Applied Immunohistochemistry

The cellular receptor for urokinase-type plasminogen activator receptor (uPAR) is a member of the glycosylphosphatidylinositol (GPI) anchored protein family. It is a specific cell surface receptor for its ligand, urokinase-type plasminogen activator, which catalyzes the formation of plasmin from plasminogen to generate the proteolytic cascade and leads to the breakdown of the extracellular matrix. uPAR has been shown to correlate with a propensity to tumor invasion and metastasis in several types of non-central nervous system tumors. In this study, the authors examined the immunohistochemical expression of uPAR in 65 primary brain tumors (5 pilocytic astrocytomas, 5 diffuse astrocytomas, 6 anaplastic astrocytomas, 8 glioblastomas, 5 oligodendrogliomas, 4 oligoastrocytomas, 6 anaplastic oligoastrocytomas, 4 gangliogliomas, 4 ependymomas, 5 medulloblastomas, 6 schwannomas, 5 meningiomas, 2 atypical meningiomas). The specimens were evaluated for intensity of immunostaining (0-3 scale), cellular localization of staining, and specific or unique patterns of staining. Some degree of uPAR expression was observed in all tumors. A significant positive correlation (P = 0.0006) between tumor grade and staining intensity was identified within the astrocytoma/glioblastoma subgroup, suggesting a possible correlation with anaplastic change and propensity to tumor invasion. Expression of uPAR in nonmalignant, noninvasive tumors such as schwannoma and meningioma suggests that uPAR may have other biologic functions in addition to promotion of tumor invasion.

Mohammad Salajegheh

Anna Rudnicki

Thomas W Smith

Expression of Urokinase-Type Plasminogen Activator Receptor (uPAR) in Primary Central Nervous System Neoplasms

原发性中枢神经系统肿瘤中尿激酶型纤溶酶原激活物受体(uPAR)的表达

The purpose of this study was to determine whether 3 tyrosine kinases known to be inhibited by imatinib mesylate are expressed in a variety of uterine sarcomas. The authors assessed c-kit, abl, and platelet-derived growth factor receptor-beta (PDGFR-beta) expression in 8 endometrial stromal sarcomas (ESSs), 5 leiomyosarcomas (LMSs), 4 high-grade endometrial sarcomas (HGESs), and 21 malignant mixed mullerian tumors (MMMTs). Tissue sections were stained with commercially available antibodies for c-kit, abl, and PDGFR-beta. Staining intensity was described as 0 (no staining), +1 (weak), +2 (moderate), and +3 (strong). Positive staining was defined as moderate to strong if found in more than 10% of tumor cells. Expression of c-kit ranged from 0% in LMSs to 25% in HGESs. Protein expression of abl was more significant, ranging from 25% in LMSs and ESSs to 43% in MMMTs. Only 1 LMS sample stained focally for abl (+1). Abl expression was observed in only the carcinomatous elements of the MMMTs, with diffuse staining in the cytoplasm and nucleus. In most, the staining intensity was +2. All tumors stained positive for PDGFR-beta. MMMT samples showed PDGFR-beta expression in both the carcinomatous and sarcomatous portions. In all samples, staining for PDGFR-beta was concentrated at the cell membrane and diffusely in the cytoplasm. These results indicate that many uterine sarcomas express 1 or more of the kinases targeted by imatinib mesylate and that further investigation of imatinib as a therapy for uterine sarcomas is warranted.

Jimmy J Caudell

Michael T Deavers

Brian M Slomovitz

Karen H Lu

Russell R Broaddus

David M Gershenson

Lois M Ramondetta

Imatinib Mesylate (Gleevec)-Targeted Kinases Are Expressed in Uterine Sarcomas

甲磺酸伊马替尼（格列卫）靶向激酶在子宫肉瘤中表达

The clinical and biologic relevance of the t(14;18) and features of germinal center (GC) differentiation in diffuse large B-cell lymphoma (DLBCL) remain controversial. The authors examined the association of t(14;18) with GC-associated markers and clinical features in 44 de novo DLBCLs (22 nodal and 22 primary extranodal). CD10, bcl-2, and bcl-6 were expressed in 50%, 62%, and 54% of cases respectively. There were no significant differences in expression of these markers between nodal and extranodal cases. Coexpression of CD10 and bcl-6 was seen in 12 of 41 cases, and was more frequent in nodal than extranodal DLBCL (9 of 21 vs. 3 of 20; P = 0.05). A CD10+/bcl-6+ phenotype was not significantly associated with bcl-2 expression, stage, complete remission rate, or survival. The t(14;18) was found in 7 of 44 (16%) cases (6 nodal, 1 extranodal; P = 0.09). It was associated with a CD10+/bcl-6+ phenotype (5 of 7 vs. 7 of 27; P = 0.015) and a trend toward more frequent bcl-6 expression (6 of 7 vs. 15 of 34; P = 0.09), but no association with bcl-2 expression, CD10, clinical stage, complete remission, or survival. Among nodal or high-stage (III-IV) DLBCL, cases with the t(14;18) showed a trend toward decreased survival (P = 0.12).

