Publications by authors named "Russell K Brynes"

30 Publications

  • Page 1 of 1

Post-Chemotherapy Histiocyte-Rich Pseudotumors: Radiologic and Endoscopic Mimics of Residual Lymphoma.

Acta Haematol 2021 Jul 20:1-12. Epub 2021 Jul 20.

Hematopathology Section, Department of Pathology, Keck School of Medicine of the University of Southern California, Los Angeles, California, USA.

Development of post-chemotherapy histiocyte-rich pseudotumor (PHP) is an underrecognized event following therapy in lymphoma patients and may mimic residual tumor using current therapy monitoring protocols. We report a series of 5 patients with PHP along with a review of the literature. In our series, we describe 3 patients with persistent hypermetabolic masses by positron emission tomography-computed tomography, one with persistent terminal ileal nodules on endoscopy, and one with bone marrow involvement, a site not associated with mass-like disease. Twenty-three patients with long-term follow-up were identified from our series and review of the literature. Forty-four percent of patients received additional therapy, and only 4% of patients died of lymphoma. This study illustrates that PHPs are not identified using current lymphoma therapy monitoring algorithms and may result in overtreatment with risk for additional therapy-related complications. The need for confirmatory tissue biopsy in this setting is recommended.
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http://dx.doi.org/10.1159/000517181DOI Listing
July 2021

Kikuchi-Fujimoto disease involving retroperitoneal lymph nodes: An uncommon presentation.

Hematol Rep 2021 Jun 5;13(2):9001. Epub 2021 Mar 5.

Department of Pathology and Hematology Division.

Kikuchi-Fujimoto disease is a self-limited disease of unknown etiology that is clinically defined by fevers accompanied by tender posterior cervical lymphadenopathy. It often presents acutely or sub-acutely, and due to its non-specific features, the differential diagnosis is broad and includes infectious, autoimmune, and malignant causes. Although cases of extra-cervical disease are not uncommon, involvement of retroperitoneal lymph nodes has only rarely been reported. Here, we describe a patient with Kikuchi-Fujimoto disease who presented with fever of unknown origin, abdominal pain, and enlarged hypermetabolic retroperitoneal lymph nodes.
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http://dx.doi.org/10.4081/hr.2021.9001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8215528PMC
June 2021

Gelatinous bone marrow transformation and emergence of clonal Philadelphia-negative cytogenetic abnormalities with excess blasts in a patient with chronic myeloid leukemia treated with dasatinib.

Anticancer Drugs 2019 04;30(4):416-421

Department of Medicine, The Jane Anne Nohl Division of Hematology and Center for the Study of Blood Diseases.

Gelatinous bone marrow transformation (GBMT) is a rare pathologic entity of unclear etiology characterized by adipose cell atrophy, focal hematopoietic tissue hypoplasia, and a distinct eosinophilic substance that stains with Alcian blue at pH 2.5. It is traditionally described in the context of malnutrition and cachexia from generalized disease and is important to identify because of its potential reversibility. Several recent case reports have described GBMT in patients with chronic myeloid leukemia (CML) on the first-generation tyrosine-kinase inhibitor (TKI) imatinib. Here, we describe a case of gelatinous transformation in a patient with CML receiving the second-generation TKI dasatinib who subsequently developed clonal cytogenetic abnormalities in Philadelphia chromosome negative cells with excess peripheral blasts consistent with advanced secondary myelodysplastic syndrome. While the development of clonal cytogenetic abnormalities in Philadelphia-negative cells has been frequently described in the setting of TKI, most abnormalities are transient and generally do not effect disease progression and/or transformation like in this case. Remarkably, after TKI discontinuation, repeat bone marrow biopsies had markedly diminished amounts of gelatinous transformation - supporting reversible GBMT with TKI removal. We review the relevant pathophysiology underlying our patient's possible therapeutic-mediated complications during CML therapy in an attempt to better understand the role of TKIs in the pathogenesis of these conditions.
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http://dx.doi.org/10.1097/CAD.0000000000000763DOI Listing
April 2019

Trends in Bone Marrow Sampling and Core Biopsy Specimen Adequacy in the United States and Canada: A Multicenter Study.

Am J Clin Pathol 2018 Oct;150(5):393-405

Pathology, State University of New York Upstate Medical University, Syracuse.

Objectives: To assess bone marrow (BM) sampling in academic medical centers.

Methods: Data from 6,374 BM samples obtained in 32 centers in 2001 and 2011, including core length (CL), were analyzed.

Results: BM included a biopsy (BMB; 93%) specimen, aspirate (BMA; 92%) specimen, or both (83%). The median (SD) CL was 12 (8.5) mm, and evaluable marrow was 9 (7.6) mm. Tissue contraction due to processing was 15%. BMB specimens were longer in adults younger than 60 years, men, and bilateral, staging, and baseline samples. Only 4% of BMB and 2% of BMB/BMA samples were deemed inadequate for diagnosis. BM for plasma cell dyscrasias, nonphysician operators, and ancillary studies usage increased, while bilateral sampling decreased over the decade. BM-related quality assurance programs are infrequent.

Conclusions: CL is shorter than recommended and varies with patient age and sex, clinical circumstances, and center experience. While pathologists render diagnoses on most cases irrespective of CL, BMB yield improvement is desirable.
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http://dx.doi.org/10.1093/ajcp/aqy066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6166687PMC
October 2018

Autoimmune Myelofibrosis: Clinical Features, Course, and Outcome.

Acta Haematol 2017;138(3):129-137. Epub 2017 Sep 2.

Division of Hematology, Department of Medicine, Los Angeles County-University of Southern California Medical Center and Jane Anne Nohl Division of Hematology, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA, USA.

Background: Autoimmune myelofibrosis (AIMF) is an underrecognized cause of nonmalignant bone marrow fibrosis which occurs in the presence or absence of a defined systemic autoimmune disease. Patients with AIMF present with cytopenias and autoantibodies, and have a distinctive nonclonal myelofibrosis on bone marrow examination. AIMF is distinguished from primary myelofibrosis by the absence of splenomegaly, eosinophilia, or basophilia, and the absence of abnormal myeloid, erythroid, or megakaryocytic morphology.

