经气腔内播散（STAS）的标准化评估与临床应用价值

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Spread Through Air Spaces (STAS): Inter-responder Agreement and Comparison between Pulmonary and General Pathologists

Michelle Garlin Politis, Anjali Saqi, Mari Mino-Kenudson

Modern Pathology 20 August 2024

Spread through air spaces (STAS), an important prognostic indicator included in the 2015 WHO classification, is defined as micropapillary, solid and/or single tumor cell clusters beyond the edge of the main mass and distinct from processing artifacts. This study aimed to assess inter-responder agreement on current STAS criteria vs artifacts, identify discrepancies, and compare responses between pulmonary and general pathologists. A multiple-choice online questionnaire illustrating multiple criteria for STAS vs artifacts was available internationally for 6 days to Pulmonary Pathology Society members, thoracic pathology course attendees and International Association for the Study of Lung Cancer pathology committee members. Additional four questions gathered demographic and practice setting information. 136 unique responses were analyzed. The majority were from North America and Europe (42.6 and 30.2%), practicing pulmonary pathology (70.6%) in academia (64.7%), and with >20 years of experience (31.6%). Excluding trainees, the greatest overall agreement was in defining solid and micropapillary tumor clusters of STAS located > 3 alveolar spaces from the main tumor edge (91.5%) and recognizing strips of ciliated cells as artifacts (97.7%). Lesser agreement on STAS was evident when tumor cell clusters were immediately adjacent to the tumor edge, a single tumor cell cluster was present at the tissue edge, tumor cell clusters were jagged-edged, or tumor cell clusters were admixed with ciliated cell strips (artifacts). There was no significant difference in agreements on STAS for multiple criteria between pulmonary vs. general pathologists. Significant inter-responder agreement on STAS vs. artifacts was achieved only for a few criteria. To improve reproducibility of STAS vs artifacts, areas of lesser agreement require further clarification. 

经气腔播散（STAS）是2015年WHO分类中包含的重要预后指标，被定义为超出主肿块边缘且与人工伪影不同的微乳头状、实体和/或单个肿瘤细胞团。这项研究旨在评估病理医师之间对当前STAS标准与伪影的一致性，识别差异，并比较肺部病理学家和普通病理学家之间的反应。一份说明STAS与伪影多个标准的多项选择在线调查问卷已在国际范围内提供给肺病理学会成员、胸部病理课程参与者和国际肺癌病理研究协会委员会成员，为期6天。另外四个问题收集了人口统计学和实践设置信息。分析了136个独特的回答。大多数来自北美和欧洲（42.6%和30.2%），在学术界（64.7%）从事肺部病理学（70.6%），并且拥有超过20年的经验（31.6%）。不包括学员，总体一致性最高的是定义距离肿瘤主要边缘> 3个肺泡空间的STAS实体和微乳头状肿瘤集群（91.5%），并将绒毛细胞条识别为伪影（97.7%）。当肿瘤细胞团紧邻肿瘤边缘、组织边缘存在单个肿瘤细胞团、肿瘤细胞团边缘呈锯齿状或肿瘤细胞团与有绒毛的细胞条（伪影）混合时，STAS的一致性明显较差。肺部病理学家与普通病理学家对STAS多个标准的一致性没有显著差异。仅针对少数标准，响应者之间就STAS与伪影达成了重要一致。为了提高STAS与伪影的可重复性，一致性较差的领域需要进一步澄清。

Prediction of spread through air spaces (STAS) by intraoperative frozen section for patients with cT1N0M0 invasive lung adenocarcinoma: a multi-center observational study (ECTOP-1016) 

Hang Cao, MD*1,2,3, Qiang Zheng, MD*3,4, Chaoqiang Deng, MD*1,2,3, Zichen Fu, MD*1,2,3, Xuxia Shen, MD3,4, Yan Jin, MD3,4, Yongguo Yang, MD5, Bin Qian, MD6, Chunyan Yuan, MD7, Weihua Wang, MD8, Lei Zhang, MD9, Qingping Song, MD10, Shuying Zuo, MD11, Junjie Ma, MD12, Shuqing You, MD13, Senzhong Zheng, MD14, Qingli Gao, MD15, Guangli Su, MD16, Yang Zhang, MD#1,2,3, Haiquan Chen, MD, PhD#1,2,3, and Yuan Li, MD, PhD#3,4 

Annals of Surgery 06 Sep 2024

Objective: To investigate the value of intraoperative assessment of spread through air spaces (STAS) on frozen sections (FS) in peripheral small-sized lung adenocarcinoma. 

