The cribriform pattern identifies a subset of acinar predominant tumors with poor prognosis in patients with stage I lung adenocarcinoma: a conceptual proposal to classify cribriform predominant tumors as a distinct histologic subtype

Abstract

The 2011 International Association for the Study of Lung Cancer (IASLC)/American Thoracic Society (ATS)/European Respiratory Society (ERS) lung adenocarcinoma classification emphasizes the prognostic significance of histologic subtypes. However, one limitation of this classification is that the highest percentage of patients (∼40%) is classified as acinar predominant tumors, and these patients display a spectrum of favorable and unfavorable clinical behaviors. We investigated whether the cribriform pattern can further stratify prognosis by histologic subtype. Tumor slides from 1038 patients with stage I lung adenocarcinoma (1995-2009) were reviewed. Tumors were classified according to the IASLC/ATS/ERS classification. The percentage of cribriform pattern was recorded, and the cribriform predominant subtype was considered as a subtype for analysis. The log-rank test was used to analyze the association between histologic variables and recurrence-free probability. The 5-year recurrence-free probability for patients with cribriform predominant tumors (n=46) was 70%. The recurrence-free probability for patients with cribriform predominant tumors was significantly lower than that for patients with acinar (5-year recurrence-free probability, 87%; P=0.002) or papillary predominant tumors (83%; P=0.020) but was comparable to that for patients with micropapillary (P=0.34) or solid predominant tumors (P=0.56). The recurrence-free probability for patients with ≥10% cribriform pattern tumors (n=214) was significantly lower (5-year recurrence-free probability, 73%) than that for patients with <10% cribriform pattern tumors (n=824; 84%; P<0.001). In multivariate analysis, patients with acinar predominant tumors with ≥10% cribriform pattern remained at significantly increased risk of recurrence compared with those with <10% cribriform pattern (P=0.042). Cribriform predominant tumors should be considered a distinct subtype with a high risk of recurrence, and presence (≥10%) of the cribriform pattern is an independent predictor of recurrence, identifying a poor prognostic subset of acinar predominant tumors. Our findings highlight the important prognostic value of comprehensive histologic subtyping and recording the percentage of each histologic pattern, according to the IASLC/ATS/ERS classification with the addition of the cribriform subtype.

Figure 1. Cribriform pattern in lung adenocarcinoma

(A) Invasive tumor nests with poorly-formed, small to intermediate-sized glandular spaces lacking intervening stroma. (B) Invasive fused tumor glands of intermediate-sized glandular spaces with extracellular mucin, lacking intervening stroma or having very thin stroma in limited areas between glandular spaces. (C) Invasive tumor nests with poorly-formed, intermediate-sized glandular spaces with back-to-back formations. (D) Invasive tumor nests with a few poorly-formed, small-sized glandular spaces with “cookie-cutter” patterns.

Figure 2. Acinar pattern in lung adenocarcinoma

(A) Simple tumor glands of tumor cells with mild nuclear atypia and desmoplastic stroma. (B) Simple tumor glands of tumor cells with moderate nuclear atypia. (C) Large, simple tumor glands with clear cytoplasm and intraglandular mucin. (D) Crowded glands mixed with simple and some complex glandular spaces but having intervening stroma in most areas between glandular spaces.

Figure 3. Solid pattern in lung adenocarcinoma

Solid pattern composed of invasive tumor nests without glandular spaces.

Figure 4. Recurrence-free probability by use of the cribriform pattern as a subtype, in addition to the IASLC/ATS/ERS classification

The 5-year recurrence-free probability for patients with cribriform predominant tumors (n=46) was 70%. Patients with adenocarcinoma in situ or minimally invasive adenocarcinoma tumors (n=36) experienced no recurrences (5-year recurrence-free probability, 100%). Patients with lepidic predominant tumors (n=106) had a low risk of recurrence (5-year recurrence-free probability, 92%). Patients with acinar (n=356) and papillary (n=242) predominant tumors had an intermediate risk of recurrence (5-year recurrence-free probability, 87% and 83%, respectively). Patients with micropapillary predominant (n=60), solid predominant (n=139), invasive mucinous (n=44), and colloid predominant (n=9) tumors had a high risk of recurrence (5-year recurrence-free probability, 62%, 70%, 77%, and 71%, respectively).

Figure 5. Recurrence- free probability, by cribriform pattern percentage, in all patients

(A) The recurrence-free probability for patients with 10%–39% cribriform pattern (n=171) was significantly lower (5-year recurrence-free probability, 76%) than that for patients with <10% cribriform pattern (n=824; 5-year recurrence-free probability, 84%; P=0.010). The recurrence-free probability for patients with ≥40% cribriform pattern (n=43) was lower (5-year recurrence-free probability, 65%) than that for patients with 10%–39% cribriform pattern, although the difference was not significant (P=0.096). (B) The recurrence-free probability for patients with ≥10% cribriform pattern (n=214) was significantly lower (5-year recurrence-free probability, 73%) than that for patients with <10% cribriform pattern (n=824; 5-year recurrence-free probability, 84%; P<0.001).

Figure 6. Recurrence-free probability, by cribriform pattern percentage, among patients with acinar predominant tumors

Among patients with acinar predominant tumors according to the original IASLC/ATS/ERS classification, the recurrence-free probability for patients with ≥10% cribriform pattern (n=124) was significantly lower (5-year recurrence-free probability, 74%) than that for patients with <10% cribriform pattern (n=287; 5-year recurrence-free probability, 90%; P<0.001).