Objectives: The objective of the study was to describe the clinical presentation and outcomes of patients with AIMF.

Methods: We conducted a single-institution, retrospective chart review of patients diagnosed with AIMF to investigate clinical presentations, therapies, and outcomes.

Results: Twelve patients with AIMF were identified with a mean follow-up of 5.8 years. All patients had detectable autoantibodies and the majority had concomitant autoimmune disorders. Four patients experienced a complete response of cytopenias and 3 patients experienced a partial response (PR) of cytopenias with immunosuppressive therapy. One patient achieved a PR following splenectomy. No patients were diagnosed with myeloproliferative neoplasms during the follow-up period.

Conclusions: AIMF contributes to cytopenias in the subset of patients with various autoimmune disorders. The majority of patients with AIMF experience an improvement in cytopenias with immunosuppressive therapy.
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http://dx.doi.org/10.1159/000479103DOI Listing
June 2018

A 2-Year, Longitudinal, Prospective Study of the Effects of Eltrombopag on Bone Marrow in Patients with Chronic Immune Thrombocytopenia.

Acta Haematol 2017 23;137(2):66-72. Epub 2016 Dec 23.

Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.

Background: The long-term effects of eltrombopag on bone marrow (BM) reticulin and/or collagen deposition in previously treated adults with chronic immune thrombocytopenia (ITP) were assessed.

Methods: Three BM biopsies were collected at baseline and after 1 and 2 years of eltrombopag treatment. Specimens were centrally processed, stained for reticulin and collagen, independently reviewed by 2 hematopathologists, and rated according to the European Consensus 0-3 scale of marrow fibrosis (MF).

Results: Of 162 patients enrolled, 93 completed all 3 protocol-specified BM biopsies. All patients with a baseline assessment were negative for collagen. Of 159 patients assessed at baseline, 150 (94%) had normal reticulin (MF-0) and 9 (6%) had minimally increased reticulin (MF-1). After 2 years, 83/93 patients (89%) with BM biopsies had MF-0, 10 (11%) had MF-1, and none had MF-2 or MF-3. Five out of 127 patients (4%) at 1 year and 1 out of 93 (1%) at 2 years had collagen deposition. None of the patients had clinical symptoms typical of BM dysfunction or abnormalities of clinical concern based on white blood cell count or peripheral blood smear.

Conclusion: For most patients with chronic ITP, eltrombopag is not associated with clinically relevant increases in BM reticulin or collagen formation.
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http://dx.doi.org/10.1159/000452992DOI Listing
March 2017

Preleukemic phase of chronic myelogenous leukemia: morphologic and immunohistochemical characterization of 7 cases.

Ann Diagn Pathol 2016 Apr 6;21:53-8. Epub 2016 Feb 6.

Department of Hematopathology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, United States. Electronic address:

Patients with chronic myelogenous leukemia (CML) present typically with an elevated white blood cell count (WBC) and cytogenetic or molecular genetic evidence of t(9;22)/BCR-ABL1 fusion gene. Rarely, CML patients may present with a normal or mildly elevated WBC and are asymptomatic, and we describe 7 patients in this study. The WBC in these patients ranged from 3.6 to 14.3 K/mm(3) with 50% to 73% granulocytes and 0% blasts. In all patients, t(9;22)(q34;q11.2) was detected by conventional cytogenetics, and BCR-ABL1 fusion was shown, supporting the diagnosis of preleukemic CML (pre-CML). We compared these patients with a group of 5 cases of CML in chronic phase (CML-CP) and 5 bone marrow specimens with a leukemoid reaction (n=5). Reticulin, CD34, and CD61 immunostains were performed on all bone marrow biopsy specimens. Peripheral blood absolute basophilia (≥200/mm(3)) was noted in only 4 of 7 pre-CML cases, whereas it was present in all CML-CP cases and absent in leukemoid reaction cases. The mean ±SD of microvascular density of pre-CML cases (10.0 ± 4.3 vessels/200× field) was twice that of leukemoid reaction cases (5.0 ± 1.0) (P=.02; Student t test) but similar to that of CML-CP cases (12.5 ± 3.6). Microvessels in pre-CML, highlighted by CD34, were tortuous with abnormal branching, although to a lesser extent than those found in CML-CP. Microvessels in leukemoid reaction were generally straight. The percentage of small, hypolobated megakaryocytes, highlighted by CD61 in pre-CML, was 40%, 3 times that found in leukemoid reaction cases (13%) but less than that of CML-CP cases (86%). We conclude that pre-CML should be suspected in patients with a normal to mildly elevated WBC and absolute basophilia. Bone marrow examination can usually distinguish pre-CML from a leukemoid reaction based on the percentage of small, hypolobated megakaryocytes; microvascular density; and morphologic features.
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http://dx.doi.org/10.1016/j.anndiagpath.2015.12.004DOI Listing
April 2016

Characterization of a variant of t(14;18) negative nodal diffuse follicular lymphoma with CD23 expression, 1p36/TNFRSF14 abnormalities, and STAT6 mutations.

Mod Pathol 2016 06 11;29(6):570-81. Epub 2016 Mar 11.

Cancer Genetics, Inc., Rutherford, NJ, USA.

