with adverse overall survival compared with GCB-DLBCL regardless of HIV status (pHIV-infected = 0.066; pHIV-uninfected = 0.038). Our data demonstrate key differences in the molecular characteristics, cell of origin and prognosis of DLBCL by HIV status in the pre-highly active antiretroviral therapy (HAART) and pre-rituximab era, supporting biologic differences in lymphomagenesis in the presence of HIV.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3109/10428194.2013.813499DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3936016PMC
March 2014

Utility of BCL2, PD1, and CD25 immunohistochemical expression in the diagnosis of T-cell lymphomas.

Appl Immunohistochem Mol Morphol 2014 ;22(2):99-104

Clarient Diagnostics/GE Healthcare, Aliso Viejo, CA.

T-cell lymphomas (TCLs) are a heterogenous group of diseases that show histologic and immunophenotypic features overlapping with reactive lymphoid proliferations and often require the use of ancillary testing for accurate diagnosis. The oncoprotein, bcl-2, is expressed in various types of lymphoma. At present, expression of this protein is useful for distinguishing several B-cell lymphomas. Although there are some anecdotal reports that the lack of bcl-2 expression by T cells might also be a useful marker for the diagnosis of TCL, there are no focused studies to address this hypothesis. Another antigen with value in TCL diagnosis is programmed death-1 (PD-1), a marker of follicular helper T cells, which has been reported to be sensitive in the detection of angioimmunoblastic TCL and peripheral T-cell lymphoma, unclassified. However, several reports have also shown that PD-1-positive cells may be increased in a number of settings other than TCL, including reactive and atypical lymphadenopathies. Finally, lymphoma cells express a variety of cytokine receptors and signaling molecules that are current or potential targets for immunomodulatory therapy. One such target is the interleukin (IL)-2 receptor (CD25), which is acted on by denileukin diftitox/ONTAK, a recombinant diphtheria toxin-IL-2 fusion protein. Selection of suitable patients for therapy often includes pretreatment assessment of CD25 expression in tumor cells. In order to further assess the diagnostic and therapeutic utility of these antigens, we compared the expression of the CD25, PD-1, and bcl-2 in 119 cases of T-cell non-Hodgkin lymphoma using immunohistochemical techniques applied to routinely processed and paraffin-embedded tissues. We show that lack of expression of bcl-2 was observed in 52% cases of TCL and may aid in identification of neoplastic T-cell populations. In combination, bcl-2, CD25, and PD-1 provide diagnostic utility and may aid in selecting appropriate patients for immunomodulatory therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/PAI.0b013e31828ef1f7DOI Listing
October 2014

EBER in situ hybridization for Epstein-Barr virus.

Methods Mol Biol 2013 ;999:223-30

Clarient Pathology Services, Inc., Aliso Viejo, CA, USA.

Epstein-Barr encoding region (EBER) in situ hybridization is the methodology of choice for the detection of the Epstein-Barr virus (EBV) in tissue sections. Because of the large numbers of copies of EBERs present in latently infected cells, non-isotopic methods can be used. Positive studies show staining in the nuclei of the EBV-infected cells, accentuating the chromatin and often excluding the nucleolus. False-negative results are most often the result of RNA degradation in the tissues, a finding that may be detected through the use of a polyT probe as a control for RNA preservation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/978-1-62703-357-2_16DOI Listing
December 2013

A multicenter study directly comparing the diagnostic accuracy of gene expression profiling and immunohistochemistry for primary site identification in metastatic tumors.

Am J Surg Pathol 2013 Jul;37(7):1067-75

Department of Pathology and Laboratory Medicine, University of Tennessee College of Medicine, Memphis, TN 38163, USA.

