HNF4α-positive, TTF-1-negative lung adenocarcinomas represent a major subset of non-terminal respiratory unit (non-TRU) tumors with gastrointestinal-type differentiation and frequent KRAS mutations; however, their structural and microenvironmental diversities remain unclear. We herein examined 114 HNF4α-positive lung adenocarcinomas, including tumors with and without interstitial pneumonia (IP). IP-associated cases were analyzed separately. Tumors were classified into three low-power architectural patterns: Alveolar-preserving (A-type), Radial-traction (R-type), and Mass-forming destructive (M-type). In IP-absent cases, in which it was possible to reliably evaluate tumor contours and the mass effect, these architectural patterns closely corresponded to the three computed tomographic growth patterns defined by tumor-lung interactions-Replacement, Spiculated, and Expansive growth-indicating the potential of computed tomographic morphology to serve as a surrogate for the underlying architecture. A-type tumors showed strong gastric differentiation with high MUC6 expression and low frequencies of pleural, lymphatic, and vascular invasion, whereas R-type and M-type tumors exhibited progressively lower MUC6 expression, more prominent intestinal differentiation, and higher rates of lymph node metastasis, particularly in M-type, representing more aggressive phenotypes. KRAS mutations were detected across all three patterns but were less frequent in M-type; KRAS G12C was enriched in A-type tumors. M-type tumors showed the poorest disease-free and overall survival irrespective of spread through air spaces (STAS) status. Despite their indolent-appearing architecture, among STAS-positive tumors, A-type was associated with worse disease-free and overall survival than R-type, identifying STAS-positive A-type as a high-risk subset within the HNF4α-positive non-TRU spectrum. RNA sequencing further identified three distinct gene expression clusters corresponding to epithelial-mesenchymal transition-related, angiogenic/tumor-associated macrophage-rich, and mucinous epithelial programs. STAS-positive A-type tumors predominantly belonged to the angiogenic/tumor-associated macrophage-rich group, implicating this microenvironment in their aggressive behavior. Since STAS-positive A-type tumors may present as radiologically indolent replacement-growth lesions, careful evaluation of resected specimens and close postoperative surveillance are warranted.
