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ALK fusions are found in various tumors, including thyroid cancer, and serve as a diagnostic marker and therapeutic target. Spectrum and outcomes of  ALK  fusions found in thyroid nodules and cancer are not fully characterized. We report a series of 44  ALK -translocated thyroid neoplasms, including 31 identified preoperatively in thyroid fine-needle aspirates (FNA). The average patients’ age was 43 years (range, 8–76 years); only one with radiation history. All 19 resected thyroid nodules with  ALK  fusion identified preoperatively were malignant. Among nodules with known surgical pathology ( n  = 32), 84% were papillary thyroid carcinomas (PTCs) and 16% poorly differentiated thyroid carcinomas (PDTCs). PTCs showed infiltrative growth with follicular architecture seen exclusively (30%) or in combination with papillary and/or solid growth (37%). Tumor multifocality was seen in 10 (31%) PTC cases. Most PDTC had a well-differentiated PTC component. Lymph node metastases were identified in 10/18 (56%) patients with neck dissection. The most common  ALK  fusion partners were  STRN  (n = 22) and  EML4  (n = 17). In five cases, novel  ALK  fusion partners were discovered. All five PDTCs carried  STRN-ALK  fusion. On follow-up, ten patients were free of disease at 2–108 months, whereas two patients with PDTC died of disease. In summary,  ALK  fusion-positive thyroid carcinomas are typically infiltrative PTC with common follicular growth, which may show tumor dedifferentiation associated with increased mortality. Compared to  EML4-ALK ,  STRN-ALK  may be more common in PDTC, and ~10% of  ALK  fusions occur to rare gene partners. When  ALK  fusion is detected preoperatively in FNA samples, malignancy should be expected.

Characterization of thyroid cancer driven by known and novel ALK fusions