Case Study
An unusual case of mediastinal mass and bilateral nodules
Asian Cardiovascular & Thoracic Annals 2014, Vol. 22(5) 623–626 ß The Author(s) 2013 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0218492313483586 aan.sagepub.com
Charlotte Lilli Elena Wichmann1, Birgit Helmchen2, Achim Weber3, Stefan Wildi4 and Giovanni Luca Carboni1,5
Abstract A 23-year-old woman presented with a mediastinal paraganglioma and multiple pulmonary chondromas following antral gastric resection for gastrointestinal stromal tumor. These tumors form the Carney triad, a rare disorder of unknown genetic background. First described in 1977, approximately 120 cases have been documented in the literature. The tumors do not harbor the specific c-kit or PDGFRA gene mutations often found in sporadic gastrointestinal stromal tumor. In most cases, gastric gastrointestinal stromal tumor is the first tumor to be detected, with secondary tumors appearing years later. Even if it is rare, Carney triad should be suspected in young patients with history of gastrointestinal stromal tumor.
Keywords Esophageal neoplasms, Gastrointestinal stromal tumors, Neoplasms, multiple primary
Introduction Carney triad describes the association of gastrointestinal stromal tumor (GIST), pulmonary chondroma and extraadrenal paraganglioma.1 It affects mostly young women. The complete triad is present in 20% of patients.1
Case report Clinical workup in a 21-year-old woman with persistent epigastralgia revealed a gastric mass in the antrum. Following endosonographically controlled fine-needle biopsy, a cytological diagnosis of CD117-positive mesenchymal neoplasm was made. On staging, multiple bilateral pulmonary lesions were detected. A computed tomography-guided biopsy of one of the pulmonal lesions showed myxoid chondroid proliferation (Figure 1). Gastric antrectomy was performed, and a multinodular tumor of 7 cm in greatest diameter was completely removed. It was diagnosed as GIST with epithelioid and spindle cellular features (Figure 2). It was in the high-risk category, based on location and mitotic count. No mutations were detected on
genotyping of the c-kit and PDGFRA genes. The patient was treated with imatinib but refused further investigations including further work-up of the pulmonary lesions at that time. On follow-up with fluorodeoxyglucose positron-emission tomography-computed tomography one year after surgery, a new fluorodeoxyglucose-enhancing nodule in the left upper mediastinum was detected (Figure 3). The pulmonary lesions were stable in size, with no fluorodeoxyglucose accumulation. Resection of the mass in the superior mediastinum and one of the stationary pulmonary nodules was 1 Division of Visceral, Thoracic and Vascular Surgery, Department of Surgery, Stadtspital, Triemli, Zurich, Switzerland 2 Department of Pathology, Stadtspital Triemli, Zurich, Switzerland 3 Department of Pathology, University Hospital Zurich, Switzerland 4 Department of Surgery, Stadtspital Waid, Zurich, Switzerland 5 Division of Thoracic Surgery, University Hospital, Berne, Switzerland
Corresponding author: Giovanni L Carboni, MD, Division of Visceral, Thoracic and Vascular Surgery, Stadtspital Triemli, Birmensdorferstrasse 497, 8063 Zurich, Switzerland. Email: [email protected]
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Asian Cardiovascular & Thoracic Annals 22(5)
Figure 1. Computed tomography of the chest: coronary section showing multiple bilateral pulmonary nodules.
