CASE REPORT. Primary Extragastrointestinal Stromal Tumor of the Pleura: Report of a Unique Case With Genetic Confirmation

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1 CASE REPORT Primary Extragastrointestinal Stromal Tumor of the Pleura: Report of a Unique Case With Genetic Confirmation Kevin B. Long, MD,* James E. Butrynski, MD,w Seth D. Blank, MD,z Kurt S. Ebrahim, DO,y Douglas M. Dressel, MD,J Michael C. Heinrich, MD,z Christopher L. Corless, MD, PhD,# and Jason L. Hornick, MD, PhD* Abstract: Gastrointestinal stromal tumors (GISTs), the most common mesenchymal neoplasms of the tubular gastrointestinal tract, usually originate in the wall of the stomach or small intestine. Most GISTs harbor oncogenic mutations in either the KIT or platelet-derived growth factor receptor a (PDGFRA) tyrosine kinase receptor genes and show differentiation along the lines of the interstitial cells of Cajal. Rarely, GISTs arise primarily in the omentum, mesentery, or retroperitoneum, at which sites they are referred to as extragastrointestinal stromal tumors (EGISTs). However, primary intrathoracic GIST arising in the pleura or lung has not been previously reported. We describe herein, a 62-year-old male who presented with a pleural-based mass unrelated to the esophagus that was morphologically typical of a spindle-cell GIST, showing strong immunoreactivity for KIT and DOG1, and harboring an exon 11 mutation in KIT. Ten years after resection, the tumor recurred as multiple masses in the pleura and mediastinum and was marginally reexcised. The patient was then treated with adjuvant imatinib mesylate with no evidence of further recurrences 13 months later. This seems to be the first EGIST arising above the diaphragm. This case shows a potential diagnostic pitfall with therapeutic consequences. Key Words: gastrointestinal stromal tumor, KIT, DOG1, interstitial cells of Cajal (Am J Surg Pathol 2010;34: ) Gastrointestinal stromal tumors (GISTs) are mesenchymal neoplasms that usually harbor activating mutations in the KIT or platelet-derived growth factor From the *Department of Pathology, Brigham and Women s Hospital and Harvard Medical School; wcenter for Sarcoma and Bone Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA; zmaine Heart Surgical Associates, Maine Medical Center; JSpectrum Medical Group, Maine Medical Center; ymaine Center for Cancer Medicine, Maine Medical Center, Scarborough, ME; zdivision of Hematology & Oncology, Portland VA Medical Center and Knight Cancer Institute, Oregon Health & Sciences University; and #Department of Pathology and Knight Cancer Institute, Oregon Health & Sciences University, Portland, OR. Funded in part from a Veterans Affairs Merit Review Grant (MCH) and funding from the GIST Cancer Research Fund (CLC, MCH). Correspondence: Jason L. Hornick, MD, PhD, Department of Pathology, Brigham and Women s Hospital, 75 Francis Street, Boston, MA ( jhornick@partners.org). Copyright r 2010 by Lippincott Williams & Wilkins receptor a (PDGFRA) tyrosine kinase genes and most often arise in the stomach (60%) or jejunum or ileum (30%), but less frequently affect the colorectum, duodenum, esophagus, or appendix (reviewed in Ref. 11). These tumors are thought to originate from, or show differentiation toward, the interstitial cells of Cajal (ICC), which are the pacemaker cells of the gastrointestinal (GI) tract found in the muscularis propria and myenteric plexus. A small subset of GISTs develop as soft tissue masses outside the tubular GI tract, including the retroperitoneum, mesentery, and omentum, at which sites they are sometimes referred to as extragastrointestinal stromal tumors (EGISTS). 12,14,19,21 EGISTs have similar morphologic, immunophenotypic, and molecular features as conventional GISTs, including a high frequency of KIT or PDGFRA gene mutations and overexpression of KIT by immunohistochemistry. 14,19,21 Soft tissue EGISTs arising in the mesentery or retroperitoneum often pursue an aggressive clinical course similar to small intestinal GISTs, 19 whereas solitary primary omental GISTs seem to be more closely related to gastric GISTs in terms of histologic features, a higher frequency of PDGFRA mutations, and a more favorable prognosis. 