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Corresponding author. Address for correspondence: Chang Chen, MD, Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, 200443, People’s Republic of China
The International Association for the Study of Lung Cancer proposed a novel grading system of invasive pulmonary adenocarcinoma (IPA), but the application of this grading system and its genotypic characterization in the real diagnostic scenario has never been reported.
Methods
We prospectively collected and analyzed the clinicopathological and genotypic features of a cohort of 9353 consecutive patients with resected IPA, including 7134 patients with detection of common driver mutation.
Results
In the entire cohort, 3 (0.3%) of lepidic, 1207 (19.0%) of acinar, and 126 (23.6%) of papillary predominant IPAs were diagnosed as grade 3. In chronological order, an evident downtrend of the proportion of grade 2 was observed in chronological order. Conversely, the diagnostic ratio of grade 1 (8.0%–14.5%) and grade 3 (27.9%–32.3%) experienced a gradual rise. EGFR mutation was more frequently detected in grade 2 (77.5%) and grade 1 (69.7%) IPA than grade 3 (53.7%, p < 0.001), whereas the mutation rates of KRAS, BRAF, ALK, and ROS1 were higher in grade 3 IPA. More importantly, the rate of EGFR mutation gradually fell as the proportion of high-grade components increased, to 24.3% in IPA with more than 90% high-grade components.
Conclusions
The grading system for IPA could be applied to stratify patients with different clinicopathological and genotypic features in a real diagnostic scenario.
The Pathology Committee of the International Association for the Study of Lung Cancer recently proposed a novel grading system for invasive pulmonary adenocarcinoma (IPA).
A grading system for invasive pulmonary adenocarcinoma: a proposal from the International Association for the Study of Lung Cancer pathology committee.
Prognostic and predictive value of the newly proposed grading system of invasive pulmonary adenocarcinoma in Chinese patients: a retrospective multicohort study.
Validation of the novel International Association for the Study of Lung Cancer grading system for invasive pulmonary adenocarcinoma and association with common driver mutations.
The novel grading system characterized unique clinicopathologic and prognostic subsets of IPA; however, huge heterogeneity emerged in the genotype representations of IPA with different histologic grades among previous studies (Supplementary Table 1),
Prognostic and predictive value of the newly proposed grading system of invasive pulmonary adenocarcinoma in Chinese patients: a retrospective multicohort study.
Validation of the novel International Association for the Study of Lung Cancer grading system for invasive pulmonary adenocarcinoma and association with common driver mutations.
even in Asian populations. Thus, further analysis with a larger sample is warranted. More importantly, this novel grading system was initially intended to serve as a handy and robust benchmark in routine histopathologic diagnosis and further assist patient management.
However, as existing publications have all been on the basis of retrospective reevaluations of specimens, the utility of applying this novel system in a real diagnostic scenario remains unclear. Therefore, in this study, we aim to determine the clinicopathological and genotypic characterizations of different histologic grades on the basis of the postoperative routine pathologic reports of 9353 consecutive patients with resected IPA.
Materials and Methods
Patients
This study was approved by the institutional review board at Shanghai Pulmonary Hospital and informed consent was waived. Our hospital started applying the novel grading system in September 2020. This study was conducted from September 2020 to March 2022 in real diagnostic scenarios. When the postoperative pathologic evaluations for patients were completed, we reviewed their baseline data for eligibility and further prospectively collected the clinical and histologic data of eligible patients. The inclusion criterion was patients with surgically resected IPAs. Those meeting one of the following criteria were excluded: multiple lesions, mucinous adenocarcinoma and variants, and receiving neoadjuvant therapy. Ultimately, 9353 patients were included.
The primary aim of this study is to investigate the application of the grading system in a real diagnostic scenario and its diagnostic shift in different study periods. In addition, to determine the genotypic characterization among IPAs with different histologic grades, we further excluded 2219 patients without gene data to generate a genetic cohort with 7134 patients. The study flowchart is illustrated in Figure 1.
Histologic analyses were performed using resected lung specimens for all cases. In terms of histologic grade, lung adenocarcinoma was classified according to the International Association for the Study of Lung Cancer’s newly proposed grading system.
A grading system for invasive pulmonary adenocarcinoma: a proposal from the International Association for the Study of Lung Cancer pathology committee.
The percentages of lepidic, acinar, papillary, solid, micropapillary, and complex glandular patterns were recorded in 5% increments. Grade 1 refers to lepidic predominant tumor, containing less than 20% high-grade patterns (micropapillary, solid, complex glandular patterns); grade 2 refers to acinar- or papillary-predominant tumor, containing less than 20% high-grade patterns; and grade 3 refers to any tumor containing greater than or equal to 20% high-grade patterns.
