Histologic features associated with metastatic potential in invasive adenocarcinomas of the lung

The International Association for the Study of Lung Cancer (IASLC) recently reclassified adenocarcinomas of the lung on the basis of histologic patterns. However, there is lack of consensus about a grading system for these tumors. We studied a series of invasive lung adenocarcinomas and correlated histologic features with lymph node and distant metastases. A series of invasive lung carcinomas resected over a 5-year period were retrospectively reviewed and classified by the IASLC system. The proportion of each histologic subtype was estimated at 5% increments, and cytologic features were blindly recorded and subsequently correlated with lymph node and distant metastases. The 125 tumors were classified on the basis of the predominant pattern as lepidic predominant (LPA) (n=9), acinar (n=71), solid (n=23), papillary (n=11), and mucinous (n=11). The acinar pattern was heterogeneous, in that a cribriform subgroup (n=34) was significantly more likely to demonstrate lymph node metastases compared with a tubular subgroup (n=37) and had a higher mitotic rate, rate of necrosis, vascular invasion, and prominent nucleoli. Mucinous tumors were LPA (n=3), tubular (n=4), and cribriform predominant (n=4). The rate of lymph node metastasis was greatest in the solid type (P=0.02). The rate of distant metastasis was greatest in the mucinous and solid groups (P<0.02). Mitotic activity (≥ 1/HPF), desmoplasia >20% of the tumor, prominent nucleoli, and vascular invasion, along with a solid growth pattern ≥ 20%, were independently associated with metastatic potential and considered poor prognostic histologic features. A 3-tiered grading system separated tumors into well differentiated (predominantly LPA, papillary, and tubular patterns), moderately differentiated (predominantly cribriform tumors), and poorly differentiated (≥ 20% solid growth pattern). Tumors in the well-differentiated group were elevated to moderately differentiated if there were poor prognostic histologic features. Using this system, there was a stepwise increase in the rate of lymph node metastasis (P<0.0001) and distant metastasis (P=0.0004) from well-differentiated, moderately differentiated, to poorly differentiated tumors, the rate being 40, 46, and 39, respectively. Application of the IASLC classification in this series resulted in a predominance of acinar adenocarcinomas. To stratify tumors into clinically relevant grades, grading by pattern (tubular, cribriform, solid), mitotic activity, and nuclear features is useful.