Second predominant subtype predicts outcomes of intermediatemalignant invasive lung adenocarcinoma

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1 European Journal of Cardio-Thoracic Surgery 51 (2017) doi: /ejcts/ezw318 Advance Access publication 6 October 2016 ORIGINAL ARTICLE Cite this article as: Ito M, Miyata Y, Yoshiya T, Tsutani Y, Mimura T, Murakami S et al. Second predominant subtype predicts outcomes of intermediate-malignant invasive lung adenocarcinoma. Eur J Cardiothorac Surg 2017; 51: Second predominant subtype predicts outcomes of intermediatemalignant invasive lung adenocarcinoma Masaoki Ito a, Yoshihiro Miyata a, Tomoharu Yoshiya a,yasuhirotsutani a,takeshimimura a,shujimurakami b, Hiroyuki Ito c, Haruhiko Nakayama c and Morihito Okada a, * a b c Department of Surgical Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan Department of Thoracic Oncology, Kanagawa Cancer Center, Yokohama, Japan Department of Thoracic Surgery, Kanagawa Cancer Center, Yokohama, Japan * Corresponding author. Department of Surgical Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Kasumi, Minami-ku, Hiroshima , Japan. Tel: ; fax: ; morihito1217@gmail.com (M. Okada). Received 29 May 2016; received in revised form 2 August 2016; accepted 3 August 2016 Abstract OBJECTIVES: Acinar predominant and papillary predominant invasive adenocarcinomas are likely to be classified as intermediatemalignant types. Although these two types of adenocarcinoma are distinguished morphologically, the differences between their malignant behaviours and prognoses are not clear. The aim of this study is to provide a prognostically relevant stratification of these similar subtypes based on pathological features. METHODS: We retrospectively reviewed 347 consecutive clinically N0M0 lung adenocarcinomas of <_3 cm in diameter that were resected between April 2006 and December 2010 at two institutes. Acinar and papillary predominant adenocarcinomas were classified into acinar/ papillary-lepidic type and acinar/papillary-non-lepidic type according to whether the second predominant component was a lepidic or invasive component. RESULTS: Fifty-four acinar and 59 papillary predominant adenocarcinoma cases were classified as acinar/papillary-lepidic type (n = 65) or acinar/papillary-non-lepidic type (n = 48) cases. Acinar/papillary-non-lepidic type cases were accompanied by more vascular invasion (13.8% vs 31.3%, P = ) and pleural invasion (9.2% vs 25.0%, P = ) than were acinar/papillary-lepidic type cases. Five-year overall survival (OS) and recurrence-free survival (RFS) also differed significantly between these types (5-year OS: acinar/papillary-lepidic type, 96.3% vs acinar/papillary-non-lepidic type, 61.8%, hazard ratio = 6.315, P = ; 5-year RFS: acinar/papillary-lepidic type, 91.4% vs acinar/papillary-non-lepidic type, 68.8%, hazard ratio = 2.967, P = ). Multivariate analysis revealed that a second predominant component was an independent prognostic factor for RFS (acinar/papillary-non-lepidic type: hazard ratio = 3.784, 95% confidence interval , P = 0.036). CONCLUSIONS: The pathological second predominant component allows intermediate-malignant adenocarcinomas to be subclassified with prognostic significance. It can be utilized when assessing postoperative risks for recurrence and when considering therapeutic strategies. Keywords: Lung adenocarcinoma Recurrence Pathology Papillary Acinar INTRODUCTION Adenocarcinoma is the major histological form of lung cancer, and has been classified and characterized according to invasive status and histological subtypes. The International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society (IASLC/ATS/ERS) classification has mainly defined three categories of invasiveness for adenocarcinoma: Presented at the 16th World Conference on Lung Cancer, Denver, CO, USA, 6 9 September preinvasive, minimally invasive and invasive [1]. The 2015 World Health Organization (WHO) classification includes a similar classification method [2]. However, in actuality, most cases that have potential risks of recurrence belong to invasive subtypes other than lepidic predominant Approximately 50 70% of such cases are diagnosed as either acinar or papillary predominant adenocarcinoma. The prognostic difference between these two subtypes has not been demonstrated, and there may be scope to subclassify them further. This study aimed to reclassify acinar and papillary predominant adenocarcinoma based on evaluation of the second predominant component. VC The Author Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.