目的：探讨冷冻切片（FS）上空气空间扩散（STAS）在周围型小肺腺癌中的价值。

Background: Surgical decision-making based on FS diagnosis of STAS may be useful to prevent local control failure after sublobar resection. 

背景：基于STAS FS诊断的手术决策可能有助于防止亚肺叶切除术后的局部控制失败。

Methods: We conducted a multicenter prospective observational study of consecutive patients with cT1N0M0 invasive lung adenocarcinoma to evaluate the accuracy of FS for the intraoperative detection of STAS. The final pathology (FP) diagnosis of STAS was based on corresponding permanent paraffin sections. 

方法：我们对连续的cT1N0 M0侵袭性肺腺癌患者进行了一项多中心前瞻性观察研究，以评估FS在手术中检测STAS的准确性。STAS的最终病理学（FP）诊断基于相应的永久性蜡块切片。

Results: This study included 878 patients with cT1N0M0 invasive lung adenocarcinoma. A total of 833 cases (95%) were assessable for STAS on FS. 26.4% of the cases evaluated positive for STAS on FP, whereas 18.2% on FS. The accuracy, sensitivity, and specificity of FS diagnosis of STAS were 85.1%, 56.4%, and 95.4%, respectively, with moderate agreement (κ=0.575). Inter-observer agreement was substantial (κ=0.756) among the three pathologists. Subgroup analysis based on tumor size or consolidation-to-tumor ratio all showed moderate agreement for concordance. After rigorous reassessment of false-positive cases, the presence of artifacts may be the main cause of interpretation errors. Additionally, true positive cases showed more high-grade histological patterns and more advanced p-TNM stages than false negative cases. 

结果：该研究纳入了878名cT 1 N 0 M0侵袭性肺腺癌患者。共有833例病例（95%）可通过FS进行STAS评估。FP组中26.4%的病例STAS呈阳性，FS组为18.2%。FS诊断STAS的准确性、敏感性和特异性分别为85.1%、56.4%和95.4%，一致性中等（k =0.575）。三位病理学家之间的观察员间一致性很大（k =0.756）。基于肿瘤大小或实变与肿瘤比率的亚组分析均显示出一致性中等一致性。经过对假阳性病例的严格重新评估，伪影的存在可能是导致解读错误的主要原因。此外，真阳性病例比假阴性病例表现出更多高级别的组织学模式和更先进的p-TNI分期。

Conclusions: This is the largest prospective observational study to evaluate STAS on FS in patients with cT1N0M0 invasive lung adenocarcinoma. FS is highly specific with moderate agreement, but is not sensitive for STAS detection. While appropriately reporting STAS on FS may provide surgeons with valuable information for intraoperative decision-making, better approaches are needed. 

结论：这是在cT1 N0 M0侵袭性肺腺癌患者中评估FS的最大规模前瞻性观察性研究。FS具有高度特异性，一致性中等，但对STAS检测不敏感。虽然在FS上适当报告STAS可以为外科医生提供手术中决策的宝贵信息，但需要更好的方法。

Paper 1目录

1. INTRODUCTION

2. Materials and Methods (Figures 1 and 2)

3. Results  (Supplementary Table 1)(Supplementary Figure 1)(Table 1 and Supplementary Tables 2-4)(Figure 3)

    3.1 Architecture (Table 1)(Supplementary Tables 2 and 4)(Supplementary Table 3)

    3.2 Distribution (Figure 1)

    3.3 Artifacts (Table 1, Supplementary Tables 2-4)

    3.4 Nuances (Table 1, Supplementary Tables 2-4)

    3.5 Distance (Figure 1)

    3.6 Intra-responder Agreement (Figure 2)

4. Discussion (Figure 3)

    4.1 STAS versus Artifact: Excellent, Good, Fair, and Poor Agreement with WHO Definition and Intra-responder Agreement 

    4.2 STAS versus Artifact: Parameters Without Defined WHO Criteria 

    4.3 STAS in the Background of Artifacts  

    4.4 Study Limitations and Advantages 

Paper 2目录

1. INTRODUCTION

2. Material and methods 

    2.1 Study Population (Supplemental Figure 1)

    2.2 Histological evaluation and inter-observer agreemen

    2.3 Statistical analysis

3. Results 

    3.1 Patient demographics (Supplemental Table 1)

    3.2 STAS diagnosis  (Supplemental Table 1)

    3.3 Accuracy of FS for identifying STAS (Table 1-2)

    3.4 Inter-observer agreement for STAS on FS diagnosis (Supplemental Table 2)

    3.5 Reasons for Misdiagnosis by Frozen Section (Supplemental Table 3) (Supplemental Figure 2)(Supplemental Table 4) 

    3.6 Integrating FS with radiological or histological features (Supplemental Table 5-7) (Supplemental Figure 3)(Supplemental Table 8)