14 Primary EGISTs arising at pleuropulmonary sites have not been described previously. We describe herein, a case of a lateral pleural mass resected from a 62-year-old male patient, which recurred locally 10 years after resection. The morphologic features were characteristic of GIST, and subsequent immunohistochemical studies revealed the tumor to be positive for KIT and DOG1, and molecular analysis showed a mutation in exon 11 of the KIT gene. We conclude that this is the first case of an EGIST occurring above the diaphragm with no apparent relationship to the esophageal wall. MATERIALS AND METHODS Surgical specimens were fixed in buffered formalin and processed routinely. Hematoxylin and eosin stains were carried out on 4 mm thick sections of formalin-fixed paraffin-embedded tissue. Immunohistochemistry was carried out using these antibodies: KIT, DOG1, CD34, caldesmon, CD99, EMA, S100 protein, AE1/AE3, and desmin; and the Envision plus detection system (Dako, Carpinteria, CA). Antibody sources and dilutions are listed in Table 1. Am J Surg Pathol Volume 34, Number 6, June

2 Long et al Am J Surg Pathol Volume 34, Number 6, June 2010 TABLE 1. Panel of Antibodies Antigen Clone Dilution KIT (CD117) Antigen Retrieval Source Polyclonal 1:250 None Dako, Carpinteria, CA DOG1 K9 1:50 Pressure cooker CD34 QBEnd-10 1:400 None Dako Caldesmon h-cd 1:300 Pressure Dako cooker CD99 O13 1:150 Pressure cooker EMA E29 1:200 None Dako S-100 Polyclonal 1:4000 None Dako Cytokeratin AE1/AE3 1: min Dako proteinase Desmin D33 1:500 None Dako EMA indicates epithelial membrane antigen. Leica Biosystems, Newcastle Upon Tyne, UK Covance, Emeryville, CA Molecular analysis was carried out as earlier described. 3 In brief, DNA was extracted and purified from 4 mm thick sections of formalin-fixed paraffinembedded tissue. Exons 9 and 11 of the KIT gene on chromosome 4 were amplified by PCR, and the products were screened for mutations. Exon 9 was wild-type based on a real-time, mutation-specific PCR assay. A deletion was detected in exon 11 by denaturing HPLC (WAVE system, Transgenomic, Inc., Omaha, NE), and confirmed by direct, bidirectional sequencing. RESULTS Clinical Findings The patient is a 62-year-old male with a past medical history of hypertension, atrial fibrillation, depression, and hypercholesterolemia who initially presented with a left chest mass noted on a preoperative radiograph for prostate biopsy. He noted some chest pressure but was otherwise asymptomatic. Routine chest x-ray showed a large mass in the lower lobe of the left lung, and chest CT scan showed a 13-cm left lower lobe mass with extension to the hilum. Bronchoscopy was unremarkable. A left posterolateral thoracotomy noted a large mass that was densely adherent to the lower lobe of the left lung, rather than arising from it. A wedge resection of the left lower lobe was carried out, the mass was separated from the mediastinum, and the pleura were incised. Medially, the mass was adjacent to the esophagus, but did not involve the esophageal wall. The tumor was adherent to the aorta, from which it was dissected. After histologic review, a diagnosis of solitary fibrous tumor of the pleura was rendered. Peribronchial and pulmonary ligament lymph node biopsies were unremarkable. The bronchial resection margin was negative for tumor; the tumor was marginally excised with respect to the pleural margin. The patient subsequently was followed with chest radiographs every 6 months to a year with negative findings until 10 years postresection, when chest radiographs and CT scans showed 3 pleural-based masses (Fig. 1A). Within the left thoracic region, the largest mass (approximately 10 cm) abutted the aorta, a 4-cm mass was noted superiorly near the aortic arch in the left lingular area, and a 4-cm mass was seen near the left ventricle in the pericardial fat. No pleural effusion or intraparenchymal lung nodules were evident. A PET-CT scan revealed the masses were highly 18 F-fluorodeoxyglucose (FDG)-avid (Fig. 1B). The patient underwent median sternotomy, and the masses were resected. An additional separate mass along the left lateral chest wall was noted during surgery and was resected extrapleurally. The patient recovered well. On the basis of the final diagnosis of recurrent