Cytomorphology and Molecular Profile of Hyalinizing Clear Cell Carcinoma of the Lung: A Case With Mucinous Differentiation

ABSTRACT Hyalinizing clear cell carcinoma (HCCC) of the lung is an exceedingly rare salivary gland‐type neoplasm with limited cytomorphologic description. We report a case highlighting these features. A 3 mm incidental left‐airway lesion enlarged to 7 mm over 5 months, prompting radial endobronchial ultrasound (EBUS)‐guided transbronchial biopsy. Touch preparations revealed abundant bland tumor cells with small round to oval nuclei, smooth nuclear membranes, and scant slightly dense cytoplasm. Scattered cells showed clear or mucinous cytoplasm. The cells displayed round, columnar, or polygonal shapes and were arranged in nests, sheets, cohesive three‐dimensional clusters, and acinar or tubular structures within a homogeneous paucicellular fibrotic stroma. Histology demonstrated tumor cells in trabeculae, nests, and cords with occasional glands and mucinous microcysts set in hyalinized stroma. Most tumors cells had eosinophilic cytoplasm with scattered clear and mucinous cells. Immunohistochemically, tumor cells were positive for p40, DOG1, CK AE1/AE3, CAM5.2, CK5/6, CK7, EMA, and p63, and negative for TTF1; stromal cells were positive for SMA. Mucinous cells were mucicarmine‐positive, and the Ki‐67 index was very low (~2%). Molecular analysis identified an EWSR1 :: ATF1 fusion and SUZ12 and WRN mutations. The tumor mutational burden was 5.4 mutations per megabase. Segmentectomy confirmed HCCC with no nodal metastasis (stations 5, 9, 10, 11). Recognition of the cytomorphology, immunohistochemical profile, and characteristic EWSR1 :: ATF1 or EWSR1 :: CREM fusions is essential for accurate diagnosis of primary pulmonary HCCC.