A predominantly diffuse growth pattern and CD23 co-expression are uncommon findings in nodal follicular lymphoma and can create diagnostic challenges. A single case series in 2009 (Katzenberger et al) proposed a unique morphologic variant of nodal follicular lymphoma, characterized by a predominantly diffuse architecture, lack of the t(14;18) IGH/BCL2 translocation, presence of 1p36 deletion, frequent inguinal lymph node involvement, CD23 co-expression, and low clinical stage. Other studies on CD23+ follicular lymphoma, while associating inguinal location, have not specifically described this architecture. In addition, no follow-up studies have correlated the histopathologic and cytogenetic/molecular features of these cases, and they remain a diagnostic problem. We identified 11 cases of diffuse, CD23+ follicular lymphoma with histopathologic features similar to those described by Katzenberger et al. Along with pertinent clinical information, we detail their histopathology, IGH/BCL2 translocation status, lymphoma-associated chromosomal gains/losses, and assessment of mutations in 220 lymphoma-associated genes by massively parallel sequencing. All cases showed a diffuse growth pattern around well- to ill-defined residual germinal centers, uniform CD23 expression, mixed centrocytic/centroblastic cytology, and expression of at least one germinal center marker. Ten of 11 involved inguinal lymph nodes, 5 solely. By fluorescence in situ hybridization analysis, the vast majority lacked IGH/BCL2 translocation (9/11). Deletion of 1p36 was observed in five cases and included TNFRSF14. Of the six cases lacking 1p36 deletion, TNFRSF14 mutations were identified in three, highlighting the strong association of 1p36/TNFRSF14 abnormalities with this follicular lymphoma variant. In addition, 9 of the 11 cases tested (82%) had STAT6 mutations and nuclear P-STAT6 expression was detectable in the mutated cases by immunohistochemistry. The proportion of STAT6 mutations is higher than recently reported in conventional follicular lymphoma (11%). These findings lend support for a clinicopathologic variant of t(14;18) negative nodal follicular lymphoma and suggests importance of the interleukin (IL)-4/JAK/STAT6 pathway in this variant.
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http://dx.doi.org/10.1038/modpathol.2016.51DOI Listing
June 2016

Pegylated interferon for the treatment of early myelofibrosis: correlation of serial laboratory studies with response to therapy.

Ann Hematol 2016 Apr 10;95(5):733-8. Epub 2016 Mar 10.

Jane Anne Nohl Division of Hematology, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, MC9172, Los Angeles, CA, 90033, USA.

Pegylated interferon α-2a (Peg-IFN) has been shown to induce hematologic and molecular responses in patients with the Philadelphia-negative myeloproliferative neoplasms (MPNs), including polycythemia vera (PV) and essential thrombocythemia (ET). We describe a series of patients with long-standing MPNs among whom Peg-IFN was initiated when they developed anemia and increased bone marrow reticulin fibrosis suggestive of early transformation to post-ET (PET) or post-PV (PPV) myelofibrosis (MF). Six patients were treated with Peg-IFN for a mean duration of 33.8 months (range 2-63 months). Five patients had long-standing ET (three were calreticulin (CALR)-positive, one janus kinase 2 (JAK2)-positive, and one JAK2-negative and CALR-negative), and one had long-standing JAK2-positive PV prior to starting Peg-IFN. This is the first study to report that, concurrent with the improvement in anemia, serial laboratory studies demonstrate an increase in serum LDH and left-shifted myeloid cells in the peripheral circulation over approximately 6 months, followed by a gradual normalization of these findings. Splenomegaly also increased and then resolved among responding patients. Serial bone marrow biopsies were available, which showed little change except for improvement in the grade of reticulin fibrosis in two patients. Among patients with early transformation to PET or PPV MF, our data support the efficacy of Peg-IFN in improving hemoglobin levels and reducing splenomegaly. These peripheral blood findings should not, therefore, be considered evidence of treatment failure within the first year of Peg-IFN therapy.
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http://dx.doi.org/10.1007/s00277-016-2631-0DOI Listing
April 2016

Recommendations for gross examination and sampling of surgical specimens of the spleen.

Ann Diagn Pathol 2015 Oct 9;19(5):288-95. Epub 2015 Jun 9.

Yale Department of Pathology, 310 Cedar St, New Haven, CT, 06520. Electronic address:

This review examines handling and processing of spleen biopsies and splenectomy specimens with the aim of providing the pathologist with guidance in optimizing examination and diagnosis of splenic disorders. It also offers recommendations as to relevant reporting factors in gross examination, which may guide diagnostic workup. The role of splenic needle biopsies is discussed. The International Spleen Consortium is a group dedicated to promoting education and research on the anatomy, physiology, and pathology of the spleen. In keeping with these goals, we have undertaken to provide guidelines for gross examination, sectioning, and sampling of spleen tissue to optimize diagnosis (Burke). The pathology of the spleen may be complicated in routine practice due to a number of factors. Among these are lack of familiarity with lesions, complex histopathology, mimicry within several types of lesions, and overall rarity. To optimize diagnosis, appropriate handling and processing of splenic tissue are crucial. The importance of complete and accurate clinical history cannot be overstated. In many cases, significant clinical history such as previous lymphoproliferative disorders, hematologic disorders, trauma, etc, can provide important information to guide the evaluation of spleen specimens. Clinical information helps plan for appropriate processing of the spleen specimen. The pathologist should encourage surgical colleagues, who typically provide the specimens, to include as much clinical information as possible.
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http://dx.doi.org/10.1016/j.anndiagpath.2015.06.004DOI Listing
October 2015

Evaluation of bone marrow reticulin in patients with chronic immune thrombocytopenia treated with eltrombopag: Data from the EXTEND study.

Am J Hematol 2015 Jul;90(7):598-601

GlaxoSmithKline, Collegeville, Pennsylvania.

Thrombopoietin receptor agonists, which raise platelet counts in patients with chronic immune thrombocytopenia, may be associated with increases in bone marrow (BM) reticulin. Patients with chronic immune thrombocytopenia participating in the Eltrombopag Extended Dosing (EXTEND) study underwent BM biopsies to identify clinically relevant BM fibrosis-related increases. Specimens were centrally reviewed by 2 hematopathologists. Two hundred thirty-two biopsy specimens were collected from 117 patients treated for ≤5.5 years. Moderate to marked reticulin fibrosis was found in 2 patients. After withdrawing from the study, the biopsy of 1 patient reverted to normal. There were no other pathologic changes identified among on-treatment specimens, and no pattern of abnormal reticulin deposition associated with eltrombopag treatment was evident.
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http://dx.doi.org/10.1002/ajh.24011DOI Listing
July 2015

Differentiating benign from malignant bone marrow B-cell lymphoid aggregates: a statistical analysis of distinguishing features.

Arch Pathol Lab Med 2015 Feb;139(2):233-40

From the Departments of Pathology and Laboratory Medicine, University of California Irvine School of Medicine, Orange (Drs Johnston, Reisian, Bhansali, Zhao, and Rezk); the University of Southern California Keck School of Medicine, Los Angeles (Dr Brynes); and Pathology and Laboratory Medicine, University of California San Francisco Medical Center, San Francisco (Dr Naemi).