GIST (see below), we recommended adjuvant imatinib mesylate 400-mg daily. Follow-up exam and imaging have shown no evidence of recurrent disease for greater than 13 months postresection. Gross Pathology Findings The primary resection from 1998 consisted of a left lower lobectomy ( cm) with an attached pleural mass ( cm). The mass was well circumscribed, lobulated, and tan in color. The lung was adherent to the fibrous pseudocapsule of the mass. On cut section, there was a central cavity containing friable material. The resection of the left lateral pleural and mediastinal masses from 2008 were received in multiple parts (3 masses), with the largest intact mass measuring cm. The tumors were well-circumscribed, tan-pink, and fleshy, with focal hemorrhage and necrosis. Histologic Findings The resection from the primary surgery showed a well-circumscribed, cellular spindle cell neoplasm, which was separated from the pulmonary parenchyma by fibrotic pleura containing scattered chronic inflammatory cells (Fig. 2). No pulmonary parenchymal invasion was identified. A fascicular and whorling architecture was evident (Fig. 3A), with interspersed medium and large-sized blood vessels, foci of hemorrhage, and minimal necrosis. The tumor cells had elongated nuclei, palely eosinophilic cytoplasm, and ill-defined cell borders imparting a syncytial appearance (Fig. 3B). Mitoses numbered up to 10 per 50 high power fields. The recurrent tumor was histologically similar to the primary tumor (Fig. 3C), but was more cellular (Fig. 3D), and mitoses numbered greater than 10 per 10 high power fields. Immunohistochemical Findings Blocks from the primary tumor were not available for immunohistochemical studies. In the recurrence, the tumor cells showed strong and diffuse cytoplasmic staining for KIT (Fig. 4A). DOG1 (Fig. 4B) and CD34 were also diffusely positive, with a membranous pattern r 2010 Lippincott Williams & Wilkins

3 Am J Surg Pathol Volume 34, Number 6, June 2010 Pleural GIST FIGURE 1. A, CT scan (coronal section) showing the 2 largest pleural-based masses in the left thoracic cavity (arrows). B, PET-CT imaging using 18 F-fluorodeoxyglucose (FDG) revealed the tumors were highly FDG-avid (arrows). Caldesmon showed immunoreactivity in a small subset of tumor cells (approximately 5%). No staining was seen with CD99, EMA, S100 protein, AE1/AE3, or desmin. FIGURE 2. The primary tumor was well circumscribed and separated from the lung parenchyma by fibrotic pleura. Molecular Genetic Analysis DNA prepared from 1 of the recurrent mediastinal lesions revealed an inframe deletion, PMYE , in KIT exon 11. No mutation was detected in KIT exon 9. DISCUSSION The case described herein is the first report of a pleural-based tumor, radiographically and grossly separate from the esophagus, that was morphologically, immunohistochemically, and molecularly indistinguishable from a GIST. As such, we believe this tumor to represent the first described example of an EGIST arising above the diaphragm. EGISTs are exceptionally uncommon, and some speculate that at least a subset of EGISTs, particularly primary omental tumors, actually represent gastric (or small intestinal) GISTs that have lost their original connection to the visceral wall and have become parasitically attached to the omentum or other soft tissues. 6,13,14 A single case report has described an esophageal GIST clinically mimicking a primary lung tumor, which on pathologic examination showed invasion into the lung parenchyma but was also noted to arise from the esophageal wall. 16 Although it is theoretically possible that a similar process occurred in this patient, the radiographic, intraoperative, and gross appearances of the primary tumor provided no indication of an esophageal connection. GISTs are believed to be related to ICCs, nerve-like cells found in the muscularis propria and myenteric plexus throughout the GI tract. ICCs also express KIT, and, given the anatomic distribution of GISTs, it has been thought that unrestrained KIT signaling may be involved in neoplastic transformation of ICCs or their precursors. An alternative hypothesis is that other mesenchymal elements recapitulate the ICC phenotype aberrantly in the tumorigenic process. ICCs and ICC-like cells have been described recently at other anatomic sites, such as the r 2010 Lippincott Williams & Wilkins 909