Statistical Analysis
Categoric variables were presented as frequency and proportions and compared using the chi-square test. Differences were considered significant when p value less than 0.05. All statistical analyses were performed using the Statistical Package for the Social Sciences (version 23.0, IBM SPSS Statistics).
Results
Patient Characteristics
The baseline characteristics of the entire cohort are summarized in Table 1. There were 5317 (56.8%) women and 5813 (62.2%) patients with age younger than 65 years old. Regarding the pathologic staging, early-stage tumors accounted for the largest proportion (T1 stage: 77.0%, n = 7204; N0 stage: 89.5%, n = 8373; stage IA: 73.4%, n = 6868). Furthermore, compared with other grades, the following were observed: (1) there were more male patients with grade 3 tumors (54.6%); (2) there was a larger proportion of positive programmed death-ligand 1 (PD-L1) expression (32.1%) found; and (3) patients were in a more advanced pathologic stage (T4 stage: 0.6%; N2 stage: 21.2%; stage Ⅲ: 22.4%). With respect to histologic grade, acinar (67.8%, n = 6346) was the most common predominant pattern, and grade 1, grade 2, and grade 3 were diagnosed in 11.2% (n = 1042), 59.3% (n = 5548), and 29.5% (n = 2763) patients, respectively.
Table 1Baseline Characteristic of the Entire Cohort
Characteristics
Entire
Grade 1
Grade 2
Grade 3
p Value
(N = 9353)
(n = 1042)
(n = 5548)
(n = 2763)
Sex, n (%)
<0.001
Female
5317 (56.8)
605 (58.1)
3457 (62.3)
1255 (45.4)
Male
4036 (43.2)
437 (41.9)
2091 (37.7)
1508 (54.6)
Age, n (%)
<0.001
<65
5813 (62.2)
592 (56.8)
3575 (64.4)
1646 (59.6)
≥65
3540 (37.8)
450 (43.2)
1973 (35.6)
1117 (40.4)
Pathologic features, n (%)
STAS
2402 (25.7)
5 (0.5)
537 (9.7)
1860 (67.3)
<0.001
VPI
1198 (12.8)
1 (0.1)
216 (3.9)
981 (35.5)
<0.001
LVI
1050 (11.2)
0 (0.0)
88 (1.6)
962 (34.8)
<0.001
Predominant pattern, n (%)
<0.001
Lepidic
1045 (11.2)
1042 (100.0)
0 (0.0)
3 (0.1)
Acinar
6346 (67.8)
0 (0.0)
5139 (92.6)
1207 (43.7)
Papillary
535 (5.7)
0 (0.0)
409 (7.4)
126 (4.6)
Micropapillary
330 (3.5)
0 (0.0)
0 (0.0)
330 (11.9)
Solid
305 (3.3)
0 (0.0)
0 (0.0)
305 (11.0)
Complex glands
792 (8.5)
0 (0.0)
0 (0.0)
792 (28.7)
PD-L1, n (%)
<0.001
Without data
2679 (28.6)
496 (47.6)
1935 (34.9)
248 (9.0)
Positive
983/6674 (14.7)
6/546 (1.1)
169/3613 (4.7)
808/2515 (32.1)
Genetic alternation, n (%)
Without genetic data
2219 (23.7)
366 (35.1)
1279 (23.1)
574 (20.8)
EGFR
4955/7134 (69.5)
471/676 (69.7)
3309/4269 (77.5)
1175/2189 (53.7)
<0.001
KRAS
368/7134 (5.2)
46/676 (6.8)
149/4269 (3.5)
173/2189 (7.9)
<0.001
BRAF
53/7134 (0.7)
3/676 (0.4)
22/4269 (0.5)
28/2189 (1.3)
0.002
ALK
245/7134 (3.4)
2/676 (0.3)
72/4269 (1.7)
171/2189 (7.8)
<0.001
ROS1
81/7134 (1.1)
2/676 (0.3)
34/4269 (0.8)
45/2189 (2.1)
<0.001
T stage, n (%)
<0.001
1
7204 (77.0)
969 (93.0)
4906 (88.4)
1329 (48.1)
2
2007 (21.5)
71 (6.8)
622 (11.2)
1314 (47.6)
3
118 (1.3)
2 (0.2)
13 (0.2)
103 (3.7)
4
24 (0.3)
0 (0.0)
7 (0.1)
17 (0.6)
N stage, n (%)
<0.001
0
8373 (89.5)
1041 (99.9)
5470 (98.6)
1862 (67.4)
1
355 (3.8)
0 (0.0)
40 (0.7)
315 (11.4)
2
625 (6.7)
1 (0.1)
38 (0.7)
586 (21.2)
TNM stage, n (%)
< 0.001
ⅠA
6868 (73.4)
969 (93.0)
4867 (87.7)
1032 (37.4)
ⅠB
1275 (13.6)
59 (5.7)
513 (9.2)
703 (25.4)
Ⅱ
545 (5.8)
13 (1.2)
122 (2.2)
410 (14.8)
Ⅲ
665 (7.1)
1 (0.1)
46 (0.8)
618 (22.4)
LVI, lymphovascular invasion; PD-L1, programmed cell death 1 ligand 1; STAS, tumor spread through air space; VPI, visceral pleural invasion.