Yin Xu

Robert W McKenna

Jeffrey E Doolittle

Christa L Hladik

Steven H Kroft

The t(14;18) in Diffuse Large B-Cell Lymphoma

弥漫性大B细胞淋巴瘤中的t(14;18)

Kaposi sarcoma (KS) is a multicentric vascular neoplasm characterized histologically by the progressive proliferation of spindle-shaped tumor cells in all epidemiologic (AIDS-related, classic, endemic, and iatrogenic) forms. Human herpesvirus 8 (HHV8) is associated with all epidemiologic forms of KS and has been shown in vitro to induce the tyrosine receptor kinase c-kit in HHV8-infected cells. To date, c-kit immunoreactivity has not been systematically studied in KS lesions. Therefore, the aim of this study was to evaluate c-kit expression by immunohistochemistry in different proliferative stages and epidemiologic forms of KS. Archival cases of formalin-fixed, paraffin-embedded KS lesions, including 9 classic, 11 AIDS-related, and 15 African (endemic) forms at various histologic stages (5 patch, 8 plaque, 22 nodular), biopsied from different sites, were stained using immunohistochemistry with antibodies to HHV8 (LNA-1) and c-kit (CD117). C-kit immunoreactivity of lesional cells was demonstrated in 15 (43%) cases overall. A total of five (56%) classic, five (45%) AIDS-related, and five (33%) endemic KS cases were positive for c-kit. There was no difference in the intensity of c-kit staining between the different epidemiologic groups and histologic stages of KS. HHV8 (LNA-1) immunoreactivity was present in all (100%) classic, 10 (91%) AIDS-related, and 9 (60%) endemic cases. LNA-1 staining was demonstrated in 13 (93%) of the c-kit-positive and 15 (75%) of the c-kit-negative KS lesions. These findings indicate that c-kit expression in lesional cells can be detected by immunohistochemistry in different epidemiologic forms and histologic stages of KS. Furthermore, the expression of c-kit does not correspond with the presence of HHV8 (LNA-1) immunoreactivity in KS lesions.

Liron Pantanowitz

Erich J Schwartz

Bruce J Dezube

Sabine Kohler

Ronald F Dorfman

Steven R Tahan

C-Kit (CD117) Expression in AIDS-Related, Classic, and African Endemic Kaposi Sarcoma

艾滋病相关型、经典型和非洲地方性卡波西肉瘤中的C-Kit (CD117) 表达

The tumor suppressor gene wt1 (Wilms tumor 1) encodes a zinc finger transcription factor reported to be expressed in many tumors, including mesotheliomas, carcinomas, and acute leukemias. However, WT1 expression in non-Hodgkin lymphomas (NHLs) has not been studied. The authors assessed for WT1 expression in six lymphoma/leukemia cell lines using Western blot methods after subcellular fractionation. We also assessed for WT1 expression in 167 NHLs using immunohistochemical methods. The B-cell NHLs analyzed were 18 diffuse large B-cell lymphomas, 13 marginal zone B-cell lymphomas, 9 small lymphocytic lymphomas, (DLBCLs), 8 follicular lymphomas, 6 mantle cell lymphomas, 5 Burkitt lymphomas, 3 lymphoplasmacytic lymphomas, and 2 B-cell lymphoblastic lymphomas. The T-cell NHLs analyzed were 43 anaplastic large cell lymphomas (ALCLs), 26 peripheral T-cell lymphomas unspecified, 13 angioimmunoblastic T-cell lymphomas, 6 cutaneous ALCLs, 6 cases of mycosis fungoides, 5 extranodal NK/T-cell lymphomas of nasal type, and 4 T-cell lymphoblastic lymphomas. WT1 levels were higher in cytoplasmic extracts than in nuclear extracts of the Karpas 299 and SU-DHL-1 lymphoma cell lines but were higher in nuclear extracts than in the cytoplasmic extracts of the Jurkat, HH, U-937, and K562 leukemia cell lines. In NHLs, WT1 was positive in 4 of 5 (80%) Burkitt lymphomas, 9 of 12 (75%) ALK-positive ALCLs, 3 of 6 (50%) lymphoblastic lymphomas (2 of 4 T-cell, 1 of 2 B-cell), 14 of 31 (45%) ALK-negative ALCLs, 6 of 18 (33%) DLBCLs, and 1 of 6 (17%) cutaneous ALCLs. WT1 was negative in all other NHLs tested. WT1 immunoreactivity was primarily cytoplasmic in all positive NHLs except T-cell lymphoblastic lymphoma. In conclusion, WT1 protein is frequently detected in the cytoplasm of a subset of high-grade NHLs.