Context: Lymphoid aggregates are seen in a minority of bone marrow biopsy specimens, and when present, their neoplastic nature is often apparent by morphologic evaluation. However, the distinction between benign and malignant aggregates can be a diagnostic challenge when there are multiple aggregates with no documented history of lymphoma.

Objective: To aid in the distinction between benign and malignant B-cell lymphoid aggregates.

Design: Previously, we described specific distribution patterns for B and T lymphocytes within bone marrow aggregates. To statistically analyze the significance of these patterns as well as previously reported criteria, we examined 128 bone marrow specimens with benign aggregates and 78 specimens with documented malignant B-cell aggregates and calculated specific odds ratios (ORs) and 95% confidence intervals (CIs) to aid in differentiating between benign and malignant B-cell aggregates.

Results: Aggregates with infiltrative edges (OR, 80.54; 95% CI, 31.76-204.21), a B-cell pattern (OR, 30.08; 95% CI, 13.28-68.10), paratrabecular location (OR, 10.17; 95% CI, 3.96-26.12), size greater than 600 μm (OR, 6.83: 95% CI, 3.61-12.93), or cytologic atypia correlated with malignancy.

Conclusions: When taken collectively, the presence of more than 2 of these characteristic features was strongly predictive of malignancy.
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http://dx.doi.org/10.5858/arpa.2013-0678-OADOI Listing
February 2015

Autoimmune myelofibrosis: an update on morphologic features in 29 cases and review of the literature.

Hum Pathol 2014 Nov 13;45(11):2183-91. Epub 2014 Aug 13.

Hematopathology Section, Department of Pathology, University of Southern California-Keck School of Medicine, Los Angeles, CA 90033.

Autoimmune myelofibrosis (AIMF) is a distinct clinicopathological entity associated with diffuse bone marrow fibrosis and a benign clinical course. Distinction from neoplastic etiologies of marrow fibrosis, particularly primary myelofibrosis, is imperative, but few studies have documented histopathologic features in a large series. We describe 29 patients with AIMF, defined as marrow reticulin fibrosis and lymphocytic infiltration in the context of an established autoimmune disorder (secondary AIMF) or autoantibodies without a defined disorder (primary AIMF). Excluded were cases with atypical megakaryocytes, dysplasia, basophilia, osteosclerosis, unexplained splenomegaly, or neoplasms associated with myelofibrosis (MF). All cases were stained for reticulin, CD3, and CD20, with a subset additionally stained for CD138, κ, λ, immunoglobulin G (IgG), and IgG4. Lymphoid aggregates, where present, were classified into T-cell and B-cell patterns of distribution. Most patients (93%) presented with cytopenias. Sixty-nine percent (n = 20) were considered secondary AIMF and the remainder primary AIMF (n = 9). Peripheral blood showed absent-to-rare blasts and teardrop erythrocytes and absence of eosinophilia or basophilia. Characteristic bone marrow findings included hypercellularity with erythroid and megakaryocytic hyperplasias, mild reticulin fibrosis, intrasinusoidal hematopoiesis, T-cell pattern in lymphoid aggregates, mild polytypic plasmacytosis, and absence of IgG4-positive plasma cells. Primary and secondary AIMF were pathologically indistinguishable, except for an increased incidence of granulocytic hyperplasia in primary AIMF. This series confirms and expands the utility of the original diagnostic criteria for AIMF. Recognizing the characteristic morphology of AIMF and its associated clinical and laboratory features distinguishes autoimmune from neoplastic causes of MF and guides further evaluation and management.
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http://dx.doi.org/10.1016/j.humpath.2014.07.017DOI Listing
November 2014

Peripheral blood smears, bone marrow aspiration, trephine and clot biopsies: methods and protocols.

Methods Mol Biol 2014 ;1180:257-69

Hematopathology Service, Department of Pathology, USC Keck School of Medicine, Los Angeles, CA, USA.

Maximum diagnostic information is obtained when peripheral blood smears, bone marrow aspiration smears, trephine biopsy imprints, trephine and clot biopsy sections are simultaneously examined. Peripheral blood smears reflect end organ function and provide clues to underlying hematolymphoid pathology that may prompt additional studies including bone marrow examination. Bone marrow aspiration alone has diagnostic utility in the evaluation of a limited number of primary hematological conditions including: megaloblastic anemias, hyporegenerative anemias, certain hemolytic anemias, normochromic normocytic anemias, neutropenias, thrombocytopenias, immunoglobulin disorders, storage diseases, and leukemias (Bain, J Clin Pathol 54:657-663, 2001). Bone marrow trephine biopsy is indicated in those situations where marrow aspiration is unsuccessful; in evaluation of cytopenias, myelofibrosis, suspicion of lymphoma, metastatic tumor, granulomatous disease, evaluation of myeloproliferative neoplasms, and for the examination of trabecular bone in metabolic diseases (Bain, J Clin Pathol 54:737-742, 2001). Many of the indications for marrow aspiration overlap with those for trephine biopsy. Because it is not possible to predict which patients will have diagnostic aspiration biopsies and which will have diagnostic trephine biopsies, both procedures are routinely performed together (Brynes et al., Am J Clin Pathol 70:753-759, 1978; Cotelingam, Adv Anat Pathol 10:8-26, 2003; Lee et al., Int J Lab Hematol 30:349-364, 2008; Peterson et al., Arch Pathol Lab Med 126:1050-1056, 2002).
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http://dx.doi.org/10.1007/978-1-4939-1050-2_14DOI Listing
February 2015

Classical Hodgkin lymphoma arising in the setting of iatrogenic immunodeficiency: a clinicopathologic study of 10 cases.