A total of 13 pathologists were involved and divided into junior (<5 y of experiences in lung tumor diagnosis; pathologist A–E), senior (5–10 y of experiences in lung tumor diagnosis; pathologist F–I) and expert groups (>10 years of experiences in lung tumor diagnosis; pathologist J–M). Compared with the junior (25.4%) and senior (28.9%) groups, a markedly larger proportion of grade 3 was observed in the expert group (33.6%) (Fig. 2A). In addition, all included patients were equally divided into three periods in the order of the date of pathologic diagnosis. Therefore, period 1 (September 2020–March 2021) represented the phase when our hospital started applying the grading system and period 3 (October 2021–March 2022) represented the phase when we have accumulated adequate experience in grading after period 1 and period 2. As described in Figure 2B, an evident downtrend of the proportion of grade 2 was observed (64.1%–53.2%). In contrast, the diagnostic ratio of grade 1 (8.0%–14.5%) and grade 3 (27.9%–32.3%) experienced a gradual rise. Furthermore, the downtrend of grade 2 (67.5%–55.5%) and uptrends of grade 1 (9.5%–17.5%) and grade 3 (23.0%–27.0%) remained evident in the subgroup of junior pathologists (Fig. 2C).
Figure 2Histograms illustrating the application of the novel grading system and its genotypic characterization in a real diagnostic scenario. (A) Diagnostic heterogeneity among different pathologists. A total of 13 pathologists were involved in this study and were divided into junior, senior, and expert groups; (B) The proportions of histologic grades in different diagnostic periods. All included patients were equally divided into three periods in the order of the date of pathologic diagnosis. Therefore, the period 1 represented the phase when our hospital started applying the grading system and the period 3 represented the phase when we have accumulated adequate experiences of grading after the period 1 and period 2; (C) The proportions of histologic grades diagnosed by junior doctors in different periods; (D-H) The mutation rates of EGFR (D), KRAS (E), BRAF (F), ALK (G) and ROS1 (H) with high-grade patterns increased.
Genotypic Characterization in IPA With Different Grades
As detailed in Table 1, the overall mutation rates for EGFR, KRAS, BRAF, ALK, and ROS1 were 69.5%, 5.2%, 0.7%, 3.4%, and 1.1%, respectively. Grade 2 tumors were associated with the highest EGFR mutation rate (77.5%, 3309 of 4269); conversely, grade 3 tumors experienced the lowest EGFR mutation rate (53.7%, 1175 of 2189). EGFR mutation was identified in 69.7% (471 of 676) of grade 1 tumors in our cohort (n = 7134). For KRAS mutation, the highest mutation rate was observed grade 3 tumors (7.9%, 173 of 2189) whereas grade 2 tumors yielded the lowest mutation rate (3.5%, 149 of 4269); the mutation rate in grade 1 tumors was 6.8% (46 of 676). In addition, significant uptrends in the BRAF (grade 1: 0.4%; grade 2: 0.5%; grade 3: 1.3%), ALK (grade 1: 0.3%; grade 2: 1.7%; grade 3; 7.8%), and ROS1 (grade 1: 0.3%; grade 2: 0.8; grade 3; 2.1%) mutation rates were observed with worsening of tumor differentiation. The relationships between high-grade patterns and genotypes are illustrated in Figure 2D to H, which indicated that the EGFR mutation rate (77.0%–24.3%) gradually fell as the high-grade proportion increased. In addition, the KRAS (3.8%–11.6%), BRAF (0.4% to 1.3%), ALK (1.3%–17.0%), and ROS1 (0.5%–3.3%) mutation rates tended to exhibit an uptrend with a larger proportion of high-grade patterns.
Discussion
To the best of our knowledge, this study is the first to evaluate the clinicopathological and genotypic features of patients with different grade IPA in a real diagnostic scenario. We found that the proportion of grade 3 IPA was 29.5% in stage I-III and 21.6% in stage I patients. In addition, only 3 of 1045 lepidic predominant IPA were diagnosed as grade 3. Presences of micropapillary, solid, or complex glandular components were potential risk factors even in lepidic predominant IPA.
