Accuracy and Reproducibility of Intraoperative Assessment on Tumor Spread Through Air Spaces in Stage 1 Lung Adenocarcinomas

Abstract

Introduction: Tumor spread through air spaces (STAS) is associated with worse prognosis in early-stage lung adenocarcinomas, particularly in sublobar resection. Intraoperative consultation for STAS has been advocated to guide surgical management. However, data on accuracy and reproducibility of intraoperative assessment of STAS remain limited. We evaluated diagnostic yield, interobserver agreement (IOA), and intraobserver agreement (ITA) for STAS detection on frozen section (FS).

Methods: A panel of three pathologists evaluated stage 1 lung adenocarcinomas (n = 100) for the presence or absence of STAS and artifacts as reference. Five pulmonary pathologists independently reviewed all cases in two rounds, detecting STAS and artifacts in FS and the corresponding FS permanent and non-FS permanent, with a consensus conference between rounds.

Results: The FS had low sensitivity (44%), high specificity (91%), relatively high accuracy (71%), and overall area under the receiver operating characteristic curve of 0.67 for detecting STAS. The average ITA was moderate for both STAS (κ_mean: 0.598) and artifact (κ_mean: 0.402) detection on FS. IOA was moderate for STAS (κ_round-1: 0.453; κ_round-2: 0.506) and fair for artifact (κ_round-1: 0.300; κ_round-2: 0.204) detection on FS. IOA for STAS improved in FS permanent and non-FS permanent, whereas ITA was similar across section types. On multivariable logistic regression, the only significant predictor of diagnostic discordance was the presence of artifacts.

Conclusions: FS is highly specific but not sensitive for STAS detection in stage 1 lung adenocarcinomas. IOA on STAS is moderate in FS and improved only marginally after a consensus conference, raising concerns regarding global implementation of intraoperative assessment of STAS and warranting more precise criteria for STAS and artifacts.

Keywords: Diagnostic yield; Frozen section; Lung adenocarcinoma; Reproducibility; Tumor spread through air spaces (STAS).

Figure 1.. Comparison of STAS and Artifact on Frozen Section and Frozen Section Permanent Slides.

Examples highlighting the morphologic spectrum of STAS and artifact on Frozen Section (FS) and FS permanent (FSP) are shown, including foci considered to be equivocal for STAS. A FS showing a cohesive small tumor cluster spatially distant from the edge of the tumor (A) is confirmed on FSP (B) to be STAS in micropapillary clusters and small solid nests. Alternatively, FS showing an irregular tumor cluster with jagged and sharp contours (C) is confirmed to be artifact on FSP (D), which further highlights the irregular contours and dyshesive morphology. A third FS (E) shows a single focus of tumor that appears to be micropapillary or solid STAS on the right (arrow), but also a more jagged focus of tumor on the left (arrowhead), which is highlighted on higher power in the inset and in isolation; this is considered to be equivocal for STAS on FS. Examination of the corresponding FSP (F) confirms the micropapillary STAS (arrow), but also reveals that the tumor cluster determined to be equivocal is likely a mixture of true micropapillary STAS and dyshesive irregular artifact that is intermixed (arrowhead and inset). Similarly, a fourth FS (G) shows a focus of linear epithelial strips definitive for artifact on the right (arrowhead), along with an indeterminate cluster composed of linear strips and small epithelial tufts (arrow and inset). Examination of the corresponding FSP (H) confirms that the focus determined to be equivocal on FS as definitive for STAS (arrow and inset).

Figure 2.. Receiver-Operating-Characteristic (ROC) Curves of Frozen section for STAS detection.

Diagnostic performance was determined by comparing the final integrated diagnosis based on review of all histology slides by the panel of there pathologists with: (A) the diagnoses obtained in Frozen section slides by the panel; (B) the individual diagnoses obtained by each of the 5 observers in Frozen section slides in the first round, and (C) those in the second round of evaluation.

Figure 3.. Variability in diagnosis of STAS across observers in Frozen section.

(A) The number of observers identifying STAS for each case is presented for round 1 (R1), and round 2 (R2). The green bar represents the STAS calls in the round 1; the orange bars represent the STAS calls in the round 2. (B) Inter-observer concordance rate for each case is presented in the heat map for both rounds. Each column represents an individual case. The bottom row represents R1; the top row R2. The scale bar below (thin rectangle) indicates the level of inter-observer concordance. Red denotes full inter-observer concordance (100%); green, poor inter-observer concordance (60%) among the five observers. (C) Differences in inter-observer concordance rates between both rounds of evaluation (∆R1-R2) are presented in the heat map. Each column represents an individual case. The scale bar below (thin rectangle) indicates the degree of difference in inter-observer concordance between both rounds of evaluation. Yellow denotes a higher difference in concordance between rounds (∆R1-R2: 40%); blue, no difference (∆R1-R2: 0%). Cases are displayed in panels B and C to match the same sequence in which they are displayed in panel A.