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Brachyury, SOX-9, and Podoplanin, New Markers in the Skull Base Chordoma Vs Chondrosarcoma Differential: a Tissue Microarray-Based Comparative Analysis

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Brachyury, SOX-9, and Podoplanin, New Markers in the Skull Base Chordoma Vs Chondrosarcoma Differential: a Tissue Microarray-Based Comparative Analysis Modern Pathology (2008) 21, 1461–1469 & 2008 USCAP, Inc All rights reserved 0893-3952/08 $30.00 www.modernpathology.org Brachyury, SOX-9, and podoplanin, new markers in the skull base chordoma vs chondrosarcoma differential: a tissue microarray-based comparative analysis Gerard J Oakley, Kim Fuhrer and Raja R Seethala Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA The distinction between chondrosarcoma and chordoma of the skull base/head and neck is prognostically important; however, both have sufficient morphologic overlap to make delineation difficult. As a result of gene expression studies, additional candidate markers have been proposed to help in separating those entities. We sought to evaluate the performance of new markers: brachyury, SOX-9, and podoplanin alongside the more traditional markers glial fibrillary acid protein, carcinoembryonic antigen, CD24, and epithelial membrane antigen. Paraffin blocks from 103 skull base/head and neck chondroid tumors from 70 patients were retrieved (1969–2007). Diagnoses were made based on morphology and/or whole-section immunohistochemistry for cytokeratin and S100 protein yielding 79 chordomas (comprising 45 chondroid chordomas and 34 conventional chordomas), and 24 chondrosarcomas. A tissue microarray containing 0.6 mm cores of each tumor in triplicate was constructed using a manual array (MTA-1; Beecher Instruments). For visualization of staining, the ImmPRESS detection system (Vector Laboratories) with 2-diaminobenzidine substrate was used. Sensitivities and specificities were calculated for each marker. Core loss from the microarray ranged from 25 to 29% yielding 66–78 viable cases per stain. The classic marker, cytokeratin, still has the best performance characteristics. When combined with brachyury, accuracy improves slightly (sensitivity and specificity for detection of chordoma 98 and 100%, respectively). Positivity for both epithelial membrane antigen and AE1/AE3 had a sensitivity of 90% and a specificity of 100% for detecting chordoma in this study. SOX-9 is apparently common to both notochordal and cartilaginous differentiation, and is not useful in the chordoma-chondrosarcoma differential diagnosis. Glial fibrillary acid protein, carcinoembryonic antigen, CD24, and epithelial membrane antigen did not outperform other markers, and are less useful in the diagnosis of chordoma vs chondrosarcoma. Podoplanin still remains the only positive marker for chondrosarcoma, though its accuracy is less than previously reported. Modern Pathology (2008) 21, 1461–1469; doi:10.1038/modpathol.2008.144; published online 26 September 2008 Keywords: chordoma; chondrosarcoma; D2-40; SOX-9; brachyury; CD24 Chordomas and chondrosarcomas represent two chondrosarcomas are well differentiated; high-grade morphologically similar, but biologically distinct and dedifferentiated chondrosarcomas are virtually categories of mesenchymal neoplasms that can nonexistent. Chondroid chordoma is a histologic involve the skull base. Chordomas are rare, slow variant of chordoma that has a predilection for the growing tumors derived from remnant notochord skull base and is defined by the presence of varying occurring anywhere along the central neural axis. In amounts of cartilaginous elements admixed with the adult, an estimated 33–37% are located at the cords and lobules of vacuolated or ‘physaliferous’ skull base.1–5 Chondrosarcomas are rare cartilagi- cells typical of conventional chordoma. Originally nous malignancies comprising 6–15% of all skull described by Heffelfinger et al5 in 1973, chondroid base tumors.2–4,6,7 The vast majority of skull base chordomas have sparked debate over the past three decades regarding their histogenesis, accurate diag- nosis, and prognosis.8–13 Correspondence: Dr RR Seethala, MD, Department of Pathology, Current evidence suggests that chondroid chordo- University of Pittsburgh Medical Center, Room A616.3, Scaife mas are indeed variants of chordomas with out- Hall, 3550 Terrace St, Pittsburgh, PA, 15261, USA. comes similar to those of conventional E-mail: [email protected] 14–18 Received 5 May 2008; revised 18 July 2008; accepted 19 July 2008; chordomas. However, the histologic similarities published online 26 September 2008 between chondroid chordoma and chondrosarcoma Chordoma vs chondrosarcoma immunohistochemistry GJ Oakley et al 1462 often still pose diagnostic challenges, especially on evaluate the performance characteristics of several small biopsies. Both are treated similarly, but, in traditional and newer markers, we used tissue spite of the introduction