Elias Drakos

George Z Rassidakis

Panagiota Tsioli

Raymond Lai

Dan Jones

L Jeffrey Medeiros

Differential Expression of WT1 Gene Product in Non-Hodgkin Lymphomas

非霍奇金淋巴瘤中WT1基因产物的差异表达

Introduction: Epidermal growth factor receptor (EGFR) gene mutations are usually detected by direct sequencing to identify patients with advanced pulmonary adenocarcinomas as candidates for tyrosine kinase inhibitor therapy. The aim of the study was to evaluate the efficacy of EGFR mutation-specific antibodies in identifying EGFR-mutated adenocarcinomas. Materials and Methods: Thirty-three consecutive cases of pulmonary adenocarcinomas sequenced for EGFR mutations were retrieved from our files. Immunohistochemistry was performed with the rabbit monoclonal antibodies E746-A750del (6B6) and L858R (43B2). The results obtained using the 2 procedures were statistically compared by Coehn κ and by calculation of sensitivity and specificity. Results: There were 21 women and 12 men, ranging in age from 48 to 78 years. All cases were lung adenocarcinomas, 23 primaries and 10 metastatic. The mutational spectrum was as follows: 12 cases mutated in exon 19 (9 with E746-A750del, 1 with homozygote L747-T751del, 1 with L747-P753del, 1 with E747-S752del), 6 in exon 21 (5 with L858R, 1 with L861Q+L862L), and 15 EGFR wild type. Immunohistochemistry detected 6/9 cases with an E746-A750del mutation (κ=0.744, sensitivity: 66.7%, specificity: 100%) and 5/5 cases with an L858R mutation (κ=1, sensitivity: 100%, specificity: 100%). Four cases showed faint and focal immunostaining and were interpreted as negative. All other cases were negative. Overall, the 2 antibodies had 61.1% sensitivity and 100% specificity for EGFR mutations. Conclusions: EGFR mutation-specific antibodies may represent a first-line screening tool to identify patients as candidates for tyrosine kinase inhibitor therapy.

Andrea Ambrosini-Spaltro

Nicoletta Campanini

Beatrice Bortesi

Cinzia Azzoni

Nadia Naldi

Luca Ampollini

Marcello Tiseo

Andrea Ardizzoni

Michele Rusca

Paolo Carbognani

Enrico M. Silini

EGFR Mutation-specific Antibodies in Pulmonary Adenocarcinoma

肺腺癌中的EGFR突变特异性抗体

We developed a triple-labeling immunofluorescence technique that simultaneously identifies total DNA (DAPI), DNA damage (antibodies), and dead cells [terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL)-positive cells] and a method that semiquantifies DNA damage in paraffin-embedded tissues. Using this technique in combination with our analysis method, scientists can now simultaneously detect and compare the relative amounts of DNA damage of almost any kind (except single-strand and double-strand breaks), using indirect fluorescent antibody labeling, in both normal and dying cells of different tissues. Simultaneous labeling of DNA damage and dead or TUNEL-positive cells can reduce processing costs and analysis time, and can lead to discoveries concerning how cells die from different DNA damages. We used increasing doses of UV (290 to 400 nm) radiation to create DNA damage in the form of cyclobutane pyrimidine dimers and 6-4 photoproducts that kill some of the cells in 3-dimensional tissue-engineered skin and vaginal samples. We describe a protocol that reliably detects and semiquantifies DNA damage in both normal and apoptotic cells. We show this triple-labeling immunofluorescence technique and analysis method yields linear UV dose response curves for damage to DNA bases that allows semiquantification of cyclobutane pyrimidine dimers and calculation of its repair rate (T=1 and 24 h), whereas TUNEL allows quantification of the number of apoptotic cells. Scientists can now create beautiful fluorescent pictures that simultaneously detect DNA damage in both normal and apoptotic cells to assess and semiquantify the damage to understand better how different insults lead to the cell's demise.

Anant Agrawal

Dianne E. Godar

Simultaneous Detection and Semiquantification of DNA Damage in Normal and Apoptotic Cells

正常和凋亡细胞中DNA损伤的同时检测与半定量分析

Departments of Pathology, Shizuoka City Shimizu Hospital, Shizuoka, Japan The authors declare no conflict of interest.

