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    • br Conflict of interest br Financial

    2022-11-30


    Conflict of interest
    Financial Support The work is supported by research grants from Clinical Key Specialty Project of China and Clinical Medical Center of Suzhou, China (Szzx201502) and Jiangsu Province Special Program of Medical Science, China (BE2016672).
    Introduction Recently, functional kinase fusions were identified in approximately half of spitzoid neoplasms, including AST, by Wiesner et al [1]. To date, ROS1, NTRK1, NTRK3, BRAF, RET, MET, and ALK fusions have been reported in spitzoid neoplasms [1], [2], and these findings are expected to enable better risk assessment and classification of spitzoid neoplasms. As a concrete example, the clinical behavior of anaplastic lymphoma kinase (ALK)–rearranged spitzoid neoplasms seems to be indolent, despite its potential for nodal metastasis [1], [3], [4], [5], [6], [7], [8], [9], [10], [11]. Therefore, the identification of ALK fusions in spitzoid neoplasms may be important for clinical decision making. Herein, we report a case of AST with a novel ALK fusion with discordant ALK immunohistochemistry (IHC) results. Our case highlights a potential diagnostic pitfall in screening of ALK-positive spitzoid neoplasms.
    Materials and methods
    Results
    Discussion Approximately 10% of spitzoid neoplasms harbor ALK rearrangement [1]. To date, 106 cases of ALK-positive spitzoid tumors have been reported in the English literature [1], [3], [4], [5], [6], [7], [8], [9], [10]. Although the number of cases with sufficient follow-up data is limited, no deaths have been reported to be associated with ALK-rearranged spitzoid neoplasm. Grossly, AST often presents as amelanotic polypoid skin lesions resembling hemangioma, as in the present case [3], [4]. Our current case also showed the characteristic histology of AST, such as fascicular growth of fusiform tumor aldehyde dehydrogenase inhibitor and infiltrative growth patterns in the deep dermis [3], [4]. ALK overexpression is associated with abnormal fusion between ALK and other partner genes. There are 6 known partner genes fused to ALK in spitzoid neoplasms, that is, TPM3, DCTN1, CLIP1, GTF3C2, NPM1, and TPR[1], [3], [4], [6]. The common fusion partners are TPM3 and DCTN1, accounting for 84.6% (22/26 cases) of the reported cases. Our ALK-rearranged AST had an in-frame fusion between MLPH with a maintained coiled-coil domain, which is theoretically considered an oncogenic fusion. This is a new oncogenic fusion not previously reported to contribute in cancer development. MLPH encodes melanophilin, which is a Rab effector protein involved in intracellular melanosome transport [13]. It functions as part of a complex with the motor protein Myo5a and the melanosome-bound Rab27a. Defects in melanophilin cause Griscelli syndrome type 3, which is a rare autosomal recessive disorder characterized by pigment dilution of the skin and hair. Because subcellular localization of ALK fusion proteins depends on the fusion partner [14], the cytoplasmic staining pattern of ALK in our case may be explained by the regular allocation of melanophilin. Currently, ALK IHC is probably the best screening method for ALK-positive spitzoid neoplasms in terms of simplicity and turnaround time for clinical practice. However, there is no recommendation for particular IHC method for screening of ALK-positive spitzoid neoplasms to date. This is probably because previously analyzed spitzoid tumors with ALK rearrangement tested for ALK IHC were all positive by the labeled streptavidin biotin method or conventional polymer method (Table), unlike ALK-positive lung cancers, which require sensitive methods for IHC screening [14]. However, our case showed that the results of ALK IHC on AST may differ based on the type of primary antibody clone and detection method or by the combination of these factors, as observed in lung cancer [14]. ALK1 is a monoclonal antibody commonly used for screening anaplastic large cell lymphoma (ALCL). ALK1 has been reported to have lower sensitivity than 5A4 or D5F3 in ALK-rearranged lung cancer [14]. Given the common ALK1 positivity in ALCL and the inefficiency of conventional IHC methods against ALK-rearranged lung cancers, we assumed that the level of ALK expression in our AST case was between those observed in ALCL and lung cancer. However, previous reports have identified ALK expression in a considerable number of ALK-rearranged ASTs using the anti-ALK1 antibody clone and Bond polymer refine detection kit, which was negative in our case [7], [8]. This discrepancy may be explained by the fact that the level of ALK expression can differ depending on the fusion partners, even for the same type of tumor [15]. Further studies are required to investigate the range of ALK levels in ASTs.