Am J Surg Pathol 2013 Aug;37(8):1290-7

Department of Hematopathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Iatrogenic immunodeficiency-associated lymphoproliferative disorders are rare. A small subset of these lesions resembles classical Hodgkin lymphoma (CHL), but there are few data in the literature about these lesions. We describe 10 patients with autoimmune diseases treated with immunomodulator therapeutic agents who developed CHL. The autoimmune diseases included rheumatoid arthritis (n=5), systemic lupus erythematosus (n=2), dermatomyositis (n=1), autoimmune hepatitis (n=1), and Crohn disease (n=1), and the immunomodulatory therapies were methotrexate, azathioprine, tumor necrosis factor-α inhibitors, and thalidomide alone or in various combinations. The study group included 9 women and 1 man with a median age of 50 years (range, 25 to 77 y). The histologic features supported CHL in all cases with Reed-Sternberg (RS) and Hodgkin (H) cells in an inflammatory cell background, although the neoplasm could only be subclassified in 3 patients: 2 nodular sclerosis and 1 mixed cellularity. Immunohistochemical analysis supported the diagnosis of CHL. In all cases the RS-H cells were CD30. Nine of 10 cases were CD15, whereas CD20 was expressed variably in 4/10 cases. CD45/LCA was negative in 8 cases assessed. In situ hybridization for Epstein-Barr virus-encoded RNA was positive in the RS-H cells in 8/10 cases. The microenvironment of these lesions depicted a predominance of T-regulatory cells and M2 histiocytes. Clinical follow-up data were available for 7 patients, with a median posttreatment period of 27 months (range, 12 mo to 7 y). In all 7 patients immunomodulatory drug therapy was discontinued, and chemotherapy for CHL was administered; 2 patients also received local radiation. All 7 patients achieved complete remission and are alive. We conclude that iatrogenic immunodeficiency-associated CHL is highly associated with Epstein-Barr virus infection, and patients usually have a good outcome after discontinuation of immunomodulatory agents and chemotherapy for CHL.
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http://dx.doi.org/10.1097/PAS.0b013e31828e6564DOI Listing
August 2013

Benign lymphoid aggregates in the bone marrow: distribution patterns of B and T lymphocytes.

Hum Pathol 2013 Apr 11;44(4):512-20. Epub 2012 Oct 11.

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

Benign lymphoid aggregates are seen in only a minority of bone marrow specimens, but their distinction from non-Hodgkin lymphoma, particularly B-cell lymphomas, can represent a diagnostic challenge. Although criteria have been proposed to help distinguish between benign and malignant aggregates, a detailed description of the distribution patterns of B and T lymphocytes within benign lymphoid aggregates has not been investigated. One hundred thirty-seven cases of bone marrow specimens containing benign aggregates were studied with a panel of immunostains. A subset of these cases was also examined for immunoglobulin gene rearrangements by polymerase chain reaction. The aggregates were categorized based on size, location (paratrabecular or random), presence of infiltrating edges, and distribution of lymphoid cell populations. In addition, we examined 40 cases of bone marrow biopsies with documented malignant lymphoid aggregates for comparison purposes. We report that the distribution of B and T lymphocytes within lymphoid aggregates may serve as a useful criterion to aid in the separation between benign and malignant aggregates. When aggregates exhibit a predominance of T cells, consist of a central core of T cells surrounded by a rim of B cells, or have a mixed distribution of B and T cells, they are more likely to be benign. On the other hand, an increased likelihood of malignancy occurs when aggregates exhibit a predominance of B cells or consist of a central core of B cells surrounded by a rim of T cells (excluding germinal center formation), and assessing other features worrisome of malignancy (large aggregate size, presence of infiltrative edges, cellular atypia, and paratrabecular location, among others) is warranted.
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http://dx.doi.org/10.1016/j.humpath.2012.06.012DOI Listing
April 2013

Histopathological findings in 29 lymph node biopsies with increased IgG4 plasma cells.

Mod Pathol 2012 Mar 11;25(3):480-91. Epub 2011 Nov 11.

Clarient /GE Healthcare, Department of Pathology, Aliso Viejo, CA, USA.

IgG4-related sclerosing disease encompasses a family of disorders associated with increased numbers of IgG4 plasma cells and mass forming lesions in various tissues. Lymphadenopathy is a common finding, seen in up to 80% of cases. In the largest series of cases to date, we describe histologic, immunohistochemical, special stain and flow cytometric findings in 29 cases of enlarged lymph nodes with increased IgG4 plasma cells. Lymph node biopsies showed all resection specimens; no needle core biopsies of tissue were evaluated. Cases were considered to have increased numbers of IgG4 plasma cells using the histological criteria outlined by Cheuk and Chan (2010): IgG4 plasma cells >50 cells in a high-power field and >40% of IgG-positive plasma cells positive for IgG4. Additionally, increased intrafollicular plasma cells were a common finding. The lymph nodes showed a variety of reactive histological features including follicular hyperplasia, progressive transformation of germinal centers, interfollicular expansions, variable degrees of fibrosis, increased histiocytes and occasionally an appearance similar to that of plasma cell Castleman disease.
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http://dx.doi.org/10.1038/modpathol.2011.177DOI Listing
March 2012

Peripheral blood polyclonal plasmacytosis mimicking plasma cell leukemia in patients with angioimmunoblastic T-cell lymphoma: report of 3 cases and review of the literature.

Int J Clin Exp Pathol 2011 Apr 18;4(4):416-20. Epub 2011 Apr 18.

Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA.

Angioimmunoblastic T-cell lymphoma (AITL) is a unique type of peripheral T-cell lymphoma. Patients with AITL may have occasional reactive plasma cells present in the peripheral circulation. Prominent peripheral blood polyclonal plasmacytosis mimicking plasma cell leukemia, however, is distinctly uncommon. Here we describe 3 such cases from two large tertiary medical centers and discuss the role of ancillary studies in the differential diagnosis of peripheral blood plasmacytosis.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3093066PMC
April 2011

B-cell lymphoma with hyaline vascular Castleman disease-like features: a clinicopathologic study.

Am J Clin Pathol 2011 Jun;135(6):901-14

Dept. of Pathology, Duke University Medical Center, Duke Hospital South, Durham, NC 27710, USA.