Tadashi Terada

Primary Signet-ring Cell Carcinoma of the Ampulla of Vater

十二指肠乳头原发性印戒细胞癌

In chronic inflammatory states, the ileal mucosa may flatten, whereas the colonic mucosa may develop a villiform surface. Accordingly, pathologic biopsies labeled by the endoscopist as “ileocolic” or “ileocecal” may generate confusion or uncertainty as to their specific origin. To facilitate distinguishing between architecturally altered ileal and colonic mucosae, we assessed the hepatocyte paraffin 1 (Hep Par 1) antibody, reported to react with normal and metaplastic small bowel epithelium but not with normal colonic epithelium, in 25 ileal biopsies (10 normal and 15 pathologic), 25 colonic biopsies (10 normal and 15 pathologic), and 20 samples labeled as “ileocecal” or “ileocolic” in which the organ of origin could not be definitely established because of mucosal inflammation and distortion. The latter group included 8 cases diagnosed as being of “probable ileal origin,” 7 cases diagnosed as being of “probable colonic origin,” and 5 cases diagnosed as “uncertain.” Diffuse granular cytoplasmic Hep Par 1 expression was detected in all normal and pathologic ileal mucosal biopsies, whereas all colonic biopsies were negative or focally reactive. Cases of “probable ileal origin” were diffusely positive (granular cytoplasmic pattern), whereas those of “probable colonic origin” were negative or focally reactive. Two of the “uncertain” cases expressed Hep Par 1, whereas 3 were negative, thus supporting their ileal and colonic derivation, respectively. In conclusion, Hep Par 1 is diffusely expressed by pathologic ileal mucosa, being negative or only focally positive in pathologic colonic mucosa. Accordingly, it represents a valuable tool for recognizing the tissue source in problematic ileocolonoscopic biopsies.

Gabriel Moises Groisman

Mary Amar

Alona Meir

Hepatocyte Antigen (Hep Par 1) Is Helpful in Distinguishing Between Inflamed and Architecturally Altered Ileal and Colonic Mucosa

肝细胞抗原（Hep Par 1）有助于区分炎症性和结构改变的回肠和结肠黏膜

The purpose of this study is to investigate the mixed lineage leukemia gene (MLL, located on chromosome 11q23) expression in T acute lymphoblastic leukemia (T-ALL)/lymphoblastic lymphoma (LBL) and its relationship to prognosis. Fifty cases of T-ALL/LBL with clinical data were selected from the Shanxi Cancer Hospital in China. The immunohistochemical EnVision method was used for the expression of CD3, CD7, CD10, CD20, CD23, CD43, CD45RO, CD99, terminal deoxynucleotidyl transferase, myeloperoxidase and ki67. Fluorescent in situ hybridization for MLL gene expression was performed on paraffin-embedded tissue. Among the 50 cases of T-ALL/LBL, the percentages of tumor cells expressing terminal deoxynucleotidyl transferase, CD99, CD3, CD7, CD10, CD43, and CD45RO were 92.0%, 96.0%, 72.0%, 92.0%, 34%, 60.0%, and 40.0%, respectively, whereas myeloperoxidase, CD20, and CD23 were all negative. A level of Ki67 expression >80% was found in 18 cases and ≤80% in 32 cases. The period of follow-up ranged from 1 to 108 months. The overall survival rate was 35.8%, with a median survival time of 330 days. Breakage of 11q23 was detected in 8 (16.00%) and amplification in 14 (28.00%) of the 50 cases. The rate of amplification in stage III-IV was higher than that in stage I-II (P<0.05). The prognosis in the 11q23 breakage group was worse than that in the nonbreakage group (P<0.05). The prognosis in the 11q23 amplification group was also worse than that in the nonamplification group (P<0.05). MLL gene rearrangement is a new subgroup concerned with prognosis in T-ALL/LBL. Both breakage and amplification of 11q23 in T-ALL/LBL might play important roles in the development and progression of T-ALL/LBL.

涉及主题	生物医学遗传学内科学病理免疫学化学计算机科学生物化学免疫组织化学
出版信息	出版商: Lippincott Williams and Wilkins Ltd.，出版周期: Bimonthly，期刊类型: journal，开源期刊: 否
基本数据	创刊年份: 1998，原创研究文献占比: 99.04%，自引率:0.00%， Gold OA占比: 11.24%
平均审稿周期	网友分享经验：较慢,6-12周
平均录用比例	网友分享经验：较易

Applied Immunohistochemistry

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