Prognostic significance of adenocarcinoma in situ, minimally invasive adenocarcinoma, and nonmucinous lepidic predominant invasive adenocarcinoma of the lung in patients with stage I disease.
having 20% to 30% high-grade patterns was associated with adverse prognosis in patients with lepidic predominant IPA. Thus, it was reasonable to reclassify the IPA with more than 20% high-grade components as grade 3 in this novel grading system.
Interestingly, a downtrend of the proportion of grade 2 was observed, whereas grade 1 and grade 3 found a gradual rise in different periods. We hypothesized that this increase reflected the improved proficiency of junior pathologists in applying this novel grading system. Overall, the junior pathologists in the current study yielded lower proportions of grade 1 and grade 3 than expert pathologists. However, in the subgroup analyses of diagnostic periods, the junior pathologists experienced gradually increasing diagnostic proportions of grade 1 and grade 3, which might imply that the improved recognitions of lepidic patterns and complex glandular patterns made the ratio of grade 1 and grade 3 relatively increased.
In this study, we also found that EGFR mutation was more frequently detected in grade 2 and grade 1 IPAs than in grade 3, whereas KRAS, BRAF, ALK, and ROS1 mutations were predominant in grade 3 tumors. These findings were similar to those of Fujikawa et al.
Validation of the novel International Association for the Study of Lung Cancer grading system for invasive pulmonary adenocarcinoma and association with common driver mutations.
in the People’s Republic of China. We previously reported that the lepidic predominant IPA was excessively reclassified to grade 3 IPA according to the new grading system in the study by Li et al.,
which might explain the high rate of EGFR mutation in their grade 3 tumors.
The novel grading system also harbors the potential in optimizing adjuvant therapy for IPAs. Our previous study found that IPAs classified as grade 3 could benefit from adjuvant chemotherapy,
Prognostic and predictive value of the newly proposed grading system of invasive pulmonary adenocarcinoma in Chinese patients: a retrospective multicohort study.
Adjuvant atezolizumab after adjuvant chemotherapy in resected stage IB-IIIA non-small-cell lung cancer (IMpower010): a randomized, multicentre, open-label, phase 3 trial.
Our study found that grade 3 IPA had a lower EGFR mutation rate and higher PD-L1 expression than grades 1 and 2, implying that grade 1 IPAs might benefit from adjuvant targeted therapy whereas adjuvant chemotherapy and immunotherapy might be better choices for grade 3 IPAs. We hope future clinical trials focusing on this point could validate our speculations.
In conclusion, the novel grading system could be applied in routine pathological diagnosis and stratifying patients with different clinical features.
CRediT Authorship Contribution Statement
Yunlang She: Conceptualization, Methodology, Software, Data curation, Writing- Original draft preparation.
Yifan Zhong: Conceptualization, Methodology, Software, Data curation, Writing- Original draft preparation.
Likun Hou: Conceptualization, Methodology, Software, Data curation, Writing- Original draft preparation, Supervision.
Shennan Zhao: Visualization, Investigation.
Liping Zhang: Supervision.
Dong Xie: Software, Validation.
Yuming Zhu: Software, Validation.
Chunyan Wu: Software, Validation.
Chang Chen: Conceptualization, Supervision, Writing- reviewing and editing.
Acknowledgments
This study was supported by National Natural Science Foundation of China (91959126, 8210071009) and Shanghai Hospital Development Center (SHDC2020CR3047B). The authors thank all pathologists for their excellent work in our hospital.
A grading system for invasive pulmonary adenocarcinoma: a proposal from the International Association for the Study of Lung Cancer pathology committee.
Prognostic and predictive value of the newly proposed grading system of invasive pulmonary adenocarcinoma in Chinese patients: a retrospective multicohort study.
Validation of the novel International Association for the Study of Lung Cancer grading system for invasive pulmonary adenocarcinoma and association with common driver mutations.
Prognostic significance of adenocarcinoma in situ, minimally invasive adenocarcinoma, and nonmucinous lepidic predominant invasive adenocarcinoma of the lung in patients with stage I disease.
Adjuvant atezolizumab after adjuvant chemotherapy in resected stage IB-IIIA non-small-cell lung cancer (IMpower010): a randomized, multicentre, open-label, phase 3 trial.
Drs. She and Zhong contributed equally to this work.
Drs. Hou and Chen are co-senior authors.
Disclosure: The authors declare no conflict of interest.
Cite this article as: She Y, Zhong Y, Hou L, et al. Application of the novel grading system of invasive pulmonary adenocarcinoma in a real diagnostic scenario: a brief report of 9353 cases. JTO Clin Res Rep. 2023;4:100465.
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