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Clinicopathologic and Genomic Characterization of Inflammatory

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Clinicopathologic and Genomic Characterization of Inflammatory ORIGINAL ARTICLE Clinicopathologic and Genomic 05/24/2021 on B1Ie3HEQKAtYlViOB6v9JkXYwHPCf2wpOZ6Gj4zLHHows5c8Cwy9/GE8tenobMw6o+askVh8Okj8o5aNeJrpPG5G953b+vs1dmmVmYK5o60oNhSlAcCbJMhr/+1KYGRtyjCfO+GDnjJqT4eFHq0Rgg== by http://journals.lww.com/ajsp from Downloaded Characterization of Inflammatory Myofibroblastic Downloaded Tumors of the Head and Neck from Highlighting a Novel Fusion and Potential Diagnostic Pitfall http://journals.lww.com/ajsp Darcy A. Kerr, MD,*† Lester D.R. Thompson, MD,‡ Laura J. Tafe, MD,*† Vickie Y. Jo, MD,§ Azfar Neyaz, MD,∥ Prashanthi Divakar, MD,¶ Joseph A. Paydarfar, MD,†¶ David A. Pastel, MD,†# Keisuke Shirai, MD, MSc,†** Ivy John, MD,†† Raja R. Seethala, MD,†† by B1Ie3HEQKAtYlViOB6v9JkXYwHPCf2wpOZ6Gj4zLHHows5c8Cwy9/GE8tenobMw6o+askVh8Okj8o5aNeJrpPG5G953b+vs1dmmVmYK5o60oNhSlAcCbJMhr/+1KYGRtyjCfO+GDnjJqT4eFHq0Rgg== Claudia M. Salgado, MD, PhD,‡‡ Vikram Deshpande, MD,∥ Julia A. Bridge, MD,§§∥∥ Karl Kashofer, PhD,¶¶ Iva Brčić, MD,¶¶ and Konstantinos Linos, MD*† event was identified in 92% (n = 11/12) of cases and an additional fl fi Abstract: In ammatory myo broblastic tumor (IMT) is a distinc- case was ALK-positive by IHC but could not be evaluated mo- fi fi tive broblastic and myo broblastic spindle cell neoplasm with an lecularly. ALK represented the driver in all but 1 case. Re- fl fi accompanying in ammatory cell in ltrate and frequent receptor arrangement of ALK, fused with the TIMP3 gene (n = 6) was most tyrosine kinase activation at the molecular level. The tumor may commonly detected, followed by 1 case each of the following fusion recur and rarely metastasizes. IMT is rare in the head and neck gene partnerships: TPM3-ALK, KIF5B-ALK, CARS-ALK, region, and limited information is available about its clin- THBS1-ALK, and a novel alteration, SLC12A2-ROS1.Theex- icopathologic and molecular characteristics in these subsites. cluded case was reclassified as spindle cell rhabdomyosarcoma after Therefore, we analyzed a cohort of head and neck IMTs through a detection of a FUS-TFCP2 rearrangement and retrospective im- multi-institutional approach. Fourteen cases were included in the munohistochemical confirmation of rhabdomyoblastic differ- provisional cohort, but 1 was excluded after molecular analysis entiation, illustrating an important diagnostic pitfall. Two IMT fi fi prompted reclassi cation. Patients in the nal cohort included 7 patients received targeted therapy with crizotinib, with a demon- males and 6 females, with a mean age of 26.5 years. Tumors were strated radiographic response. One tumor recurred but none met- = = = locatedinthelarynx(n 7), oral cavity (n 3), pharynx (n 2), and astasized. These results add to the growing body of evidence that = mastoid (n 1). Histologically, all tumors showed neoplastic spin- kinase fusions can be identified in the majority of IMTs and that dle cells in storiform to fascicular patterns with associated chronic molecular analysis can lead to increased diagnostic accuracy and fl in ammation, but the morphologic spectrum was wide, as is broadened therapeutic options for patients. characteristic of IMT in other sites. An underlying fusion gene Key Words: inflammatory myofibroblastic tumor, head and neck, mesenchymal neoplasms, soft tissue tumors, ALK From the Departments of *Pathology and Laboratory Medicine; immunohistochemistry, ROS1 #Radiology; **Medical Oncology; ¶Section of Otolaryngology, Dartmouth-Hitchcock Medical Center, Lebanon; †Geisel School of (Am J Surg Pathol 2021;00:000–000) Medicine at Dartmouth, Hanover, NH; ‡Department of Pathology, Southern California Permanente Medical Group, Woodland Hills, CA; §Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School; ∥Department of Pathology, Massachusetts nflammatory myofibroblastic tumor (IMT) is a distinc- General Hospital and Harvard Medical School, Boston, MA; tive fibroblastic/myofibroblastic neoplasm that harbors a †† ‡‡ I Department of Pathology, University of Pittsburgh; Department chronic inflammatory cell infiltrate of lymphocytes, plas- on of Pathology, Children’s Hospital of Pittsburgh, Pittsburgh, PA; 05/24/2021 1 fi §§Molecular Division, ProPath LLC, Dallas, TX; ∥∥Department of ma cells, and/or eosinophils. Most IMTs occur in the rst Pathology and Microbiology, University of Nebraska Medical Cen- 3 decades of life (mean age = 10 y), although cases can ter, Omaha, NE; and ¶¶Diagnostic and Research Institute of Path- occur throughout adulthood. IMTs occur throughout the ology, Medical University of Graz, Graz, Austria. fl body, most frequently involving the lung, abdomen/pelvis, Con icts of Interest and Source of Funding: NGS studies were supported and retroperitoneum. Symptoms