Hyalinizing clear cell carcinoma (HCCC) of the lung represents an exceptionally rare salivary gland-type neoplasm. Because it presents with nonspecific symptoms, a primary pulmonary HCCC diagnosis often requires a combination of cytomorphologic, immunohistochemical, and molecular analyses. This tumor generally follows an indolent clinical course. Consequently, its rarity makes it a significant diagnostic challenge for clinicians. Pathologists must distinguish it from more common lung cancers using specific cellular features and architectural patterns.

Challenges in Primary Pulmonary HCCC Diagnosis

The cytomorphology of HCCC reveals nests or sheets of bland tumor cells with clear or eosinophilic cytoplasm. These cells often exhibit small nuclei with smooth membranes and scant cytoplasm. Furthermore, the presence of a hyalinized paucicellular stroma is a hallmark feature of this disease. Immunohistochemically, these tumors typically express markers like p40 and CK7. However, they consistently lack TTF-1 and Napsin A expression. Therefore, this specific immunoprofile helps distinguish HCCC from common lung malignancies like adenocarcinoma or squamous cell carcinoma.

Molecular Markers and Management

Recent advances in pathology have identified the EWSR1::ATF1 fusion as a characteristic molecular driver of this tumor. In addition, identifying this fusion through molecular analysis is essential for a definitive diagnosis. Moreover, surgical resection remains the primary treatment of choice for localized cases. Most patients show excellent long-term outcomes following a successful segmentectomy or lobectomy. Nevertheless, clinicians should maintain long-term follow-up because of the potential for late recurrence or rare metastasis in some clinical settings.

What are the primary immunohistochemical markers for pulmonary HCCC?

Pulmonary HCCC typically tests positive for p40, p63, and CK7, while remaining negative for TTF-1 and Napsin A. This specific profile helps in differentiating it from common primary lung adenocarcinomas.

Why is molecular testing important for HCCC?

Molecular testing identifies characteristic EWSR1::ATF1 or EWSR1::CREM fusions. These markers are critical because they confirm the diagnosis and rule out other clear-cell-containing mimics like mucoepidermoid carcinoma.

Disclaimer: This content is for informational and educational purposes only. It does not constitute medical advice or a professional relationship. Refer to the latest local and national guidelines for clinical practice.

References

1. Lin JZ et al. Cytomorphology and Molecular Profile of Hyalinizing Clear Cell Carcinoma of the Lung: A Case With Mucinous Differentiation. Diagn Cytopathol. 2026 Mar 19. doi: 10.1002/dc.70114. PMID: 41856936.


2. Leduc C, Zhang L, Chasen B, et al. Hyalinizing Clear Cell Carcinoma of the Lung: Case Report and Review of the Literature. Arch Pathol Lab Med. 2017;141(9):1282-1288.


3. Wang H, et al. Primary pulmonary hyalinizing clear cell carcinoma of the lung: a case report and literature review. BMC Pulm Med. 2024;24(1):582.