Abstract: 【Abstract】 Objective To investigate the expression of anaplastic lymphoma kinase （ALK）, tropomyosin receptor kinase （TRK）, and recombinant C-Ros oncogene 1, receptor tyrosine kinase （ROS1） in Spitz tumors, and to analyze their associations with clinical and histopathological features of Spitz tumors. Methods Clinical and histopathological characteristics, as well as follow-up data, were collected from patients with Spitz tumors at Department of Pathology, Hospital of Dermatology, Chinese Academy of Medical Sciences from January 2017 to August 2023, and retrospectively analyzed. Immunohistochemical staining for ALK, pan-TRK, and ROS1 was performed on skin tissues, and associations between the expression of these kinase proteins and clinicopathological features were analyzed. Results A total of 57 patients with Spitz tumors were collected, including 36 females and 21 males. Immunohistochemical staining showed that 30（52.6%） patients were positive for ALK, 4 （7.0%） were positive for ROS1, only 2 （3.5%） were positive for TRK, and 21 （36.8%） were negative for the three kinase proteins. Among the 30 ALK-positive patients, the median age was 9.5 years, 21 （70.0%） were females, and 15 （50.0%） presented with lesions on the face, which mainly manifested as papules or nodules; histologically, 29 （96.7%） patients had hypopigmented tumors with an exophytic growth pattern, and the tumor cells were mainly large and long spindle cells arranged in long cord-like, plexiform or fascicular patterns. Among the 4 ROS1-positive patients, there were 3 females and 1 male, presenting with exophytic papules or polyps; histologically, tumor cells were mostly arranged in small nests, without obvious clefts around cell nests. Two TRK-positive patients were both males aged 20 and 50 years respectively, and presented with brown and skin-colored flat papules, respectively; histologically, the tumors were located superficially with a flat base, and tumor cells spread in a pagetoid pattern in the epidermis, with some epithelioid cells and small cell nests. Among the 21 patients negative for the 3 kinase proteins, 9 were males and 12 were females, and they clinically presented with macules, papules and polypoid lesions; histologically, most tumors were located superficially, consisting of a mixture of epithelioid cells and spindle cells, with rare cytological atypia and mitotic figures, and 2 cases showed mild tissue structural and cellular atypia. Fifty-seven patients were followed up for 2 - 83.3 months, with a median follow-up of 19.2 months. Only 1 ALK-positive child experienced a recurrence, and no recurrence or lymph node metastasis was observed in the other cases. Conclusions Among the three kinase proteins, ALK showed the highest positive rate in Spitz tumors in this study, while TRK- and ROS1-positive cases were sporadic. Histopathologically, ALK-positive Spitz tumor cells were mainly long spindle cells arranged in long cord-like or plexiform patterns, while TRK- and ROS1-positive Spitz tumors tended to have small cell nests. Both the kinase protein-positive and -negative Spitz tumors mostly had a good prognosis.

Key words: Nevus, epithelioid and spindle cell, Spitz tumor, Histopathology, Kinase fusion gene, Prognosis