recommended. One nodule in the left upper lobe was laser-excised in a noncontact technique for parenchymal-sparing purposes (Biolitec Diode Laser, 1318 nm wavelength, 30–40 W). The mediastinal mass was adjacent to the left brachiocephalic vein and aortic arch, requiring lateral resection and suture of the vein. Frozen section revealed a chondroid lesion within the lung. The postoperative outcome was uneventful. The patient was discharged on the 4th postoperative day. After pathological workup including immunohistochemical staining, the mediastinal mass was diagnosed as paraganglioma (Figure 4). The pulmonary lesion was a chondroma (Figure 5). In view of the close resection margins and the high local recurrence rate of paragangliomas,2 postoperative radiotherapy was recommended. The upper ventral mediastinum was treated
Figure 2. Histological features of the excised paraganglioma. (a) Overview of the hematoxylin and eosin stained specimen. The tumor measured 15 mm in diameter and was well-circumscribed. (b) The tumor cells grew in conglomerates (zellballen) and showed moderate polymorphism. Hematoxylin and eosin stain, original magnification 10. (c) The tumor cells were intensely positive for synaptophysin, original magnification 10. (d) Immunostain for chromogranin was positive, original magnification 10.
Figure 3. Histological features of the pulmonary chondroma. (a) Overview of the hematoxylin and eosin stained specimen. The tumor measured 15 mm in diameter and the consistency was soft and partly colloidal. (b) Detail showing the myxohyaline matrix with inconspicuous chondroid cells. Hematoxylin and eosin stain, original magnification 10.
Downloaded from aan.sagepub.com at UNIV OF PENNSYLVANIA on June 16, 2015
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Figure 5. Whole body positron-emission tomography-computed tomography showing fluorodeoxyglucose accumulating in a nodule in the left anterior and middle mediastinum adjacent to the pulmonary artery, aortic arch, and left brachiocephalic vein.
Figure 4. Histological features of the gastrointestinal stromal tumor. (a) Overview, hematoxylin and eosin stain. (b) The tumor cells show a predominantly epithelioid partly spindle cellular growth pattern. Hematoxylin and eosin stain, original magnification 4. (c) Immunostain of CD117, original magnification 4. The tumor cells were positive for CD117.
with 45 Gy in 25 fractions beginning 8 weeks after surgery. Genetic counselling and regular clinical follow-up were recommended but refused by the patient.
Discussion Carney triad is defined by the synchronous or metachronous occurrence of GIST, pulmonal chondroma, and extraadrenal paraganglioma. It was described in 1977, and affects mostly young women.3 To date, approximately 120 cases of this rare disorder have been reported in the literature. The genetic background is still unclear. Only in one-fifth of the patients with Carney triad, are all 3 tumors detected. Most patients
present with GIST typically located in the gastric antrum, which are often multifocal and have a biphasic growth pattern histologically.4 GIST in Carney triad lack specific KIT and PDGFRA mutations.1 One third of patients develop lymph node metastasis, and one fourth have liver metastasis.1 Nevertheless, the outcome of Carney triad appears to be better than in sporadic GIST, with a 10-year survival of 100%.5 Incomplete Carney triad has to be differentiated from the autosomal dominant inherited CarneyStratakis syndrome, characterized by GIST and paragangliomas associated with germline loss of function mutations of succinate dehydrogenase complex subunits B, C, and D.6 Recent observations indicate that further tumors are part of the Carney triad. It seems to be at least a pentad with additional esophageal leiomyoma and adrenocortical adenoma.6 Surgery is the mainstay of treatment for GIST and paraganglioma.7 Imatinib is a tyrosine kinase inhibitor that inhibits BCR-ABL, KIT, and PDGRF.7 Because of lack of mutations in these genes in patients with Carney triad, the role of imatinib is unclear and probably less important. In our case, Carney triad was confirmed with metachronous development of GIST, pulmonary chondroma, and a mediastinal paraganglioma. There were no signs for presence of an esophageal leiomyoma or adrenocortical adenoma. In young patients presenting with mediastinal or lung masses following resection of GIST without gaining functional mutations of c-kit and PDGFRA, suspicion of Carney triad should be raised. Funding This research received no specific grant from any funding agency in the public, commerical, or not-for-profit sectors.
