Reproducibility of histopathological subtypes and invasion in pulmonary adenocarcinoma. An international interobserver study

Abstract

Histological subtyping of pulmonary adenocarcinoma has recently been updated based on predominant pattern, but data on reproducibility are required for validation. This study first assesses reproducibility in subtyping adenocarcinomas and then assesses further the distinction between invasive and non-invasive (wholly lepidic) pattern of adenocarcinoma, among an international group of pulmonary pathologists. Two ring studies were performed using a micro-photographic image-based method, evaluating selected images of lung adenocarcinoma histologic patterns. In the first study, 26 pathologists reviewed representative images of typical and 'difficult' histologic patterns. A total number of scores for the typical patterns combined (n=94) and the difficult cases (n=21) were 2444 and 546, respectively. The mean kappa score (±s.d.) for the five typical patterns combined and for difficult cases were 0.77±0.07 and 0.38±0.14, respectively. Although 70% of the observers identified 12-65% of typical images as single pattern, highest for solid and least for micropapillary, recognizing the predominant pattern was achieved in 92-100%, of the images except for micropapillary pattern (62%). For the second study on invasion, identified as a key problem area from the first study, 28 pathologists submitted and reviewed 64 images representing typical as well as 'difficult' examples. The kappa for typical and difficult cases was 0.55±0.06 and 0.08±0.02, respectively, with consistent subdivision by the same pathologists into invasive and non-invasive categories, due to differing interpretation of terminology defining invasion. In pulmonary adenocarcinomas with classic morphology, which comprise the majority of cases, there is good reproducibility in identifying a predominant pattern and fair reproducibility distinguishing invasive from in-situ (wholly lepidic) patterns. However, more precise definitions and better education on interpretation of existing terminology are required to improve recognition of purely in-situ disease, this being an area of increasing importance.

Figure 1

Distribution of kappa scores between all pairs of pathologists for typical cases (a) and difficult (b) cases.

Figure 2

Box plot distribution of the dominant pattern score (1 = perfect agreement, 0 = no agreement) is shown for the ‘typical’ patterns according to the submitting pathologist for each of the five histologic subtypes: acinar, lepidic, microp(apillary), papillary and solid. Note that box represents interquartile range (IQR), line in the box is median, wiskers 1.5× IQR and occasional outliers (o,*) are numbered cases.

Figure 3

Examples of unanimous lepidic (a), acinar (b), micropapillary (c), papillary (d) and solid (e) pattern are shown, as well as examples of more than one pattern with percent of pathologists recording that pattern (with judgement on second image, f–j). Patterns scored by >10% of the pathologists are mentioned. f: overlap solid (96%), acinar (93%), micropapillary (15%), papillary (15%); g: overlap micropapillary (96%), papillary (11%); h: overlap AIS (92%), acinar (78%); i: overlap AIS (78%), papillary (54%); j: overlap AIS (66%), micropapillary (42%), papillary (30%) and acinar (27%).

Figure 3

Examples of unanimous lepidic (a), acinar (b), micropapillary (c), papillary (d) and solid (e) pattern are shown, as well as examples of more than one pattern with percent of pathologists recording that pattern (with judgement on second image, f–j). Patterns scored by >10% of the pathologists are mentioned. f: overlap solid (96%), acinar (93%), micropapillary (15%), papillary (15%); g: overlap micropapillary (96%), papillary (11%); h: overlap AIS (92%), acinar (78%); i: overlap AIS (78%), papillary (54%); j: overlap AIS (66%), micropapillary (42%), papillary (30%) and acinar (27%).

Figure 4

Examples of unanimous absence of invasion (a) and definite invasion (b) are shown, as well examples of cases (judgement on second image) with split opinion (c–h) having at least nine pathologists for invasion (‘invasion yes ≥ 9’) and a different group of at least 9 for non-invasion (‘NO ≥ 9’). In two cases images of another slide (same case) was available as well (e3, e4 elastic stain and f3, f4 elastic stains).

Figure 4

Examples of unanimous absence of invasion (a) and definite invasion (b) are shown, as well examples of cases (judgement on second image) with split opinion (c–h) having at least nine pathologists for invasion (‘invasion yes ≥ 9’) and a different group of at least 9 for non-invasion (‘NO ≥ 9’). In two cases images of another slide (same case) was available as well (e3, e4 elastic stain and f3, f4 elastic stains).