Hyaline vascular Castleman disease (HV-CD) is a localized benign mass characterized by follicular hyperplasia with atrophic germinal centers, mantle zone hyperplasia, hyaline deposits, and vascular proliferation. Before establishing a diagnosis of CD, several B-cell lymphomas (BCLs) must be considered, including follicular lymphoma (FL), mantle cell lymphoma (MCL), and nodal marginal zone lymphoma (NMZL). Conversely, BCLs with prominent atrophic germinal centers and hyaline vascular penetration may closely resemble HV-CD, leading to misdiagnosis. We report 6 cases of BCL with prominent HV-CD-like features, including FL (2 cases), MCL, NMZL (2 cases), and interfollicular large B-cell lymphoma. Histologically, all were initially considered to be HV-CD before additional tests revealed a neoplastic B-cell proliferation. We highlight the clinicopathologic features of these cases in comparison with cases diagnostic of HV-CD. In contrast with HV-CD, BCLs with HV-CD-like features are more likely to manifest clinically with systemic symptoms or generalized lymphadenopathy. Careful histopathologic examination, supported with immunohistochemical studies, flow cytometric immunophenotyping, and judicious use of cytogenetic and molecular analyses, allows identification of the masked neoplastic process. A multifaceted approach, integrating clinical, histologic, and ancillary tests, can help avoid this diagnostic pitfall.
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http://dx.doi.org/10.1309/AJCPF5AESY7OWIXFDOI Listing
June 2011

Adult leukemic synovitis is associated with leukemia of monocytic differentiation.

J Clin Rheumatol 2011 Apr;17(3):130-4

Department of Pathology, University of Southern California/Los Angeles County Medical Center, Los Angeles, CA, USA.

Background: Leukemic synovitis is a rare complication of adult myeloid leukemias characterized by joint pain and swelling. It is important to recognize this diagnostic challenge as it may be the initial manifestation of leukemia or of relapse.

Methods: A retrospective search of patient files from 2 teaching hospitals identified 4 adult patients who presented with large joint arthritis and concurrent or subsequent leukemic synovitis. All patients presented with inflammatory arthritis of large joints, and leukemic synovitis was identified by the presence of leukemic cells in the synovial fluid or infiltrating the synovial membrane seen at biopsy.

Results: A leukemia of monocytic origin-acute myelomonocytic leukemia or chronic myelomonocytic leukemia-was diagnosed in all 4 patients. In 2 cases, leukemic synovitis was the initial manifestation of leukemia. In the third case, it was the first sign of relapse, and in the remaining case, it developed shortly after diagnosis of leukemia. All patients had either osteoarthritis or rheumatoid arthritis. One patient was diagnosed simultaneously with osteoarthritis and leukemia. The remaining patients had a prior history of arthritis.

Conclusions: Adult leukemic synovitis occurs in association with leukemias of monocytic differentiation. Data presented here, and review of isolated case reports, support this association. The finding of large joint arthritis as a comorbidity in these 4 cases raises questions about the role of antecedent arthritis as a predisposing factor in the pathophysiology of leukemic synovitis.
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http://dx.doi.org/10.1097/RHU.0b013e318214befeDOI Listing
April 2011

Systemic mastocytosis associated with t(8;21)(q22;q22) acute myeloid leukemia.

J Hematop 2009 Mar 10;2(1):27-33. Epub 2009 Feb 10.

Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, 10833 Le Conte Avenue, CHS, A7-149, Los Angeles, CA, 90095-1732, USA,

Although KIT mutations are present in 20-25% of cases of t(8;21)(q22;q22) acute myeloid leukemia (AML), concurrent development of systemic mastocytosis (SM) is exceedingly rare. We examined the clinicopathologic features of SM associated with t(8;21)(q22;q22) AML in ten patients (six from our institutions and four from published literature) with t(8;21) AML and SM. In the majority of these cases, a definitive diagnosis of SM was made after chemotherapy, when the mast cell infiltrates were prominent. Deletion 9q was an additional cytogenetic abnormality in four cases. Four of the ten patients failed to achieve remission after standard chemotherapy and seven of the ten patients have died of AML. In the two patients who achieved durable remission after allogeneic hematopoietic stem cell transplant, recipient-derived neoplastic bone marrow mast cells persisted despite leukemic remission. SM associated with t(8;21) AML carries a dismal prognosis; therefore, detection of concurrent SM at diagnosis of t(8;21) AML has important prognostic implications.
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http://dx.doi.org/10.1007/s12308-009-0023-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2713498PMC
March 2009

Phlegmonous gastritis in a patient with myeloid sarcoma: a case report.

Appl Immunohistochem Mol Morphol 2009 Oct;17(5):458-62

Department of Pathology, Keck School of Medicine, LAC+USC Medical Center, University of Southern California, Los Angeles, CA 90030, USA.

Phlegmonous gastritis is a rare acute bacterial infection of the gastric wall with an extremely high mortality rate. Early diagnosis is crucial for immediate treatment that could improve the outcomes. Here we report a case in which a patient with underlying chronic myelomonocytic leukemia was diagnosed with phlegmonous gastritis on biopsy. This 57-year-old man presented with shortness of breath and intermittent upper quadrant abdominal pain for 4 days. Laboratory tests showed markedly increased white blood cell. A diagnosis of chronic myelomonocytic leukemia was made based on a peripheral blood smear and flow cytometry. Gastric biopsy showed suppurative inflammation in the submucosal region, prompting the diagnosis of phlegmonous gastritis. The patient was given empirical antibiotic treatment, and the white blood cell decreased dramatically. Surgical intervention was discussed but deferred. Despite continued antibiotics treatment, the patient died. The limited autopsy confirmed the diagnosis of phlegmonous gastritis. Immunohistochemical studies further revealed the occurrence of myeloid sarcoma that involved the gastrointestinal tract.
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http://dx.doi.org/10.1097/PAI.0b013e31819f86e2DOI Listing
October 2009

High lifetime incidence of adult acute lymphoblastic leukemia among Hispanics in California.

Cancer Epidemiol Biomarkers Prev 2009 Feb;18(2):611-5

Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095-1732, USA.

Background: The higher incidence of acute lymphoblastic leukemia (ALL) among Hispanic children relative to that in other racial/ethnic groups is well-known. We evaluated the incidence patterns of ALL in adults.