Conflict of interest statement None declared
Downloaded from aan.sagepub.com at UNIV OF PENNSYLVANIA on June 16, 2015
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Asian Cardiovascular & Thoracic Annals 22(5)
References 1. Stratakis CA and Carney JA. The triad of paragangliomas, gastric stromal tumours and Pulmonary chondromas (Carney triad), and the dyad of paragangliomas and gastric Stromal sarcomas (Carney-Stratakis syndrome): molecular genetics and clinical Implications. J Intern Med 2009; 266: 43–52. 2. Lamy A, Fradet G, Luoma A and Nelems B. Anterior and middle mediastinum paraganglioma: complete resection is the treatment of choice. Ann Thorac Surg 1994; 57: 249–252. 3. Carney JA, Sheps SG, Go VL and Gordon H. The triad of gastric leiomyosarcoma, functioning extra-adrenal paraganglioma and pulmonary chondroma. N Engl J Med 1977; 296: 1517–1518. 4. Otto C, Agaimy A, Braun A, et al. Multifocal gastric gastrointestinal stromal tumors (GISTs) with lymph
node metastases in children and young adults: a comparative clinical and histomorphological study of three cases including a new case of Carney triad. Diagn Path 2011; 6: 52. 5. Zhang L, Smyrk TC, Young WF, Stratakis CA and Carney JA. Gastric stromal tumors in Carney triad are different clinically, pathologically, and behaviorally from sporadic gastric gastrointestinal stromal tumors: findings in 104 cases. Am J Surg Pathol 2010; 34: 53–64. 6. Carney JA. Carney triad: a syndrome featuring paraganglionic, adrenocortical, and possibly other endocrine tumors. J Clin Endocrinol Metab 2009; 94: 3656–3662. 7. Knop S, Schupp M, Wardelmann E, et al. A new case of Carney triad: gastrointestinal stromal tumours and leiomyoma of the esophagus do not show activating mutations of KIT and platelet-derived growth factor receptor a. J Clin Path 2006; 59: 1097–1099.
Downloaded from aan.sagepub.com at UNIV OF PENNSYLVANIA on June 16, 2015
An unusual case of mediastinal mass and bilateral nodules
Asian Cardiovascular & Thoracic Annals 2014, Vol. 22(5) 623–626 ß The Author(s) 2013 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0218492313483586 aan.sagepub.com
Charlotte Lilli Elena Wichmann1, Birgit Helmchen2, Achim Weber3, Stefan Wildi4 and Giovanni Luca Carboni1,5
Abstract A 23-year-old woman presented with a mediastinal paraganglioma and multiple pulmonary chondromas following antral gastric resection for gastrointestinal stromal tumor. These tumors form the Carney triad, a rare disorder of unknown genetic background. First described in 1977, approximately 120 cases have been documented in the literature. The tumors do not harbor the specific c-kit or PDGFRA gene mutations often found in sporadic gastrointestinal stromal tumor. In most cases, gastric gastrointestinal stromal tumor is the first tumor to be detected, with secondary tumors appearing years later. Even if it is rare, Carney triad should be suspected in young patients with history of gastrointestinal stromal tumor.
