Neuroendocrine and biologic features of primary tumors and tissue in pulmonary large cell carcinomas

Because biological behavior in lung tumors with neuroendocrine differentiation is highly dependent on cell death (apoptosis) and angiogenesis, p21 waf1/cip1 and microvessel density have been targeted as potentially useful tumor markers. We sought to validate the importance of p21 waf1/cip1 and microvessel density and study their interrelationship, analyzing clinical factors, subclassifications, and tumor and stromal markers. We examined p21 waf1/cip1 and other markers in tissue from 61 patients with surgically excised large cell carcinomas. The amount of tumor staining for p21 waf1/cip1 and microvessel density was evaluated by immunohistochemistry and morphometry. The study outcome was survival time until death from recurrent lung cancer. Multivariate Cox model analysis demonstrated that after surgical excision, histologic subtypes were significantly related to survival time ( p = 0.02), but quantitative staining of the tumor for p21 waf1/cip1 and microvessel density added prognostic information and these variables were more strongly prognostic than histologic subtype ( p = 0.00). Cut points at the median staining of 3.5% and 3.0% for p21 waf1/cip1 and microvessel density, respectively, divided patients into two groups with distinctive survival times. Patients with p21 waf1/cip1 staining of more than 3.5% and microvessel density staining of more than 3.0% had a median survival time of 14 months. Tumor staining for p21 waf1/cip1 and microvessel density in resected large cell carcinomas and certain other types of lung tumors was strongly related to survival. Patients with more than 3.0% staining in their tumors were at high risk of death from lung cancer and may be an appropriate target for prospective studies of adjuvant chemotherapy after surgical resection.