2 M. Ito et al. / European Journal of Cardio-Thoracic Surgery 219 MATERIALS AND METHODS Patients Table 1: Characteristics of all reviewed patients with pathological N0 cases We retrospectively reviewed 347 consecutive lung adenocarcinoma cases that were clinically diagnosed as T1a-1bN0M0 and were resected between April 2006 and December 2010 at Hiroshima University Hospital and Kanagawa Cancer Center. All cases were reviewed by pathologists at each institution. After excluding two cases where co-existence of a large cell carcinoma component could not be excluded, second pathological components were evaluated for the 113 pn0m0 acinar and papillary predominant adenocarcinoma cases. One hundred and eight pn0m0 lepidic predominant adenocarcinoma cases were also evaluated as a potential subtype of intermediate-malignant adenocarcinoma. This study was approved by the institutional review boards of Hiroshima University Hospital and Kanagawa Cancer Center. Type classification All cases were diagnosed according to the IASLC/ATS/ERS classification and histological components were recorded quantitatively in 5% increments by pathologists in each institution. Diagnoses were reached by consensus among pathologists of the same institution and they were blinded to the patient outcomes. We used the pathological second predominant component to classify acinar and papillary predominant adenocarcinomas. If the second predominant component was a lepidic lesion, the case was classified as acinar/papillary-lepidic type (Aci/Pap-Lep type). On the other hand, if the second-predominant component was an invasive lesion, the case was classified as acinar/papillary-nonlepidic type (Aci/Pap-NonLep type). Pure type cases (a unique component of acinar or papillary subtypes) and cases that included the same proportions of lepidic and invasive lesions (i.e. papillary 60%, acinar 20% and lepidic 20%) were assigned to the Aci/Pap-NonLep type. Statistical analysis Rates of overall survival (OS) and recurrence-free survival (RFS) were compared between Aci/Pap-Lep and Aci/Pap-NonLep types. In addition, lepidic predominant adenocarcinoma was included in a secondary statistical analysis as a potential subtype of intermediate-malignant adenocarcinoma. The statistical significance of differences in frequencies was evaluated using the chi-square test. Overall survival and RFS rates were calculated using the Kaplan Meier method, and associations with variables were analysed using the log-rank test. Overall survival was defined as the interval from the day of the operation to the day of death from any cause. Recurrence-free survival was defined as the interval from the day of the operation to the day of recurrence or death from any cause. Hazard ratios were estimated in univariate and multivariate analyses using the Cox proportional hazards model. P-values were derived from two-tailed tests, and values of <0.05 were considered significant. Clinicopathological characteristic Cases (n =324) Age, years Median 66 Range Sex, n (%) Male 136 (42.0) Female 188 (58.0) Surgical procedure, n (%) Lobectomy 171 (52.8) Sublobar resection 153 (47.2) Pathological tumour size, n (%) <_2 cm 216 (66.7) >2 and <_3 cm 98 (30.2) >3 cm 10 (3.1) Predominant subtype, n (%) AIS 56 (17.3) MIA 