Rare Pulmonary Cancer With EWSR1::ATF1 Fusion Diagnosed in 60-Year-Old Woman

A rare lung tumor that closely mimics a more common salivary gland–type cancer has been documented in a new case report, in which molecular testing proved decisive after standard diagnostic workup fell short. Surgeons and pathologists in Japan describe a 60-year-old woman whose persistent cough and intermittent hemoptysis led to the discovery of a 3.0-centimeter solid nodule in her left lower lobe, protruding into the lumen of the B9 segmental bronchus. Only after the tumor was surgically removed and analyzed with fluorescence in situ hybridization could the team confirm an unexpected diagnosis: primary pulmonary hyalinizing clear cell carcinoma harboring an EWSR1::ATF1 fusion, an exceedingly uncommon entity that is easily mistaken for mucoepidermoid carcinoma.

The case, published in the journal General Thoracic and Cardiovascular Surgery Cases, illustrates why molecular diagnostics have become indispensable when salivary gland–type tumors arise in the lung. Hyalinizing clear cell carcinoma, abbreviated HCCC, is a rare tumor that most commonly develops in the oral cavity and oropharynx and only occasionally arises from the tracheobronchial glands. Because HCCC and mucoepidermoid carcinoma, or MEC, share substantial morphological features, distinguishing between them on stained tissue sections alone is often impossible. The two tumors differ, however, at the genetic level: most MECs carry CRTC1/3::MAML2 fusions, whereas nearly all HCCC cases show EWSR1::ATF1 or EWSR1::CREM fusions. Detecting which fusion is present therefore settles an otherwise ambiguous diagnosis.

The patient’s story began with a two-month history of persistent cough and intermittent coughing up of blood. Her medical history included type 2 diabetes mellitus, and she was a former smoker with a 10-pack-year history. Physical examination was unremarkable, and routine laboratory tests, including serum tumor markers, were within normal limits. Chest computed tomography revealed a well-defined 3.0-centimeter solid nodule protruding into the lumen of the left lower lobe bronchus. Positron emission tomography–computed tomography showed increased fluorodeoxyglucose uptake in the lesion, with a maximum standardized uptake value of 8.9, and no abnormal uptake anywhere else in the body. Bronchoscopy revealed a smooth-surfaced, protruding endobronchial mass arising from the B9 bronchus.

Notably, the team did not attempt an endobronchial biopsy. The lesion appeared hypervascular, raising concern about procedure-related bleeding, so no preoperative histological diagnosis could be established. The radiological and bronchoscopic differential diagnosis included primary pulmonary malignancies, particularly salivary gland–type tumors such as MEC, as well as carcinoid, metastatic tumors, and benign endobronchial lesions. Given the hemoptysis, the tumor size, and the relatively high FDG uptake, the lesion was clinically treated as a primary lung malignancy and staged as cT1cN0M0, Stage IA3. The surgical team performed a robot-assisted left lower lobectomy with systematic mediastinal lymph node dissection, serving both diagnostic and therapeutic purposes.

Gross examination of the resected specimen revealed a firm, solitary, well-circumscribed yellowish-white mass measuring 3.0 centimeters in its greatest dimension, located near the bronchial resection margin. Under the microscope, the tumor consisted of relatively uniform small- to medium-sized epithelioid cells with clear-to-pale eosinophilic cytoplasm and round-to-oval nuclei with inconspicuous nucleoli. Marked nuclear pleomorphism, brisk mitotic activity, and tumor necrosis were all absent. The cells were arranged in cords, nests, and trabeculae embedded in prominent, hyalinized acellular stroma, the hallmark architecture of HCCC. The tumor sat within the bronchial wall adjacent to the bronchial cartilage, with normal bronchial submucosal glands in close proximity, supporting an origin from the bronchial submucosal glands. Infiltration through the bronchial wall into adjacent peripheral alveolar tissue was also observed.

Immunohistochemistry added a partly confusing picture. The tumor cells were positive for CK7 and CK5/6, and most cells showed nuclear positivity for p40, squamous-type markers frequently expressed by both HCCC and pulmonary MEC. The Ki-67 labeling index was approximately 1 percent, indicating very low proliferative activity. The tumor cells tested negative for TTF-1, S100, SOX10, GFAP, synaptophysin, chromogranin A, and smooth muscle actin. Because no immunohistochemical marker cleanly separates HCCC from MEC or other salivary gland–type lung tumors, the differential diagnosis remained between low-grade MEC with clear cell features and HCCC, prompting additional molecular studies.

