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Expression of ALK1 and P80 in Inflammatory Myofibroblastic Tumor and Its Mesenchymal Mimics: a Study of 135 Cases Melissa H

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Expression of ALK1 and P80 in Inflammatory Myofibroblastic Tumor and Its Mesenchymal Mimics: a Study of 135 Cases Melissa H Expression of ALK1 and p80 in Inflammatory Myofibroblastic Tumor and Its Mesenchymal Mimics: A Study of 135 Cases Melissa H. Cessna, M.D., Holly Zhou, M.D., Warren G. Sanger, Ph.D., Sherrie L. Perkins, M.D., Ph.D., Sheryl Tripp, M.T., Diane Pickering, M.S., Clark Daines, M.D., Cheryl M. Coffin, M.D. Department of Pathology, Primary Children’s Medical Center and University of Utah School of Medicine, Salt Lake City, Utah (MHC, HZ, SLP, ST, CD, CMC); and Department of Pediatrics, University of Nebraska Medical Center, Omaha, Nebraska (WGS, DP) between structural abnormalities involving 2p23 or Abnormalities of chromosome 2p23 with expres- additional copies of 2p23, it supports the concept of sion of ALK1 and p80 occur in both inflammatory ALK involvement in a larger group of neoplasms, myofibroblastic tumor (IMT) and anaplastic large some of which have other documented clonal ab- cell lymphoma. This immunohistochemical study normalities. In IMT, immunohistochemistry for investigates whether the ALK family of neoplasms ALK1 and p80 is useful as an indicator of a 2p23 includes fibroblastic–myofibroblastic, myogenic, abnormality, but it must be interpreted in the con- and spindle cell tumors. Formalin-fixed paraffin- text of histologic and other clinicopathologic data if embedded archival tissues from 10 IMTs and 125 used as an adjunct to differential diagnosis. other soft tissue tumors were stained for ALK1 and p80 with standard immunohistochemistry. ALK1 KEY WORDS: ALK gene rearrangements, ALK im- and/or p80 reactivity was observed in a cytoplasmic munohistochemistry, Anaplastic large cell lym- pattern in IMT (4/10; 40%), malignant peripheral phoma, Inflammatory myofibroblastic tumor. nerve sheath tumor (4/10; 40%), rhabdomyosar- Mod Pathol 2002;15(9):931–938 coma (6/31; 19%), leiomyosarcoma (1/10; 10%), and malignant fibrous histiocytoma (1/11; 9%). No Inflammatory myofibroblastic tumor (IMT), a tumor staining was observed in nodular fasciitis, desmoid, of myofibroblastic spindle cells accompanied by a infantile myofibromatosis, infantile fibrosarcoma, lymphoplasmacytic and eosinophilic inflammatory synovial sarcoma, leiomyoma, or myofibrosarcoma. infiltrate, and anaplastic large cell lymphoma share Alveolar rhabdomyosarcomas (4/16; 25%) displayed clonal aberrations involving the short arm of chromo- a distinctive dot-like cytoplasmic positivity. No some 2 in region p21–p23 (1–5). Chromosome 2p23 is cases displayed nuclear reactivity. Fluorescent in the site of the human ALK gene, which codes for situ hybridization on 12 of the positive cases re- anaplastic lymphoma kinase, a tyrosine kinase recep- vealed a combination of abnormalities including tor and member of the insulin growth factor receptor ALK break-apart signals, nucleophosmin (NPM)/ superfamily. Antibodies to the protein product of the ALK fusions, or extra copies of 2p23. This study ALK gene detect both ALK expression associated with demonstrates that in addition to IMT, abnormalities 2p23 rearrangements and other abnormalities in ALK of ALK1 and p80 expression with a variety of struc- deregulation. tural chromosomal changes are found in several sarcomas, especially rhabdomyosarcoma and ma- ALK rearrangements and/or ALK1 and p80 im- lignant peripheral nerve sheath tumor. Although munoreactivity have been reported in 36–60% of immunoreactivity in non-IMTs cannot distinguish IMTs and 8–33% of “inflammatory pseudotumors” (3, 5, 6–9). Fusion oncogenes have been identified in a small proportion of IMTs with ALK rearrange- Copyright © 2002 by The United States and Canadian Academy of ments and include TPM3-ALK and TPM4-ALK (4). Pathology, Inc. VOL. 15, NO. 9, P. 931, 2002 Printed in the U.S.A. In anaplastic large cell lymphoma, the clonal ab- Date of acceptance: May 20, 2002. normalities of ALK include a characteristic translo- Presented in part at the United States and Canadian Academy of Pathol- ogy, Atlanta, GA, on March 8, 2001. cation t(2, 5)(p23;q35), variant translocations, and a Address correspondence to: Cheryl M. Coffin, M.D., Department of Pa- TPM3-ALK fusion oncogene in some cases (2, 10– thology, University of Utah School of Medicine, 50 North Medical Drive, Salt Lake City, UT 84132; e-mail: [email protected]; fax: 801-588-3169. 