Rethinking a Non-Predominant Pattern in Invasive Lung Adenocarcinoma: Prognostic Dissection Focusing on a High-Grade Pattern

SIMPLE SUMMARY: Prognostic considerations for non-predominant histologic patterns are necessary because most lung adenocarcinomas have a mixed histologic pattern. We aimed to identify prognostic stratification by second most predominant pattern of lung adenocarcinomas and to more accurately assess prognostic factors with CT imaging analysis, particularly enhancing non-predominant but high-grade pattern. We confirmed that the second most predominant histologic pattern can stratify lung adenocarcinoma patients according to prognosis. Especially, when the second most predominant pattern was high-grade, recurrence risk increased by 4.2-fold compared with the low-grade group. Thus, predicting the malignant potential and establishing treatment policies should not rely only on the most predominant pattern. Also, imaging parameters of higher non-contrast CT value and higher SUVmax value are associated with non-predominant but high-grade histologic pattern. ABSTRACT: Background: Prognostic considerations for non-predominant patterns are necessary because most lung adenocarcinomas (ADCs) have a mixed histologic pattern, and the spectrum of actual prognosis varies widely even among lung ADCs with the same most predominant pattern. We aimed to identify prognostic stratification by second most predominant pattern of lung ADC and to more accurately assess prognostic factors with CT imaging analysis, particularly enhancing non-predominant but high-grade pattern. Methods: In this prospective study, patients with early-stage lung ADC undergoing curative surgery underwent preoperative dual-energy CT (DECT) and positron emission tomography (PET)/CT. Histopathology of ADC, the most predominant and second most predominant histologic patterns, and preoperative imaging parameters were assessed and correlated with patient survival. Results: Among the 290 lung ADCs included in the study, 231 (79.7%) were mixed-pathologic pattern. When the most predominant histologic pattern was intermediate-grade, survival curves were significantly different among the three second most predominant subgroups (p = 0.004; low, lepidic; intermediate, acinar and papillary; high, micropapillary and solid). When the second most predominant pattern was high-grade, recurrence risk increased by 4.2-fold compared with the low-grade group (p = 0.005). To predict a non-predominant but high-grade pattern, the non-contrast CT value of tumor was meaningful with a lower HU value associated with the histologic combination of lower grade (low-grade as most predominant and intermediate-grade as second most predominant pattern, OR = 6.15, p = 0.005; intermediate-grade as most predominant and high-grade as second most predominant pattern, OR = 0.10, p = 0.033). SUVmax of the tumor was associated with the non-predominant but high-grade pattern, especially in the histologic combination of intermediate-high grade (OR = 1.14, p = 0.012). Conclusions: The second most predominant histologic pattern can stratify lung ADC patients according to prognosis. Thus, predicting the malignant potential and establishing treatment policies should not rely only on the most predominant pattern. Moreover, imaging parameters of non-contrast CT value and SUVmax could be useful in predicting a non-predominant but high-grade histologic pattern.