As the biologic behavior in lung tumors with neuroendocrine differentiation is highly dependent on cell death (apoptosis) and extracellular matrix invasion, Bcl2 and extracellular matrix density have been targeted as potentially useful tumor markers. In this study, we sought to validate the importance of Bcl2 and ECM density and to study the relationships of Bcl2 and ECM density with clinical factors and other tumor or stromal markers. We examined Bcl2 and several other markers in tumor tissues from 55 patients with surgically excised pulmonary typical carcinoid. We used histochemistry, immunohistochemistry, and morphometry to evaluate the amount of tumor staining for Bcl2 and ECM; the surrogate markers for aggressive potential for our study were tumor size and lymph node metastasis determined at diagnosis. Multivariate logistic model analysis demonstrated that after surgical excision control, tumor size was significantly related to nodal metastasis (P = 0.01), but quantitative staining of the tumor for Bcl2 and ECM added prognostic information and was as strongly prognostic as tumor size (P<0.01). Cutpoints at the median staining of 3.1% and 9.8 microm2 for Bcl2 and ECM, respectively, divided patients into two groups with distinctive risk for nodal metastasis. Those with Bcl2 > 3.1% and ECM <9.8 microm2 had high risk for nodal metastasis. We concluded that tumor staining for Bcl2 and ECM in resected PTC is strongly related to tumor size and nodal metastasis. Patients with > 3.1% and <9.8 microm2 staining in their tumors comprise a subset with a high hazard for nodal metastasis and may be an appropriate target for prospective studies of adjuvant chemotherapy after surgical resection.