Atypical thymomas with squamoid and spindle cell features: clinicopathologic, immunohistochemical and molecular genetic study of 120 cases with long-term follow-up.

Thymomas are rare tumors characterized by a broad range of morphologic appearances that can sometimes give rise to difficulties for classification. We have studied a series of 120 thymoma patients in whom the tumors were characterized by sheets of atypical epithelial cells with squamoid and/or spindle cell features. They occurred in 63 men and 57 women and presented as a discrete mass in the anterior mediastinum measuring 2-23 cm (mean: 8.2 cm). Patients' ages ranged from 14 to 86 years (mean: 57.8) and most had symptoms referable to a mass lesion. 20 patients had myasthenia gravis or other autoimmune disorder. 76 cases were characterized by a predominant population of round to polygonal tumor cells while 32 cases were characterized by atypical oval or spindle cells. 12 cases showed mixed features and 16 cases showed the development of thymic carcinoma arising from thymoma. All cases were positive for p40/p63 and cytokeratin AE1/AE3. 23 cases were positive for CD5 (25%), and 13 for CD117 (14%). MIB1 showed a significant increase in proliferative activity (mean = 11.6%). Next generation sequencing in 47 cases did not disclose any variants amenable to current targeted therapies. Clinical follow up ranging from 2 to 29 years showed a progressive increase in aggressive behavior and fatality rate with advancing stage. Overall survival was 87% at 5 years, 67% at 10 years, and 23% at 20 years. Completeness of resection and staging were the most significant parameters for survival. The more aggressive tumors followed a protracted clinical course with multiple recurrences and metastases over a long period of time (mean = 19.8 years from time of initial relapse to death). Atypical thymomas are a distinct category of thymic epithelial neoplasm characterized by a slowly progressive clinical course with increased potential for metastases, transformation to a higher-grade malignancy, and fatal outcome in some cases.