Methods: We analyzed the incidence patterns of ALL (International Classification of Diseases for Oncology 3 codes 9835-9837) among all patients diagnosed from 1988 to 2004 in California using data from the California Cancer Registry to determine whether adult Hispanics also had higher incidence rates of ALL compared with non-Hispanic Whites (Whites). Age-adjusted incidence rates (AAIR), incidence rate ratios (IRR), and 5-year survival rates were obtained using SEER*Stat. AAIRs of other leukemia subtypes and IRRs relative to non-Hispanic Whites were also examined as references for ALL.

Results: AAIRs of ALL in Hispanic males and females ages 20 to 54 years were higher compared with those in White males and females (IRR, 1.99; 95% confidence interval, 1.74-2.28 and IRR, 1.91; 95% confidence interval, 1.60-2.25, respectively). A higher AAIR of ALL was also observed among older (55+ years) Hispanic females (IRR, 1.84; 95% confidence interval, 1.52-2.21), but not in males (IRR, 1.07; 95% confidence interval, 0.84-1.34). Among Hispanics, low socioeconomic status was associated with a higher AAIR compared with high/middle socioeconomic status (IRR, 1.33; 95% confidence interval, 1.04-1.70). The respective 5-year survival rates among ALL patients were 38% and 30% for Whites and Hispanics ages 20 to 54 years, and 8% and 12% for patients 55 years of age or older. Compared with other racial/ethnic groups, Hispanics did not have an increased IRR of the other major leukemia subtypes.

Conclusion: Hispanics experience a higher incidence of ALL throughout life, but not other subtypes.
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http://dx.doi.org/10.1158/1055-9965.EPI-07-2949DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3191882PMC
February 2009

Indeterminate cell tumor: a rare dendritic neoplasm.

Am J Surg Pathol 2008 Dec;32(12):1868-76

Department of Pathology and Laboratory Medicine, University of California Irvine (UCI), Irvine, CA, USA.

Indeterminate cell tumor (ICT) is a rare neoplastic dendritic cell disorder that has been poorly defined due to its rarity and poorly understood histogenesis and pathogenesis. It is characterized by a proliferation of dendritic cells, which mimic Langerhans cells immunophenotypically (positive for CD1a and S-100 protein), but lack Birbeck granules characteristic of Langerhans cells. The clinical, morphologic, immunophenotypic, and ultrastructural features of 5 ICT cases are reported in an attempt to further define ICT and to examine the postulated relationship between indeterminate cells and Langerhans cells. Four of 5 patients were females, and 4 of 5 were older than 68 years. Three of 5 patients had cutaneous lesions, whereas 2 presented with cervical lymph node involvement. Two patients had a possible association with lymphoma: first patient had a history of progressive follicular lymphoma that led to patient's demise and the second patient had unexplained systemic lymphadenopathy and died 1 week after the biopsy. All 5 ICT cases expressed CD1a and S-100 protein, but lacked Langerin expression and Birbeck granules ultrastructurally. Interestingly, a t(14;18) was detected by fluorescence in situ hybridization in the ICT cells of the patient with previous follicular lymphoma and a monoclonal kappa light chain gene rearrangement was detected by polymerase chain reaction in the patient with systemic lymphadenopathy. In both cases, there was no morphologic or immunophenotypic evidence of a concurrent B-cell lymphoma. In conclusion, ICT is a rare neoplasm that can occur de novo or in association with a B-cell lymphoma, possibly as a result of B-cell dedifferentiation caused by relatively unknown mechanisms. Finally, Langerin immunostaining may be used as a surrogate marker for the ultrastructural demonstration of Birbeck granules, the absence of which represents a strong diagnostic criterion for ICT.
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http://dx.doi.org/10.1097/PAS.0b013e31818593d6DOI Listing
December 2008

Body cavity-based presentation of natural killer cell lymphoma.

Leuk Lymphoma 2005 Feb;46(2):293-6

Division of Hematology, Department of Medicine, University of Southern California School of Medicine, Los Angeles, USA.

We describe an unusual case of a 31-year-old Mexican woman who presented with pleural and peritoneal effusions involved by Epstein-Barr virus-positive non-Hodgkin's lymphoma of natural killer (NK)-cell lineage. The patient had no symptoms that could be related to her nasal region, and physical examination and radiologic studies showed no evidence of lymphadenopathy, organomegaly, or other extranodal masses. Thus, this case clinically mimicked body cavity-based lymphoma. Extranodal NK/T-cell lymphoma of nasal type is the current designation for these neoplasms in the recently proposed World Health Organization classification of lymphoid neoplasms. These tumors previously have been referred to many other names, including lethal midline granuloma, midline malignant reticulosis, polymorphic reticulosis, angiocentric immunoproliferative lesion, and angiocentric lymphoma. Nasal-type NK/T-cell lymphomas typically involve the nasal region, but may involve other extranodal sites, such as skin and gastrointestinal tract. The malignant cytologic features and the presence of azurophilic granules within the cell cytoplasm observed in Wright-Giemsa-stained cytocentrifuge preparations led to immunophenotypic and molecular genetic studies that were essential in establishing the correct diagnosis. As demonstrated in the case reported, extranodal NK/T-cell lymphomas of nasal-type can be clinically aggressive and may be associated with paraneoplastic phenomena.
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http://dx.doi.org/10.1080/10428190400015659DOI Listing
February 2005

Systemic mastocytosis with associated clonal hematological non-mast-cell lineage disease: analysis of clinicopathologic features and activating c-kit mutations.

Am J Hematol 2003 May;73(1):12-7

Division of Hematology, University of Southern California Keck School of Medicine, Los Angeles, CA, USA.