4 Long et al Am J Surg Pathol Volume 34, Number 6, June 2010 FIGURE 3. The primary tumor had a fascicular architecture (A) and was composed of uniform spindle cells with pale eosinophilic cytoplasm and ill-defined cell borders (B). The recurrent tumor (C) was more highly cellular and had a higher mitotic rate (D). urinary bladder, extrahepatic bile ducts, gallbladder, and pancreas. 1,8,17,18 These cells have been shown to express KIT and CD34 and display ultrastructural features of ICCs, such as numerous mitochondria and distinctive cell processes, although their physiologic role at these sites has not yet been definitively characterized. Thus, similar to their GI counterparts, it is as yet uncertain whether the pathogenesis of EGISTs relates to neoplastic transformation of ICC-like cells outside of the GI tract or an aberrantly acquired ICC-like phenotype. This case also highlights a potential diagnostic pitfall with therapeutic consequences. As GISTs are uncommon in the esophagus, they are not typically considered in the usual differential diagnosis of spindle cell neoplasms arising above the diaphragm. Furthermore, especially at pleural sites, a GIST may mimic solitary fibrous tumor in its spindle cell morphology and diffuse CD34 positivity. It is important to note that in this case the typical morphology of GIST was evident: ill-defined ( syncytial ) cell borders, uniform oval nuclei, and a fascicular or whorling architecture. In the differential diagnosis of solitary fibrous tumor versus GIST, an immunohistochemical panel that includes KIT or DOG1 is essential, and it is important to have an understanding of the sensitivities and specificities of these 2 antibodies. The overall sensitivity of DOG1 and KIT in GISTs is similar (greater than 90%), 10,15,20 although DOG1 is expressed in a significant subset of KIT-negative tumors 11 and in a higher percentage of GISTs with PDGFRA mutations. 5 Among other soft tissue neoplasms, the specificities of KIT and DOG1 for GIST are also similar. In a large tissue microarray-based series including 775 soft tissue tumors in the differential diagnosis with GIST (such as leiomyosarcoma, malignant peripheral nerve sheath tumor, synovial sarcoma, and, notably, solitary fibrous tumor), DOG1 positivity was restricted to 1/326 leiomyosarcomas, 1/39 synovial sarcomas, and 1/10 desmoplastic melanomas. 5 In the same study, KIT positivity was observed in only 3/331 leiomyosarcomas, 1/87 undifferentiated sarcomas, and 1/10 desmoplastic melanomas. 5 These researchers also reported exceptionally rare DOG1 positivity in other sarcomas and nonsarcomas compared with KIT. 5 In another large series of GISTs and other mesenchymal and nonepithelial tumors, DOG1 positivity was seen in 15/562 non-gists, including minor subsets of uterine-type retroperitoneal r 2010 Lippincott Williams & Wilkins

5 Am J Surg Pathol Volume 34, Number 6, June 2010 Pleural GIST FIGURE 4. A, Strong diffuse cytoplasmic immunoreactivity for KIT. B, Immunohistochemical positivity for DOG1 with a membranous pattern of staining. leiomyomas, peritoneal leiomyomatosis, and synovial sarcomas. 15 Other tumors typically or variably KIT positive, such as mastocytosis, metastatic melanoma to the GI tract, and seminoma, were all negative for DOG1. 15 It is also important to note that variations in immunohistochemical technique may lead to discrepancies in positive staining for KIT and false-positive results. 9 This case also illustrates the growing importance of molecular genetic testing in soft tissue tumors, as both a diagnostic and predictive tool. In-frame KIT exon 11 deletions of the type identified in this case are present in approximately 60% of GISTs, but are exceedingly rare in other tumors, being detected in <0.1% of melanomas 2 and <5% of thymic carcinomas (Corless & Heinrich, unpublished results). In this particular case, the KIT exon 11 mutation not only helped confirm the diagnosis of GIST, but also provided rationale for treatment with the tyrosine kinase inhibitor imatinib mesylate, which has been shown to increase progression-free survival for patients with GISTs harboring this mutation. 