of newer radiotherapy- microarray methodology to assess a large series of based modalities, chondroid chordoma retains a chordomas and chondrosarcomas of the skull base. worse prognosis compared to chondrosarcoma in this region.14,19,20 A variety of immunohistochemical markers have been used to better delineate these Materials and methods entities. Historically, the selection of these discri- Case Selection minatory markers has been modeled after the expression profile of notochord.21–24 Of these, the This study was approved by our institutional review most effective and well-established markers selec- board (no. 0701113). Paraffin blocks and slides from tively expressed in chordomas, but not chondrosar- 103 skull base/head and neck tumors from 70 comas, are cytokeratin, followed by epithelial patients were successfully retrieved from the Uni- membrane antigen (EMA).13,25–27 Although these versity of Pittsburgh Medical Center Department of markers have performed well in the literature, a Pathology Archives (1969–2007). The tumors con- panel-based approach incorporating multiple mar- sisted of 79 chordomas (45 chondroid chordomas, kers may provide a more robust confirmation of 34 conventional chordomas), and 24 chondrosarco- diagnosis—especially if one stain is equivocal or mas (23 grades 1–2, 1 grade 3). Three chondrosarco- technically compromised.15,28 Other markers such as mas also showed at least focal dedifferentiation. One carcinoembryonic antigen (CEA) and glial fibrillary chondrosarcoma was seen in the setting of Mafucci acidic protein (GFAP) have shown far less utility in syndrome. In 32% (25 of 79) of the chordomas, solid distinguishing chordoma from chondrosarcoma.29–31 cellular areas consisted greater than 5% of the Recently, gene expression profiling has expanded tumor. The original whole-section slides and/or the list of possible discriminatory markers. Among recuts and immunohistochemical stains were ver- those selectively expressed in chordoma are CD24 and ified by two observers (GJO and RRS) to establish brachyury.16,32,33 CD24 is a glycoprotein that functions gold standard diagnoses. For 63 of the 70 patients in cell adhesion and has been shown to be expres- clinical follow-up data were available. Median sed by the notochord-derived nucleus pulposus.33 follow-up on surviving patients was 85 months Brachyury is the transcription factor protein product (range: o1–230 months). Patient outcome character- of a T-box gene whose function is to regulate form- istics in our series are summarized in Table 1. ation of the mesoderm and notochord in humans.34 Immunohistochemical studies demonstrated that brachyury expression is highly sensitive and speci- Tissue Microarray Construction and fic for chordomas.16 In fact, because of its initial Immunohistochemistry performance, brachyury has recently been proposed as the ultimate solution to this differential diagnosis.15 Paraffin ‘donor’ blocks were selected for each case. The bulk of investigative efforts in this differential Using a manual tissue arrayer (MTA-1; Beecher diagnosis have focused on markers that are selectively Instruments, Sun Prairie, WI, USA) 0.6 mm cores expressed in chordoma. But recently, Huse et al28 have were transferred from each donor block to a blank discovered the first reliable immunohistochemical recipient paraffin block and arrayed in triplicate by marker that is selectively expressed in chondrosarco- one of the authors (RRS). Use of decalcified blocks mas, namely, D2-40, a monoclonal antibody that recognizes the O-linked sialoglycoprotein, podoplanin. Table 1 Patient outcome characteristics However, the performance of this marker has not been evaluated on a large series of tumors. Another Mean age (years) P-value purported chondrogenesis-selective marker is SOX-9. SOX-9 is a homeobox transcription factor that is Overall 40 (range: 3–77) heavily involved in chondrogenesis in mammals.35,36 Chondrosarcoma 41 (range: 22–62) NS (t-test) SOX-9 expression has been identified in chondrosar- Chordoma 40 (range: 3–77) 37 comas and has been used in distinguishing mesen- Gender (male:female) chymal chondrosarcoma from other round blue cell Overall 1.6:1 tumors.38 However, SOX-9 is also vital to other organ Chondrosarcoma 2:1 NS (Fisher’s exact test) development and is expressed in other tumor types as Chordoma 1.5:1 well, suggesting that its utility would be limited to Median OS (months) 39,40 specific diagnostic considerations. To date, this Overall 163 marker has not been evaluated with respect to the Chondrosarcomaa 226 0.035 (log-rank test) chordoma-chondrosarcoma differential diagnosis. Chordoma 122 Although many of these newer markers are promising, they have not been compared system- NS, not significant; OS, overall survival. aThree cases of chondrosarcoma with focal dedifferentiation were atically to each other or to the more traditional excluded from this survival analysis. Two of these three
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