Metastatic tumors with an uncertain primary site can be a difficult clinical problem. In tens of thousands of patients every year, no confident diagnosis is ever issued, making standard-of-care treatment impossible. Gene expression profiling (GEP) tests currently available to analyze these difficult-to-diagnose tumors have never been directly compared with the diagnostic standard of care, immunochemistry (IHC). This prospectively conducted, blinded, multicenter study compares the diagnostic accuracy of GEP with IHC in identifying the primary site of 157 formalin-fixed paraffin-embedded specimens from metastatic tumors with known primaries, representing the 15 tissues on the GEP test panel. Four pathologists rendered diagnoses by selecting from 84 stains in 2 rounds. GEP was performed using the Pathwork Tissue of Origin Test. Overall, GEP accurately identified 89% of specimens, compared with 83% accuracy using IHC (P=0.013). In the subset of 33 poorly differentiated and undifferentiated carcinomas, GEP accuracy exceeded that of IHC (91% to 71%, P=0.023). In specimens for which pathologists rendered their final diagnosis with a single round of stains, both IHC and GEP exceeded 90% accuracy. However, when the diagnosis required a second round, IHC significantly underperformed GEP (67% to 83%, P<0.001). GEP has been validated as accurate in diagnosing the primary site in metastatic tumors. The Pathwork Tissue of Origin Test used in this study was significantly more accurate than IHC when used to identify the primary site, with the most pronounced superiority observed in specimens that required a second round of stains and in poorly differentiated and undifferentiated metastatic carcinomas.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/PAS.0b013e31828309c4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5266589PMC
July 2013

Epstein-Barr virus patterns in US Burkitt lymphoma tumors from the SEER residual tissue repository during 1979-2009.

APMIS 2014 Jan 23;122(1):5-15. Epub 2013 Apr 23.

Division of Cancer Epidemiology and Genetics, Department of Health and Human Services, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

Burkitt lymphoma (BL) occurs at all ages, but the patterns of Epstein-Barr virus (EBV) positivity in relation to human immunodeficiency virus (HIV), immunoprofiles and age have not been fully explored. BL tissues from residual tissue repositories, and two academic centers in the United States were examined by expert hematopathologists for morphology, immunohistochemistry, MYC rearrangement, EBV-encoded RNA (EBER), and diagnosed according to the 2008 WHO lymphoma classification. Analysis was done using frequency tables, Chi-squared statistics, and Student's t-test. Of 117 cases examined, 91 were confirmed as BL. The age distribution was 26%, 15%, 19%, and 29% for 0-19, 20-34, 35-59, 60+ years, and missing in 11%. MYC rearrangement was found in 89% and EBER positivity in 29% of 82 cases with results. EBER positivity varied with age (from 13% in age group 0-19 to 55% in age group 20-34, and fell to 25% in age group 60+ years, p = 0.08); with race (56% in Blacks/Hispanics vs 21% in Whites/Asians/Pacific Islanders, p = 0.006); and by HIV status (64% in HIV positive vs 22% in HIV negative cases, p = 0.03). EBER positivity was demonstrated in about one-third of tumors and it was strongly associated with race and HIV status, and marginally with age-group.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/apm.12078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3723754PMC
January 2014

Follicular dendritic cells: origin, function, and different disease-associated patterns.

Hum Pathol 2013 Jun 17;44(6):937-50. Epub 2013 Jan 17.

Department of Pathology and Laboratory Medicine, University of California, Irvine, Irvine, CA 92868, USA.

Follicular dendritic cells (FDCs) are a specialized type of antigen-presenting dendritic cells that are largely restricted to lymphoid follicles. They form dense three-dimensional meshwork patterns within benign follicles, which maintain the follicular architecture. The FDC function is to bind and retain antigens by linking to complement and immune complexes and then present these antigens to germinal center B cells that start the secondary immune response. FDCs aid in the rescue of bound B cells from apoptosis, and induce the differentiation of B cells into long-term memory B cell clones or plasma cells. We will discuss the different patterns of the FDC meshwork observed in different types of reactive and neoplastic disorders, which may be due to underlying different roles that FDCs may play in these disorders and whether changes in the architecture of the FDC meshwork can be useful in routine diagnostic practice or have a prognostic value.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.humpath.2012.10.005DOI Listing
June 2013

Blinded comparator study of immunohistochemical analysis versus a 92-gene cancer classifier in the diagnosis of the primary site in metastatic tumors.