4,7 GISTs, similar to many other soft tissue tumors, have characteristic anatomic sites of involvement, and this case highlights the diagnostic use of molecular testing in the setting of an unusual anatomic site. Molecular testing can also serve to confirm the diagnosis of soft tissue neoplasms arising in typical locations but having atypical clinical or pathologic features. REFERENCES 1. Ahmadi O, de L Nicholson M, Gould ML, et al. Interstitial cells of Cajal are present in human extrahepatic bile ducts. J Gastroenterol Hepatol. 2010;25: Beadling C, Jacobson-Dunlop E, Hodi FS, et al. KIT gene mutations and copy number in melanoma subtypes. Clin Cancer Res. 2008;14: Corless CL, McGreevey L, Haley A, et al. KIT mutations are common in incidental gastrointestinal stromal tumors one centimeter or less in size. Am J Pathol. 2002;160: Debiec-Rychter M, Sciot R, Le Cesne A, et al. KIT mutations and dose selection for imatinib in patients with advanced gastrointestinal stromal tumours. Eur J Cancer. 2006;42: Espinosa I, Lee C-H, Kim MK, et al. A novel monoclonal antibody against DOG1 is a sensitive and specific marker for gastrointestinal stromal tumors. Am J Surg Pathol. 2008;32: Goh BK, Chow PK, Kesavan SM, et al. A single-institution experience with eight CD117-positive primary extragastrointestinal stromal tumors: critical appraisal and a comparison with their gastrointestinal counterparts. J Gastrointest Surg. 2009;13: Heinrich MC, Owzar K, Corless CL, et al. Correlation of kinase genotype and clinical outcome in the North American Intergroup Phase III trial of imatinib mesylate for treatment of advanced gastrointestinal stromal tumor: CALGB study by Cancer and Leukemia Group B and Southwest Oncology Group. J Clin Oncol. 2008;26: Hinescu ME, Ardeleanu C, Gherghiceanu M, et al. Interstitial Cajallike cells in human gallbladder. J Mol Histol. 2007;38: Hornick JL, Fletcher CD. Immunohistochemical staining for KIT (CD117) in soft tissue sarcomas is very limited in distribution. Am J Clin Pathol. 2002;117: r 2010 Lippincott Williams & Wilkins 911

6 Long et al Am J Surg Pathol Volume 34, Number 6, June Liegl B, Hornick JL, Corless CL, et al. Monoclonal antibody DOG1.1 shows higher sensitivity than KIT in the diagnosis of gastrointestinal stromal tumors, including unusual subtypes. Am J Surg Pathol. 2009;33: Liegl B, Hornick JL, Lazar AJ. Contemporary pathology of gastrointestinal stromal tumors. Hematol Oncol Clin N Am. 2009;23: Miettinen M, Monihan JM, Sarlomo-Rikala M, et al. Gastrointestinal stromal tumors/smooth muscle tumors (GISTs) primary in the omentum and mesentery: clinicopathologic and immunohistochemical study of 26 cases. Am J Surg Pathol. 1999;23: Miettinen M, Sobin LH, Lasota J. Gastrointestinal stromal tumors of the stomach: a clinicopathologic, immunohistochemical, and molecular genetic study of 1765 cases with long-term follow-up. Am J Surg Pathol. 2005;29: Miettinen M, Sobin LH, Lasota J. Gastrointestinal stromal tumors presenting as omental masses a clinicopathologic analysis of 95 cases. Am J Surg Pathol. 2009;33: Miettinen M, Wang Z-F, Lasota J. DOG1 antibody in the differential diagnosis of gastrointestinal stromal tumors. Am J Surg Pathol. 2009;33: Papaspyros S, Papagiannopoulos K. Gastrointestinal stromal tumor masquerading as a lung neoplasm: a case presentation and literature review. J Cardiothorac Surg. 2008;3: Popescu LM, Hinescu ME, Ionescu N, et al. Interstitial cells of Cajal in pancreas. J Cell Mol Med. 2005;9: Rasmussen H, Rumessen JJ, Hansen A, et al. Ultrastructure of Cajal-like interstitial cells in the human detrusor. Cell Tissue Res. 2009;335: Rieth JD, Goldblum JR, Lyles RH, et al. Extragastrointestinal (soft tissue) stromal tumors: an analysis of 48 cases with emphasis on histologic predictors of outcome. Mod Pathol. 2000;13: West RB, Corless CL, Chen X, et al. The novel marker, DOG1, is expressed ubiquitously in gastrointestinal stromal tumors irrespective of KIT or PDGFR mutation status. Am J Pathol. 2004;165: Yamamoto H, Oda Y, Kawaguchi K, et al. C-kit and PDGFRA mutations in extragastrointestinal stromal tumor (gastrointestinal stromal tumor of the soft tissue). Am J Surg Pathol. 2004;28: r 2010 Lippincott Williams & Wilkins