Those studies proved decisive. Dual-color break-apart fluorescence in situ hybridization showed no evidence of MAML2 gene rearrangement, arguing against MEC. In contrast, the assay demonstrated split signals for both EWSR1 and ATF1, strongly supporting the presence of an EWSR1::ATF1 fusion. Together with the characteristic histomorphology, these molecular findings established the definitive diagnosis of primary pulmonary HCCC. The molecular profile is consistent with previously reported pulmonary HCCC cases and underscores the diagnostic value of testing for EWSR1 and MAML2 rearrangements in salivary gland–type lung tumors with overlapping histological features.

The pathological staging revealed one unusual feature. Venous invasion was present, a histological finding rarely described in pulmonary HCCC, although lymphatic invasion, perineural invasion, pleural invasion, and lymph node metastases were all absent, and the bronchial resection margins were tumor free. No lymph node metastases were identified among the dissected nodes, and the final pathological stage was pT1cN0M0, Stage IA3. The authors note that the prognostic significance of venous invasion in this tumor type remains unclear because of the limited number of reported cases and short follow-up periods. Despite that finding, the patient remained free of recurrence one year after surgery, and careful surveillance was recommended given the paucity of long-term outcome data, particularly in cases with invasive features.

The report also carries practical lessons for thoracic surgeons and pathologists. HCCC should be considered in the differential diagnosis of centrally located or endobronchial pulmonary tumors, particularly when a definitive preoperative diagnosis is difficult to obtain safely. Bronchoscopically, HCCC often appears as a smooth-surfaced or polypoid lesion, whereas squamous cell carcinoma tends to present as a more irregular or ulcerated lesion, although adenoid cystic carcinoma can similarly appear as a submucosal lesion with intact mucosa. Diagnosis on small biopsy specimens can be challenging because of overlapping morphological and immunohistochemical features, making molecular testing for EWSR1 rearrangements or EWSR1-associated fusions particularly useful. When a definitive preoperative diagnosis cannot be safely obtained, complete surgical resection may serve both diagnostic and therapeutic purposes, as it did in this case.

Prognostically, pulmonary HCCC is generally considered a low-grade malignancy with a favorable outcome after complete resection, and most reported cases follow an indolent course. Tumors are often detected incidentally or present with nonspecific respiratory symptoms such as cough or hemoptysis. Lymph node metastasis and local recurrence have been documented in a few cases, but disease-related mortality appears exceedingly rare. Surgical resection with negative margins remains the treatment of choice, while the role of adjuvant therapy has not yet been established. In this patient, the relatively high FDG uptake on PET-CT contrasted with the low-grade histological picture: the Ki-67 index of roughly 1 percent, scarce mitotic figures, and absent necrosis all supported low-grade biological behavior, echoing previous reports of low proliferative activity in pulmonary HCCC despite variable radiological findings. Because only a limited number of molecularly confirmed cases have been reported, the authors emphasize that accurate classification is critical for appropriate prognostic assessment, postoperative surveillance, and the reliable accumulation of clinicopathological data needed to define the biological behavior and long-term outcomes of this exceptionally rare pulmonary tumor, and they call for additional molecularly confirmed cases with long-term follow-up.

Subject of Research: A rare primary pulmonary hyalinizing clear cell carcinoma with an EWSR1::ATF1 fusion diagnosed by molecular testing after surgical resection

Article Title: Primary pulmonary hyalinizing clear cell carcinoma harboring EWSR1::ATF1 fusion: a case report

Article References: Teishikata, T., Hashiguchi, M., Nakahara, K., Okamoto, Y., Hiratsuka, M., & Kamohara, K. (2026). Primary pulmonary hyalinizing clear cell carcinoma harboring EWSR1::ATF1 fusion: a case report. General Thoracic and Cardiovascular Surgery Cases, 5(1), Article 44. https://doi.org/10.1186/s44215-026-00280-3

Image Credits: AI Generated

DOI: 10.1186/s44215-026-00280-3

Keywords: hyalinizing clear cell carcinoma, EWSR1::ATF1 fusion, mucoepidermoid carcinoma, MAML2, fluorescence in situ hybridization, salivary gland-type lung tumor, robot-assisted lobectomy, endobronchial tumor, Ki-67 index, venous invasion, case report, molecular diagnostics