Diagnostic Challenges in Primary Pulmonary Adenocarcinoma with Signet-Ring Cell Features
Primary pulmonary adenocarcinoma with signet-ring cell features (PASRF) remains one of the more elusive and diagnostically complex subtypes of lung cancer. Its morphological resemblance to metastatic signet-ring cell carcinomas (SRCCs) originating from the gastrointestinal tract or breast often leads to diagnostic confusion, underscoring the need for a deliberate and layered approach to differentiation that draws on both histopathological and molecular techniques.
These tumors are characterized by the presence of cells filled with intracytoplasmic mucin that displaces the nucleus, forming the classic “signet-ring” appearance. Yet this feature alone cannot distinguish PASRF from its metastatic counterparts. Immunohistochemistry becomes indispensable in such cases. Markers commonly expressed in primary lung adenocarcinomas—such as TTF-1, CK7, and napsin A—offer crucial clues. In contrast, markers like CK20 and CDX2, often seen in gastrointestinal malignancies, tend to be absent. This contrast was underscored in a case published in The Journal of the American Osteopathic Association, where a pulmonary tumor’s immunophenotype—positive for TTF-1, CK7, and napsin A, and negative for gastrointestinal markers—supported a primary lung origin through careful immunoprofiling via comprehensive marker analysis.
The clinical presentation of PASRF compounds the challenge. Patients frequently exhibit nonspecific respiratory symptoms such as cough and shortness of breath—symptoms easily mistaken for infections or chronic inflammatory conditions. Radiologic findings often mimic benign processes, making imaging alone an unreliable diagnostic tool. As highlighted in Pathology - Research and Practice, definitive diagnosis hinges on tissue biopsy coupled with immunohistochemical confirmation, especially when standard workups fail to account for the full clinical picture, as demonstrated in a detailed case analysis.
Prognostically, PASRF tends to behave more aggressively than typical lung adenocarcinomas. It often presents at an advanced stage, with early lymphatic and distant spread. A retrospective cohort study in Surgical and Experimental Pathology found that signet-ring cell features in pulmonary adenocarcinoma correlate with a higher incidence of nodal involvement and distant metastasis, contributing to poorer overall survival. Compounding these challenges is the tumor’s reported resistance to conventional chemotherapy regimens, which further emphasizes the urgency of timely, precise diagnosis.
Molecular profiling has begun to provide promising therapeutic insights. PASRF has been associated with driver mutations, including ALK rearrangements, which may confer sensitivity to targeted therapies. In one reported case, a patient with ALK-positive PASRF responded favorably to ALK inhibition, illustrating how early molecular testing can directly influence treatment efficacy. These insights, presented in Pathology - Research and Practice, highlight the importance of integrating genotyping into initial diagnostic algorithms.
Ultimately, the management of PASRF demands a coordinated, multidisciplinary strategy. Pulmonologists, pathologists, oncologists, and radiologists must work in tandem to navigate its complex presentation. Advances in immunohistochemistry and molecular diagnostics continue to sharpen the precision of PASRF diagnosis and open doors to targeted treatment strategies—critical steps toward improving outcomes in this uncommon but consequential variant of lung cancer.