J Mol Diagn 2013 Mar 31;15(2):263-9. Epub 2012 Dec 31.

Clarient Inc., Aliso Viejo, California, 92656, USA.

Accurate tumor classification is fundamental to inform predictive biomarker testing and optimize therapy. Gene expression-based tests are proposed as diagnostic aids in cases with uncertain diagnoses. This study directly compared the diagnostic accuracy of IHC analysis versus molecular classification using a 92-gene RT-PCR assay for determination of the primary tumor site. This prospectively defined blinded study of diagnostically challenging cases included 131 high-grade, primarily metastatic tumors. Cases were reviewed and reference diagnoses established through clinical correlation. Blinded FFPE sections were evaluated by either IHC/morphology analysis or the 92-gene assay. The final analysis included 122 cases. The 92-gene assay demonstrated overall accuracy of 79% (95% CI, 71% to 85%) for tumor classification versus 69% (95% CI, 60% to 76%) for IHC/morphology analysis (P = 0.019). Mean IHC use was 7.9 stains per case (median, 8; range, 2 to 15). IHC/morphology analysis accuracy was 79%, 80%, and 46% when 1 to 6 (n = 42), 7 to 9 (n = 41), and >9 (n = 39) IHC stains were used, respectively, versus 81%, 85%, and 69%, respectively, with the 92-gene assay. Results from this blinded series of high-grade metastatic cases demonstrate superior accuracy with the 92-gene assay versus standard-of-care IHC analysis and strongly support the diagnostic utility of molecular classification in difficult-to-diagnose metastatic cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jmoldx.2012.10.001DOI Listing
March 2013

Benign lymphadenopathies.

Mod Pathol 2013 Jan;26 Suppl 1:S88-96

Clarient Pathology Services, Inc., 31 Columbia, Aliso Viejo, CA 92656, USA.

Benign lymphadenopathy is a common biopsy finding, and may often be confused with malignant lymphoma. It may be separated into major morphologic patterns, each with its own differential diagnosis with certain types of lymphoma. Most cases of reactive follicular hyperplasia is easy to diagnosis, but some cases may be confused with follicular lymphoma, but key morphologic, immunohistochemical, and molecular findings may usually distinguish between the two, particularly assessment of bcl-2 staining. Molecular studies to demonstrate B-cell clonality, as well as the t(14;18), may also be of great use in difficult cases. IgG4-associated sclerosing disease is discussed, as one recently described example of a specific type of reactive follicular hyperplasia in which the etiology may be suggested based on pathologic studies. While overlapping with the other types of hyperplasia, a high index of suspicion as well as IgG and IgG4 immunostains will help raise the possibility of the diagnosis that can be confirmed by further clinical studies. Reactive paracortical/interfollicular hyperplasia is another pattern of reactive hyperplasia, which may easily be confused with Hodgkin and non-Hodgkin lymphoma, particularly T-cell lymphoma. Epstein-Barr virus-associated infectious mononucleosis is an example of reactive paracortical/interfollicular hyperplasia, which may often simulate a malignant lymphoma. Attention to clinical findings, as well as a combination of immunohistochemical stains and in situ hybridization studies for Epstein-Barr early RNA (EBER) will usually allow a definitive diagnosis. In addition, lymph nodes with extensive necrosis may simulate malignant lymphoma. Kikuchi necrotizing histiocytic lymphadenitis is an example of a benign process with extensive necrosis, which may easily be confused with non-Hodgkin lymphoma. Clinical and morphologic features, particularly the presence of abundant karyorrhectic debris along with a paucity of granulocytes, as well as immunohistochemical studies to rule out lymphoma, are most helpful in establishing the correct diagnosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/modpathol.2012.176DOI Listing
January 2013