The majority of patients with systemic mastocytosis with associated clonal, hematological non-mast cell lineage disease (SM-AHNMD) have a myeloid stem cell malignancy including myelodysplastic syndromes (MDS), myelodysplastic/myeloproliferative disorders, acute myeloid leukemia (AML), or chronic myeloproliferative disease. The clinicopathologic features of SM-AHNMD have not been fully characterized. We describe seven cases of this entity: 3 with MDS, 3 with AML, and 1 with chronic myelomonocytic leukemia. In the majority of cases, SM was diagnosed concurrently with the myeloid malignancy and aberrant mast cell morphology was observed. The commonly described c-kit enzymatic site mutation Asp816Val was detected only in 2 cases, while 3 patients carried the Asp816His mutation. Among the 3 cases with AML, 2 patients carried the translocation t(8;21). On the basis of our results and other reported cases, there appears to be a specific association between SM and AML with t(8;21). Concurrent occurrence of SM may define a subset of patients with de novo AML and other myeloid malignancies who have an adverse prognosis. As clinically effective tyrosine kinase inhibitors that inhibit enzymatic-type c-kit mutations are being developed, detection of mast cell proliferation associated with myeloid malignancy may have important therapeutic implications.
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http://dx.doi.org/10.1002/ajh.10322DOI Listing
May 2003

Immunohistochemical expression of the transcription factor DP-1 and its heterodimeric partner E2F-1 in non-Hodgkin lymphoma.

Appl Immunohistochem Mol Morphol 2002 Dec;10(4):322-6

Department of Pathology, Los Angeles County and University of Southern California Medical Center, Los Angeles, California, USA.

DP-1 is a G1 cell cycle-related protein that forms heterodimers with E2F, a family of transcriptional factors regulating the expression of genes important for G1 to S progression. Although the exact role of DP-1 is not well understood, it has been shown to stabilize DNA binding of E2F proteins. By immunohistochemistry, the authors examined the expression of DP-1 in lymphoid tissues, including 8 cases of reactive follicular hyperplasia and 69 cases of B-cell non-Hodgkin lymphoma. The expression of the cell cycle-related proteins E2F-1 and Ki-67 was also assessed. Scoring was based on the proportion of labeled nuclei (1-10%, 11-25%, 26-50%, and > 50%). In reactive follicular hyperplasia, staining for DP-1, E2F-1, and Ki-67 was largely confined to the germinal centers. All 25 cases of follicular lymphoma, regardless of grade, had a high proportion (> 50%) of DP-1-positive cells but a lower proportion of cells marking for E2F-1 and Ki-67 (P < 0.001). The diffuse large B-cell lymphomas (n = 24) had high DP-1 and Ki-67 scores but low E2F-1 scores (P < 0.001). Small lymphocytic (n = 10), marginal zone (n = 3), and mantle cell lymphomas (n = 5) contained relatively low proportions of cells labeled for all three markers. Precursor B-cell lymphoblastic lymphoma (n = 2) displayed high proportions of cells positive for DP-1, Ki-67, and E2F-1 (> 50% in both cases). Except in follicular center cell lesions, DP-1 expression generally correlated with that of Ki-67. However, the expression of DP-1 was discordant with that of E2F-1 in benign and malignant follicular center cells, suggesting that DP-1 may have functions other than facilitating E2F-1-dependent gene regulation and cell cycle progression in these neoplasms.
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http://dx.doi.org/10.1097/00129039-200212000-00006DOI Listing
December 2002

Primary autoimmune myelofibrosis: definition of a distinct clinicopathologic syndrome.

Am J Hematol 2003 Jan;72(1):8-12

Division of Hematology, Keck School of Medicine, University of Southern California, Los Angeles, California 91010-300, USA.

Myelofibrosis is characterized by reticulin fibrosis of the bone marrow with resulting features of myelophthisis. Besides hematopoietic malignancies and other neoplasms involving the bone marrow, myelofibrosis has been described in association with autoimmune disorders, especially systemic lupus erythematosus. We describe the clinicopathologic features of a primary form of autoimmune myelofibrosis (AIMF) in patients who do not have systemic lupus erythematosus or another well-defined autoimmune syndrome. Absence of marked splenomegaly, peripheral blood cytopenias with mild teardrop poikilocytosis and leukoerythroblastosis, bone marrow lymphoid aggregates, and presence of autoantibodies are some of the salient features of primary AIMF. AIMF should especially be differentiated from chronic idiopathic myelofibrosis, a neoplastic myeloproliferative disease. Primary AIMF appears to have an excellent prognosis, with all patients reported in this series responding to a short course of corticosteroid therapy.
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http://dx.doi.org/10.1002/ajh.10258DOI Listing
January 2003

Immunohistochemical expression of cyclin D1, E2F-1, and Ki-67 in benign and malignant thyroid lesions.

J Pathol 2002 Oct;198(2):157-62

Department of Pathology, Los Angeles County/USC Medical Center, 2011 Zonal Avenue, Los Angeles, CA 90093, USA.

Cyclin D1 and E2F-1 proteins are essential for the regulation of the G1/S transition through the cell cycle. Cyclin D1, a product of the bcl-1 gene, phosphorylates the retinoblastoma protein, releasing E2F-1, which in turn activates genes involved in DNA synthesis. Expression patterns of E2F-1 protein in thyroid proliferations have not been reported. This study used monoclonal antibodies for cyclin D1 and E2F-1 proteins to immunostain sections of normal thyroid, hyperplastic (cellular) nodules, follicular adenomas, follicular carcinomas, and papillary carcinomas. The proliferation rate was examined using an antibody specific for the Ki-67 antigen. Fluorescence in situ hybridization (FISH) methods and chromosome 11-specific probes were also employed to determine chromosome copy number and to assess for evidence of amplification at the 11q13 locus in papillary and follicular carcinomas with cyclin D1 overexpression. Concurrent overexpression of Ki-67, cyclin D1, and E2F-1 was found in the majority of benign and malignant thyroid lesions, compared with normal thyroid tissue. Cyclin D1 up-regulation was not due to extra copies of chromosome 11, or bcl-1 gene amplification. Malignant tumours showed the highest expression for all three markers, particularly papillary carcinomas. E2F-1 was detected at the same or slightly lower levels than cyclin D1. It was only found when cyclin D1 was overexpressed. Because cyclin D1 normally activates E2F-1, up-regulation of cyclin D1 may lead to E2F-1 overexpression in benign and malignant thyroid lesions.
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http://dx.doi.org/10.1002/path.1185DOI Listing
October 2002
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