Tumor cell heterogeneity and subpopulations with metastatic ability in differentiated adenocarcinoma of the lung. Histologic and cytofluorometric DNA analyses. To investigate tumor cell heterogeneity and subpopulations with metastatic ability in differentiated adenocarcinoma of the lung, the primary and metastatic lesions in 20 cases of differentiated adenocarcinoma were examined by histologic and cytofluorometric DNA analyses. The primary tumor was divided histologically into three compartments: tumor area of type 1, papillary adenocarcinoma with thin stroma; tumor area of type 2, papillary adenocarcinoma with thickened fibrovascular stroma: tumor area of type 3; solid carcinoma with scant gland formation. The nuclear DNA content (NDC) was higher in type 2 than in type 1 tumor in terms of mean NDC and DNA histogram pattern (p less than 0.01). Metastatic tumors in distant organs often resembled the type 2 of primary tumors histologically and also in their DNA histogram patterns, and their mean NDC values were significantly correlated with each other (p less than 0.01). Metastatic tumors in regional lymph nodes had a significantly lower mean NDC than those in distant organs (p less than 0.01). These results suggest that (1) type 2 tumors originate from type 1 tumors by malignant progression and metastasize hematogenously, and (2) hematogenous metastases are composed of tumor subclones different from those of lymphatic metastases. 