15 (4.6) Lepidic 108 (33.3) Acinar 54 (16.7) Papillary 59 (18.2) Micropapillary 4 (1.2) Solid 28 (8.6) Lymphatic invasion, n (%) 28 (8.6) Vascular invasion, n (%) 43 (13.3) Pleural invasion, n (%) 38 (11.7) Visceral invasion 33 (10.2) Parietal invasion 5 (1.54) Recurrence, n (%) 24 (7.4) AIS: adenocarcinoma in situ; MIA: minimally invasive adenocarcinoma. RESULTS The characteristics of the patients are shown in Table 1. Among the 347 patients with clinical T1a-1bN0M0 disease, 108 cases of pn0 lepidic predominant adenocarcinoma, 54 cases of pn0 acinar predominant adenocarcinoma and 59 cases of pn0 papillary predominant adenocarcinoma were reviewed. The 54 cases of acinar predominant adenocarcinoma were divided into 33 cases of the acinarlepidic type and 21 cases of the acinarnonlepidic type. The 59 cases of papillary predominant adenocarcinoma were divided into 32 cases of the papillary-lepidic type and 27 cases of the papillary-non-lepidic type. Altogether, 65 Aci/ Pap-Lep cases and 48 Aci/Pap-NonLep cases were included in this study. The clinicopathological features of each group are shown in Table 2. The median duration of follow-up was 1260 days (range days). The cases of acinar predominant adenocarcinoma and papillary predominant adenocarcinoma did not differ significantly in terms of the frequencies of lymphatic invasion (9.26% vs 22.0%, P = 0.110), vascular invasion (22.2% vs 20.3%, P = 0.807), pleural invasion (13.0% vs 17.0%, P = 0.742), or recurrence (13.0% vs 15.3%, P = 0.937). However, as classified according to the second predominant component, Aci/Pap-NonLep type cases were accompanied by more vascular invasion (13.8% vs 31.3%, P = ) and pleural invasion (9.2% vs 25.0%, P = ) than were Aci/Pap-Lep type cases. In comparison with the Aci/ Pap-NonLep type, the tumour size of the Aci/Pap-Lep type was significantly larger (median and range: 2.1 cm, cm vs 1.75 cm, cm P = ). There was no significant THORACIC

3 220 M. Ito et al. / European Journal of Cardio-Thoracic Surgery Table 2: Characteristics of patients with pathological N0 Lepidic, Aci/Pap-Lep and Aci/Pap-NonLep subtypes Clinicopathological characteristic, n (%) Total, 221 (100) Lepidic, 108 (48.9) Aci/Pap-Lep, 65 (29.4) Aci/Pap-NonLep, 48 (21.7) Age, years Median Range Sex, n (%) Male 87 (39.4) 36 (33.3) 26 (40.0) 25 (52.1) Female 134 (60.6) 72 (66.7) 39 (60.0) 23 (47.9) Surgical procedure, n (%) Lobectomy 134 (60.6) 51 (47.2) 49 (75.4) 34 (70.8) Sublobar resection 87 (39.4) 57 (52.8) 16 (24.6) 14 (29.2) Pathological tumour size, n (%) Median (cm) Range (cm) <_2 cm 132 (59.7) 64 (59.3) 32 (49.2) 36 (75.0) >2 and <_3 cm 79 (35.7) 39 (36.1) 30 (46.2) 10 (20.8) >3 cm 10 (4.5) 5 (4.6) 3 (4.6) 2 (4.2) Predominant subtype, n (%) Lepidic 108 (48.9) 108 (100) 0 (0) 0 (0) Acinar 54 (24.4) 0 (0) 33 (50.8) 21 (43.8) Papillary 59 (26.7) 0 (0) 32 (49.2) 27 (56.3) Lymphatic invasion, n (%) 19 (8.6) 1 (0.93) 9 (13.8) 9 (18.8) Vascular invasion, n (%) 28 (12.7) 4 (3.7) 9 (13.8) 15 (31.3) Pleural invasion, n (%) 20 (9.0) 2 (1.9) 6 (9.2) 12 (25.0) Visceral invasion 16 (7.2) 2 (1.9) 5 (7.7) 9 (18.8) Parietal invasion 4 (1.8) 0 (0) 1 (1.5) 3 (6.3) Recurrence, n (%) 16 (7.2) 0 (0) 6 (9.2) 10 (20.8) Aci/Pap-Lep: acinar/papillary-lepidic; Aci/Pap-NonLep: acinar/papillary-non-lepidic. difference regarding surgical procedure between the two subtypes (P = 0.588). The 5-year OS rates of lepidic, acinar and papillary predominant adenocarcinoma were 96.8, 85.8 and 77.4%, respectively (acinar vs papillary: P = 0.224). The 5-year RFS rates of lepidic, acinar and papillary predominant adenocarcinoma were 98.8, 84.2 and 79.7%, respectively (acinar vs papillary: P = 0.233). When the cases were classified according to second predominance, significant prognostic differences were confirmed for both OS (5-year OS: Aci/Pap-Lep, 96.3% vs Aci/Pap-NonLep, 61.8%, P = ) and RFS (5-year RFS: Aci/Pap-Lep, 91.4% vs Aci/Pap-NonLep, 68.8%, P = ) (Fig. 1). Univariate analyses indicated that Aci/Pap- NonLep type, vascular invasion, and pleural invasion were significant predictive factors for worse RFS. Multivariate analysis revealed that Aci/Pap-NonLep type was a significant contributor to RFS (Table 3]). DISCUSSION Classifications of adenocarcinoma based on the predominant component were established by the IASLC/ATS/ERS [1] and have been employed in the 2015 WHO classification [2]. The stratification in these classifications was more detailed than that in the 2004 WHO classification, which handled most adenocarcinoma as a mixed subtype [3]. Regardless of the revised classification, approximately 50 70% of adenocarcinoma cases have been diagnosed as either acinar or papillary predominant adenocarcinoma, irrespective of stage [4 9]. Reported frequencies of acinar predominant adenocarcinoma and papillary predominant adenocarcinoma have varied widely [4, 6, 10, 11]. A prognostic difference between these two subtypes has been neither clearly identified [12] nor discussed. Furthermore, acinar predominant adenocarcinoma and papillary predominant adenocarcinoma, sometimes also including lepidic predominant adenocarcinoma, have been often generalized as intermediate-malignant adenocarcinoma instead of being classified independently by the predominant component [9, 13 15]. These facts suggest that acinar and papillary predominant adenocarcinoma are similar subtypes and there may be scope to subclassify them further. The concept of the intermediate-malignant category identifies two or three major subtypes as one category. Although generalizing similar subtypes might be rational, it may conflict with the classifying tendency of the IASLC/ATS/ERS and 2015 WHO classifications. Adenocarcinomas have been subclassified by the invasive status (preinvasive, minimally invasive and invasive). Therefore, we hypothesized invasive adenocarcinoma could be also subdivided by invasive extent, and we focused on the second predominant component as a factor reflecting invasive extent. Similar to other studies, this study did not find significant differences in OS or RFS between acinar and papillary predominant types. We chose to regard both of these types as belonging to the same category, and reclassified them into Aci/Pap-Lep and Aci/Pap-NonLep types based on the second predominant component. The Aci/Pap-Lep type had a significantly larger tumour size compared with the Aci/Pap-NonLep type. Regardless of the tendency towards a smaller tumour size, the Aci/Pap-NonLep type included more vascular/pleural invasion and had a worse prognosis.