4. Comment

— Paper1图表汇总—

2. Materials and Methods

Figures 1 Representative figures from questionnaire and examples of H&E equivalent 

Representative images from questionnaire and H&E. Continuous tracing of solid tumor cell clusters (A) and micropapillary pattern (B). C) random tracing of tumor cell clusters. D) Single tumor cell cluster at the edge of the tissue section. E) Single tumor cell cluster with ragged/jagged edges at the edge of the tissue section. F) Ratio 5:5 tumor cell clusters and strips of ciliated cells. The histologic image represents strips of ciliated cells with reactive changes. G) Distance separated from the edge of main tumor (1: no alveolar space, 2: one alveolar space, 3: >3 alveolar spaces). Note: The H&E images serve as equivalents to the illustrations but were not included in the questionnaire. 

Figures 2 Questionnaire with illustrations 

Fourteen multiple-choice questions evaluating STAS (versus not) in the five scenarios with corresponding illustrations and % responses of all participants except trainees. 

3. Results

Supplementary Table 1. All Participants’ Demographics

*Total includes 6 trainees representing 4 continents: Asia, Europe, North America, South America.

Supplementary Figure 1

Table 1 STAS: Pulmonary vs. General Pathology Practice* 

Supplementary Tables 2  STAS Evaluation: Academic vs. Non-academic Practice*

Supplementary Tables 3. STAS: by continent of practice*

Supplementary Tables 4. STAS: by Years of Practice*

Figure 3 Summary of WHO criteria relevant to the survey with features of agreement and disagreement among participants  

The left-side-column represents the criteria of STAS or artifacts according to WHO 2021, which were included in the questionnaire. 

The two middle columns show the responses by all survey participants except trainees, and the right-side column represents the overall agreement with WHO criteria among the participants.  The agreements were categorized as excellent (>75%), lesser (40-74%) including fair (40-59%) and good (60-74%), and poor (<40%) based on previously applied ranges. Of note, there was no poor agreement (<40%) on any features among participants. Agreement of survey participants correlated variably with the WHO criteria. 

— Paper2图表汇总—

    2.1 Study Population

Supplemental Figure 1 Flowchart of the prospective study.

ADC, adenocarcinoma; AIS, adenocarcinoma in situ; MIA, minimally invasive adenocarcinoma; FS, frozen section; STAS, spread through air space.

    2.2 Histological evaluation and inter-observer agreemen

    2.3 Statistical analysis

3. Results 

    3.1 Patient demographics

Supplemental Table 1 Clinicopathological features in tumors with and without tumor spread through air spaces (STAS)

    3.2 STAS diagnosis

    3.3 Accuracy of FS for identifying STAS

Table 1. Diagnostic performance of frozen section for detection of STAS compared to final pathology 

Table 2 Diagnostic performance of frozen section for detection of STAS stratified by radiologic appearance 

    3.4 Inter-observer agreement for STAS on FS diagnosis 

Supplemental Table 2. Interobserver and intra-observer agreement for STAS on frozen section diagnosis

    3.5 Reasons for Misdiagnosis by Frozen Section 

Supplemental Table 3. Factors contributing to the interpretation errors of false positive cases

Supplemental Figure 2. Radiological features of discrepant and consistent cases.

False negative and true positive cases (A). False positive and true negative cases (B). CTR, consolidation-to-tumor ratio.

Supplemental Table 4. Characteristics of discrepant cases between frozen section and final pathology.

    3.6 Integrating FS with radiological or histological features

Supplemental Table 5 Univariable logistic analysis of selected factors for predicting STAS

Supplemental Table 6 Multivariable logistic analysis results in four models

Supplemental Table 7 Multicollinearity of the predictors

Supplemental Figure 3 ROC curves of four models for predicting STAS in lung adenocarcinoma in this study.

ROC, receiver operating characteristic; STAS, spread through air space; AUC, area under the curve; TPR, true positive rate; FPR, false positive rate.

Supplemental Table 8 Diagnostic performance of four models for detection of STAS

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