Keywords Esophageal neoplasms, Gastrointestinal stromal tumors, Neoplasms, multiple primary
Introduction Carney triad describes the association of gastrointestinal stromal tumor (GIST), pulmonary chondroma and extraadrenal paraganglioma.1 It affects mostly young women. The complete triad is present in 20% of patients.1
Case report Clinical workup in a 21-year-old woman with persistent epigastralgia revealed a gastric mass in the antrum. Following endosonographically controlled fine-needle biopsy, a cytological diagnosis of CD117-positive mesenchymal neoplasm was made. On staging, multiple bilateral pulmonary lesions were detected. A computed tomography-guided biopsy of one of the pulmonal lesions showed myxoid chondroid proliferation (Figure 1). Gastric antrectomy was performed, and a multinodular tumor of 7 cm in greatest diameter was completely removed. It was diagnosed as GIST with epithelioid and spindle cellular features (Figure 2). It was in the high-risk category, based on location and mitotic count. No mutations were detected on
genotyping of the c-kit and PDGFRA genes. The patient was treated with imatinib but refused further investigations including further work-up of the pulmonary lesions at that time. On follow-up with fluorodeoxyglucose positron-emission tomography-computed tomography one year after surgery, a new fluorodeoxyglucose-enhancing nodule in the left upper mediastinum was detected (Figure 3). The pulmonary lesions were stable in size, with no fluorodeoxyglucose accumulation. Resection of the mass in the superior mediastinum and one of the stationary pulmonary nodules was 1 Division of Visceral, Thoracic and Vascular Surgery, Department of Surgery, Stadtspital, Triemli, Zurich, Switzerland 2 Department of Pathology, Stadtspital Triemli, Zurich, Switzerland 3 Department of Pathology, University Hospital Zurich, Switzerland 4 Department of Surgery, Stadtspital Waid, Zurich, Switzerland 5 Division of Thoracic Surgery, University Hospital, Berne, Switzerland
Corresponding author: Giovanni L Carboni, MD, Division of Visceral, Thoracic and Vascular Surgery, Stadtspital Triemli, Birmensdorferstrasse 497, 8063 Zurich, Switzerland. Email: [email protected]
Downloaded from aan.sagepub.com at UNIV OF PENNSYLVANIA on June 16, 2015
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Asian Cardiovascular & Thoracic Annals 22(5)
Figure 1. Computed tomography of the chest: coronary section showing multiple bilateral pulmonary nodules.
recommended. One nodule in the left upper lobe was laser-excised in a noncontact technique for parenchymal-sparing purposes (Biolitec Diode Laser, 1318 nm wavelength, 30–40 W). The mediastinal mass was adjacent to the left brachiocephalic vein and aortic arch, requiring lateral resection and suture of the vein. Frozen section revealed a chondroid lesion within the lung. The postoperative outcome was uneventful. The patient was discharged on the 4th postoperative day. After pathological workup including immunohistochemical staining, the mediastinal mass was diagnosed as paraganglioma (Figure 4). The pulmonary lesion was a chondroma (Figure 5). In view of the close resection margins and the high local recurrence rate of paragangliomas,2 postoperative radiotherapy was recommended. The upper ventral mediastinum was treated
Figure 2. Histological features of the excised paraganglioma. (a) Overview of the hematoxylin and eosin stained specimen. The tumor measured 15 mm in diameter and was well-circumscribed. (b) The tumor cells grew in conglomerates (zellballen) and showed moderate polymorphism. Hematoxylin and eosin stain, original magnification 10. (c) The tumor cells were intensely positive for synaptophysin, original magnification 10. (d) Immunostain for chromogranin was positive, original magnification 10.
Figure 3. Histological features of the pulmonary chondroma. (a) Overview of the hematoxylin and eosin stained specimen. The tumor measured 15 mm in diameter and the consistency was soft and partly colloidal. (b) Detail showing the myxohyaline matrix with inconspicuous chondroid cells. Hematoxylin and eosin stain, original magnification 10.
Downloaded from aan.sagepub.com at UNIV OF PENNSYLVANIA on June 16, 2015
Wichmann et al.
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Figure 5. Whole body positron-emission tomography-computed tomography showing fluorodeoxyglucose accumulating in a nodule in the left anterior and middle mediastinum adjacent to the pulmonary artery, aortic arch, and left brachiocephalic vein.
Figure 4. Histological features of the gastrointestinal stromal tumor. (a) Overview, hematoxylin and eosin stain. (b) The tumor cells show a predominantly epithelioid partly spindle cellular growth pattern. Hematoxylin and eosin stain, original magnification 4. (c) Immunostain of CD117, original magnification 4. The tumor cells were positive for CD117.
with 45 Gy in 25 fractions beginning 8 weeks after surgery. Genetic counselling and regular clinical follow-up were recommended but refused by the patient.