depend on the site of by internal research funding from the D&R Institute of Pathology, 1,2 Medical University of Graz, Austria. The authors have disclosed that involvement. Approximately 14% to 18% of ex- they have no significant relationships with, or financial interest in, any trapulmonary IMTs involve the head and neck region, commercial companies pertaining to this article. most commonly the orbit and upper airways including the Correspondence: Darcy A. Kerr, MD, Dartmouth-Hitchcock Medical larynx.3,4 About 25% of extrapulmonary IMTs recur lo- Center, Department of Pathology, One Medical Center Drive, Borwell Level 4, Lebanon, NH 03756 (e-mail: [email protected]). cally, partially related to anatomic considerations, Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved. whereas metastasis is rare (< 5%); lung, brain, liver, and Am J Surg Pathol Volume 00, Number 00, ’’ 2021 www.ajsp.com | 1 Copyright r 2021 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. Kerr et al Am J Surg Pathol Volume 00, Number 00, ’’ 2021 bone are the reported sites of metastatic spread.1,5 Reli- mitotic index (mitoses per 2 mm2), percent neoplastic cellu- able prognostic indicators for conventional IMT are larity (2-dimensional area occupied by spindle cells based on lacking.1,6,7 H&E slide review, supplemented by IHC), predominant in- IMT has historically been included within the rubric of flammatory component (lymphocytes, plasma cells, eosino- inflammatory pseudotumor, a descriptive term applied to phils, histiocytes), the extent of inflammation (diffuse, numerous neoplastic and non-neoplastic processes.6 How- occupying ≥ 50% of the tumor surface; limited, < 50%), and ever, molecular analysis has helped distinguish IMT as a density of inflammation (3+, evident at ×4; 2+, evident at distinctive neoplasm largely characterized by receptor ty- ×10; 1+; evident at ×20, using standard ×10 ocular).15 The rosine kinase (RTK) activation. Overall, 50% to 70% contain presence or absence of the following features was recorded: rearrangements of the anaplastic lymphoma kinase (ALK) surface ulceration, atypical mitotic figures, necrosis, lym- gene on chromosome 2p23. The correlation with age is ro- phovascular invasion, ganglion-like cells, granular cell bust, with 80% to 90% of pediatric IMTs demonstrating a change, intranuclear inclusions, and marked pleomorphism. fusion.8,9 Rearrangements involve an ever-expanding list of Each tumor was classified according to the relative pro- partner genes, including TPM3, TPM4, CLTC, RANBP2, portion of each of the 3 previously described, frequently ATIC, CARS, SEC 31A, SEC 31L1, EML4, TFG,andFN1, commingled histologic patterns: myxoid, compact spindle among others.1,2 In patients above 40 years of age at pre- cell, or dense collagenous.4 The myxoid pattern was char- sentation, ALK rearrangements are uncommon.1 Although acterized by loose spindle cells in a myxoid or edematous ALK-negative tumors may be more likely to metastasize, background with prominent vasculature, reminiscent of ALK status does not correlate with recurrence risk in con- nodular fasciitis. The compact spindle cell pattern demon- ventional IMT.4,6,7 ThepresenceofaclonalALK re- strated a densely cellular spindle cell proliferation in stori- arrangement generally correlates with reactivity for ALK form and fascicular arrangements. The dense collagenous immunohistochemistry (IHC).6,10,11 Alternatively, re- pattern was relatively hypocellular, composed of collagen arrangements of ROS1, PDGFRB, NTRK3, ETV6, IGFR1, with few spindle cells, similar to scar or fibromatosis.4,6,15 and RET have also been implicated as driver mutations in subsets of IMTs,12,13 such that the majority of IMTs harbor kinase fusions, ranging from 68%8 to 85%.2 While surgical Immunohistochemistry excision is the mainstay of treatment for IMT, targeted mo- IHC studies interpreted at the time of original di- lecular therapy via RTK inhibition may be applied in certain agnosis were reviewed and recorded. The following IHC clinical scenarios with variable effectiveness.2,14 Overall, IMTs antibodies were performed: ALK, ROS1, smooth muscle are relatively rare within the head and neck region, and actin (SMA), muscle-specific actin (MSA), desmin, pan- whether IMTs in this site have distinctive features is not cytokeratin, p63, S100 protein, and CD34. Additional specifically reported. Therefore, a multi-institutional study was studies were performed on 4-µm formalin-fixed, paraffin- undertaken to define the clinical, morphologic, im- embedded (FFPE) tissue sections using a Leica BOND-III munohistochemical, and genetic features of a large case series. (Leica Biosystems, Buffalo Grove, IL) automated IHC stainer with appropriate positive and negative controls. MATERIALS AND METHODS Several different ALK antibodies were used based on
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