15). Various investigators have shown that ALK DOI: 10.1097/01.MP.0000026615.04130.1F gene rearrangements and ALK expression are found 931 in cell lines of neuroblastoma, neuroectodermal tu- Antibodies and Immunostaining mors, malignant melanoma, small cell lung carci- Immunohistochemical studies were performed noma, and rhabdomyosarcoma and in central ner- on 4-␮m-thick formalin-fixed, paraffin-embedded vous system tissue (12, 15). Thus, it appears that tissue sections, using a standard heat-induced structural or functional abnormalities of the ALK epitope retrieval method, a standard avidin–biotin gene are found in a group of mesenchymal neo- peroxidase complex detection technique, and an plasms including anaplastic large cell lymphoma, automated immunostainer (Ventana Medical Sys- IMT, and possibly others. tems, Tucson, AZ). The purpose of this study is to systematically The monoclonal ALK1 antibody was obtained investigate by immunohistochemical means, with from DAKO Company (Carpinteria, CA). ALK1 selective fluorescence in situ hybridization (FISH) staining was done after heat-induced epitope re- analysis, whether the ALK family of tumors, whose trieval in an electric pressure cooker for 3 minutes current members are IMT and anaplastic large cell (total time in pressure cooker, 30 min) in a citrate lymphoma, also includes mesenchymal tumors buffer at pH 6.0. The antibody was applied at a with a predominantly spindle cell phenotype and dilution of 1:25 for 32 minutes using the Ventana rhabdomyosarcoma. Nexus autostainer with a basic diaminobenzidine detection kit, endogenous peroxidase blocking, and staining amplification kit. MATERIALS AND METHODS The polyclonal p80NPM/ALK antibody was ob- tained from Monosan (Leiden, the Netherlands). Case Selection p80 staining was done after heat-induced epitope Formalin-fixed, paraffin-embedded archival tis- retrieval in an electric pressure cooker for 3 minutes sue was obtained from institutional and consulta- (total time in pressure cooker, 30 min) in a citrate tion files. Cases included 10 IMTs and 125 small buffer at pH 6.0. The antibody was applied at a round blue cell and spindle cell tumors. These in- dilution of 1:30 for 32 minutes using the Ventana cluded 31 rhabdomyosarcomas, 10 nodular fasciiti- Nexus autostainer with a basic diaminobenzidine des, 10 desmoid-type fibromatoses, 10 infantile detection kit, endogenous peroxidase blocking, and myofibromatoses, 10 infantile fibrosarcomas, 11 staining amplification kit. malignant fibrous histiocytomas, 10 synovial sarco- Appropriate positive and negative controls were mas, 10 malignant peripheral nerve sheath tumors, used. Reactivity was interpreted as positive or neg- 3 myofibrosarcomas, 10 leiomyomas, and 10 ative. Positive cases were graded according to the leiomyosarcomas. The rhabdomyosarcomas in- percentage of tumor cells with staining, with 1ϩ cluded 16 alveolar and 15 embryonal (including 2 representing 0–30% positivity, 2ϩ representing anaplastic, 1 spindle cell, and 2 botyroid) types. Soft Ͼ30–70% positivity, and 3ϩ representing Ͼ70% tissue tumors were classified according to the positivity. Cases of positive staining were assessed World Health Organization Classification of Soft as to the localization of staining to cytoplasm, nu- Tissue Tumors (16), the International Classification cleus, or both of tumor cells. Diffuse cytoplasmic of Rhabdomyosarcoma (17), and published de- staining of nontumor cell types was not observed. scriptions for myofibrosarcoma (18–20). Clinico- pathologic and immunohistochemical findings for some cases of IMT, rhabdomyosarcoma, and infan- FISH Methods for Detection of t(2, 5)(p23;q35) tile fibrosarcoma had been previously published (1, and Other Rearrangements of 2p23 (ALK), using 3, 8, 21–23). Five of 10 IMTs were included in a ALK and NPM/ALK Probes on Paraffin- previous study of ALK-1 and p80 expression and Embedded Tumor Tissue chromosome 2p23 rearrangements (5), and 8 were FISH procedures were performed on 4- to 5-␮m included in a separate study (8). All specimens were unstained tissue sections using an NPM/ALK two- originally diagnosed between 1976 and 2000. All of color FISH probe specific for the t(2, 5)(p23;q35) the inflammatory myofibroblastic tumors, rhabdo- and a two-color, break-apart ALK probe that flanks myosarcoma, infantile myofibromatoses, infantile the ALK gene region at 2p23 for detection of the fibrosarcomas, and myofibrosarcomas were from alternative rearrangements involving the ALK gene. children and adolescents. All of the leiomyomas The NPM/ALK probes were obtained from Dr. Steve were from adults. The remaining tumors occurred Morris, and the ALK break-apart probe is commer- in both children and adults. The original surgical cially available (Vysis, Downers Grove, IL). Before pathology reports were reviewed, and the diagnoses the hybridization, the slides were pretreated using were confirmed by review of hematoxylin and eo- the VP2000 automated slide processor (Vysis) using sin–stained sections and immunohistochemical the program specified for paraffin slides. Briefly, the studies. One representative block for each case was program included deparaffinization of the slides, selected for immunohistochemical staining. followed by dehydration, 0.2 N HCL treatment for 932
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