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Journal of Clinical Oncology, Vol 22, No 10 (May 15), 2004: pp. 2029-2031 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.07.152
Soft Tissue SarcomasCASE 3. Gastrointestinal Stromal Tumor and Carney's TriadDepartments of Pathology, Genetics, and Medicine, Institute Gustave-Roussy, Villejuif, France. In 1987, a 17-year-old girl presented to a general hospital with microcytic anemia suggesting occult bleeding. An upper digestive tract endoscopy was performed, revealing a 2.5cm mass in the fundus. Histologic analysis revealed a gastric epithelioid leiomyosarcoma. Three weeks later, a subtotal proximal gastric resection was performed. Light microscopy showed a diffuse pattern of rounded cells with eosinophilic cytoplasm and uniform round-to-ovoid nuclei (Fig 1A). Some eosinophilic hyaline fibers were present (Fig 1B). Mitotic count showed three mitoses per 50 high power fields. Immunohistochemical reactions on tumor cells were positive for KIT (CD117, Fig 1C), smooth-muscle actin, and CD34 but negative for desmin and S-100 protein, consistent with the diagnosis of gastrointestinal stromal tumor (GIST). The initial computed tomography (CT) scan revealed no evidence of hepatic metastases but showed a round 2cm mass in the lung (Fig 1D). The patient was considered to have a malignant GIST with synchronous lung metastasis and received four courses of combination chemotherapy with ifosfamide, dactinomycin, and vincristine. Because of the absence of a response, wedge resection of the tumor mass was performed. Histologic examination revealed a chondroma. The association of chondroma with GIST was highly suggestive of an incomplete Carney's triad.
No evidence of tumor progression was observed until the occurrence of hemoptysis in 1990 and 1995, revealing recurrent lung chondromas confirmed by histology. In 2000 the patient consulted our institute, and chest CT revealed a mediastinal tumor mass 3cm in diameter (Fig 1E) with recurrent chondroma. Positron emission tomography showed medistinal uptake but no positivity in the lung at the sites of previous chondromas (Fig 1F). A few weeks later, the patient presented with a 2cm right cervical mass. Head and neck CT and magnetic resonance imaging revealed the presence of bilateral carotid glomus masses. Octreoscan (Fig 1G) and iodine 131 metaiodobenzylguanidine (MIBG) scintigrams (Fig 1H) showed a bilateral retention of both tracers in the head and neck area and mediastinum, highly suggestive for a paraganglioma of the mediastium with bilateral cervical chemodectomas. Adrenal biomarkers were at physiologic levels consistent with the diagnosis of multiple nonfunctioning extra adrenal paragangliomas. Fifteen years after the initial diagnosis, the patient has completed her Carney's triad. Carney et al1 originally reported in 1977 the association of gastric epithelioid leiomyosarcoma, pulmonary chondroma, and extra-adrenal paraganglioma, further referred to as the "Carney triad." This triad was primarily isolated from the analysis of GIST because of a puzzling pattern associating slow-growing tumors with distinct pathologic phenotypes occurring in multiple organs in young (mainly female) patients.2 Although this suggested an inherited disorder, no germline-mutation has been identified to date. In 1999, Carney published an update3 of the clinical presentation combining case reports of 79 patients showing that the evolution although chronic and indolent in many cases was associated with severe morbidity due to multiple resections of pulmonary chondromas and cervical or mediastinal paragangliomas. In 2002, Carney and Stratakis4 identified a new syndrome associating familial paraganglioma and gastric stromal sarcoma, which they separated from the Carney's triad. Mutations in SDHB, SDHC, and SDHD that have been identified in hereditary paragangliomas5 have not been reported in this syndrome and were not found in our patient. Most patients with primary GIST in the context of Carney's triad could develop synchronous or metachronous pulmonary nodules (76%) as well as mediastinal and/or cervical nodes not related to metastases but to multiple primary lung chondromas, extra-adrenal paraganglioma (47%) of the mediastinum, and/or cervical chemodectoma.3 This is particularly important in young female patients, who are more likely to develop this syndrome. Recently, imatinib mesylate (Gleevec) was reported as a promising treatment for patients with advanced GIST.6,7 Considering that an increasing number of patients with GIST tumors will be treated with imatinib mesylate for advanced metastatic diseases, the absence of response of lung metastases should be regarded as a sign of possible misdiagnosed lung chondroma. The absence of paraganglioma, which usually completes the triad after several years (median, 6 years), does not allow rejecting a diagnosis of Carney's triad. It is noteworthy that, although both the GIST and the chondromas were strongly positive for CD117, our patient had no germline mutation of KIT (direct sequencing of exons 1 to 21) and a 4-month treatment with imatinib mesylate had no effect on her chondromas and paragangliomas.8 Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest.
Acknowledgment We are grateful to Jean-Michel Coindre for his critical review of the manuscript. REFERENCES 1. Carney JA, Sheps SG, Go VLW, et al: The triad of gastric leiomyosarcoma, functioning extra-adrenal paraganglioma and pulmonary chondroma. N Engl J Med 296:1517-1518, 1977[Medline] 2. Appelman HD: The Carney Triad: A lesson in observation, creativity, and perseverance. Mayo Clin Proc 74:638-640, 1999[Medline] 3. Carney JA: Gastric stromal sarcoma, pulmonary chondroma, and extra-adrenal paraganglioma (Carney Triad): Natural history, adrenocortical component, and possible familial occurrence. Mayo Clin Proc 74:543-552, 1999[Abstract] 4. Carney JA, Stratakis CA: Familial paraganglioma and gastric stromal sarcoma: A new syndrome distinct from the Carney triad. Am J Med Genet 108:132-139, 2002[CrossRef][Medline]
5. Neumann HP, Bausch B, McWhinney SR, et al: Germ-line mutations in nonsyndromic pheochromocytoma. N Engl J Med 346:1459-1466, 2002
6. Demetri GD, von Mehren M, Blanke CD, et al: Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med 347:472-480, 2002 7. van Oosterom AT, Judson I, Verweij J, et al: Safety and efficacy of imatinib (STI571) in metastatic gastrointestinal stromal tumours: A phase I study. Lancet 358:1421-1423, 2001[CrossRef][Medline]
8. Heinrich MC, Blanke CD, Drucker BJ, et al: Inhibition of KIT tyrosine kinase activity: A novel molecular approach to the treatment of KIT-positive malignancies. J Clin Oncol 20:1692-1703, 2002
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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