Discussion Carney triad is defined by the synchronous or metachronous occurrence of GIST, pulmonal chondroma, and extraadrenal paraganglioma. It was described in 1977, and affects mostly young women.3 To date, approximately 120 cases of this rare disorder have been reported in the literature. The genetic background is still unclear. Only in one-fifth of the patients with Carney triad, are all 3 tumors detected. Most patients
present with GIST typically located in the gastric antrum, which are often multifocal and have a biphasic growth pattern histologically.4 GIST in Carney triad lack specific KIT and PDGFRA mutations.1 One third of patients develop lymph node metastasis, and one fourth have liver metastasis.1 Nevertheless, the outcome of Carney triad appears to be better than in sporadic GIST, with a 10-year survival of 100%.5 Incomplete Carney triad has to be differentiated from the autosomal dominant inherited CarneyStratakis syndrome, characterized by GIST and paragangliomas associated with germline loss of function mutations of succinate dehydrogenase complex subunits B, C, and D.6 Recent observations indicate that further tumors are part of the Carney triad. It seems to be at least a pentad with additional esophageal leiomyoma and adrenocortical adenoma.6 Surgery is the mainstay of treatment for GIST and paraganglioma.7 Imatinib is a tyrosine kinase inhibitor that inhibits BCR-ABL, KIT, and PDGRF.7 Because of lack of mutations in these genes in patients with Carney triad, the role of imatinib is unclear and probably less important. In our case, Carney triad was confirmed with metachronous development of GIST, pulmonary chondroma, and a mediastinal paraganglioma. There were no signs for presence of an esophageal leiomyoma or adrenocortical adenoma. In young patients presenting with mediastinal or lung masses following resection of GIST without gaining functional mutations of c-kit and PDGFRA, suspicion of Carney triad should be raised. Funding This research received no specific grant from any funding agency in the public, commerical, or not-for-profit sectors.
Conflict of interest statement None declared
Downloaded from aan.sagepub.com at UNIV OF PENNSYLVANIA on June 16, 2015
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Asian Cardiovascular & Thoracic Annals 22(5)
References 1. Stratakis CA and Carney JA. The triad of paragangliomas, gastric stromal tumours and Pulmonary chondromas (Carney triad), and the dyad of paragangliomas and gastric Stromal sarcomas (Carney-Stratakis syndrome): molecular genetics and clinical Implications. J Intern Med 2009; 266: 43–52. 2. Lamy A, Fradet G, Luoma A and Nelems B. Anterior and middle mediastinum paraganglioma: complete resection is the treatment of choice. Ann Thorac Surg 1994; 57: 249–252. 3. Carney JA, Sheps SG, Go VL and Gordon H. The triad of gastric leiomyosarcoma, functioning extra-adrenal paraganglioma and pulmonary chondroma. N Engl J Med 1977; 296: 1517–1518. 4. Otto C, Agaimy A, Braun A, et al. Multifocal gastric gastrointestinal stromal tumors (GISTs) with lymph
node metastases in children and young adults: a comparative clinical and histomorphological study of three cases including a new case of Carney triad. Diagn Path 2011; 6: 52. 5. Zhang L, Smyrk TC, Young WF, Stratakis CA and Carney JA. Gastric stromal tumors in Carney triad are different clinically, pathologically, and behaviorally from sporadic gastric gastrointestinal stromal tumors: findings in 104 cases. Am J Surg Pathol 2010; 34: 53–64. 6. Carney JA. Carney triad: a syndrome featuring paraganglionic, adrenocortical, and possibly other endocrine tumors. J Clin Endocrinol Metab 2009; 94: 3656–3662. 7. Knop S, Schupp M, Wardelmann E, et al. A new case of Carney triad: gastrointestinal stromal tumours and leiomyoma of the esophagus do not show activating mutations of KIT and platelet-derived growth factor receptor a. J Clin Path 2006; 59: 1097–1099.
Downloaded from aan.sagepub.com at UNIV OF PENNSYLVANIA on June 16, 2015