4 M. Ito et al. / European Journal of Cardio-Thoracic Surgery 221 Figure 1: Overall survival and RFS based on first predominant or second predominant histologic component of adenocarcinoma. (A) OS curves of lepidic, acinar and papillary predominant adenocarcinoma. Five-year OS rates were 96.8, 85.8 and 77.4%, respectively (lepidic predominant vs acinar predominant: P=0.210, acinar predominant vs papillary predominant P=0.224). (B) RFS curves of lepidic, acinar and papillary predominant adenocarcinoma. Five-year RFS rates were 96.8, 84.2 and 79.7%, respectively (lepidic predominant vs acinar predominant P=0.581, acinar predominant vs papillary predominant P=0.233). (C) OS curves of lepidic predominant adenocarcinoma, Aci/Pap-Lep type and Aci/Pap-NonLep type. Five-year OS rates were 96.8, 96.3 and 61.8%, respectively (lepidic predominant adenocarcinoma vs Aci/Pap-Lep type P=0.887, Aci/Pap-Lep type vs Aci/Pap-NonLep type: P= ). (D) RFS curves of lepidic predominant adenocarcinoma, Aci/Pap-Lep type and Aci/Pap-NonLep type. Five-year RFS rates were 96.8, 91.4 and 68.8%, respectively (lepidic predominant adenocarcinoma vs Aci/Pap-Lep type P=0.0832, Aci/Pap-Lep type vs Aci/Pap-NonLep type P=0.0210). OS: overall survival; RFS: recurrence-free survival. Table 3: Univariate and multivariate analyses for factors related to recurrence-free survival Prognostic factor Univariate analysis Multivariate analysis HR (95% CI) P-value HR (95% CI) P-value Age (>59 years) ( ) ( ) Sex (male) ( ) ( ) Procedure (sublobar resection) ( ) ( ) Pathological tumour size (>2.0 cm) ( ) ( ) Aci/Pap-NonLep (vs Aci/Pap-Lep) * ( ) ( ) Lymphatic invasion (positive) ( ) ( ) Vascular invasion (positive) ( ) ( ) Pleural invasion (positive) ( ) ( ) THORACIC HR: hazard ration; Aci/Pap-NonLep: acinar/papillary-non-lepidic; Aci/Pap-Lep: acinar/papillary-lepidic. *significant.

5 222 M. Ito et al. / European Journal of Cardio-Thoracic Surgery In the general course of adenocarcinoma development, greater tumour progression is usually accompanied by reductions of the lepidic component and increases of the invasive component. The classification method by the second predominant component was simple.it reflects the progressive phase of tumour invasion and was capable of subdividing subtypes of invasive adenocarcinoma. In resemblance with adenocarcinoma in situ and minimally invasive adenocarcinoma showing 100% 5-year survival or recurrencefree interval rates [16 18], lepidic predominant adenocarcinoma also showed almost 100% OS and RFS rates in this study. However, five lepidic predominant cases were accompanied by recurrent risks (one case of lymphatic invasion, four cases of vascular invasion and two cases of pleural invasion). Therefore, in addition to comparing OS and RFS between acinar and papillary predominant adenocarcinomas, we performed a secondary analysis of OS and RFS by including lepidic predominant adenocarcinoma as a potential intermediate-malignant subtype. Although, the difference between the RFS rates of lepidic predominant and Aci/Pap-Lep types narrowly missed statistical significance in this study (98.8% vs 91.4%, P = ), this might have been a consequence of the small number of cases. Lepidic predominant status is an earlier invasive phase of acinar or papillary predominant adenocarcinoma. If the different extent of invasiveness can distinguish Aci/Pap-NonLep type from Aci/Pap- Lep type, prognostic significance will be reached between lepidic predominant adenocarcinoma and Aci/Pap-Lep type in a larger cohort. Even among invasive adenocarcinomas, estimating the extent of invasiveness will contribute to further classification. To better quantitate the first and second predominant subtype, highresolution computed tomography (HRCT) will be useful. HRCT can show different appearances in early-stage lung adenocarcinoma according to the invasive extent: solid, part-solid, or pure groundglass nodule (GGN) appearances. If the pathological diagnosis regarding quantitative subtypes shows discrepancy in comparison with radiological features, intensive discussion, including pathologists, should be undertaken. Larger studies that include more cases or have prospective designs are warranted for further evaluation. Evaluation of genotype might be beneficial for further classification. In conclusion, the pathological second predominant component allows acinar predominant adenocarcinoma and papillary predominant adenocarcinoma to be subclassified in a manner that has prognostic significance. Predictions of malignant potential and the subsequent management after surgery should not rely solely on the predominant component. 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