Negative prognostic influence of micropapillary pattern in stage IA lung adenocarcinoma

Transcription

1 European Journal of Cardio-Thoracic Surgery 49 (2016) doi: /ejcts/ezv058 Advance Access publication 11 March 2015 ORIGINAL ARTICLE Cite this article as: Tsubokawa N, Mimae T, Sasada S, Yoshiya T, Mimura T, Murakami S et al. Negative prognostic influence of micropapillary pattern in stage IA lung adenocarcinoma. Eur J Cardiothorac Surg 2016;49: a Negative prognostic influence of micropapillary pattern in stage IA lung adenocarcinoma Norifumi Tsubokawa a, Takahiro Mimae a, Shinsuke Sasada a, Tomoharu Yoshiya a, Takeshi Mimura a, Shuji Murakami b, Hiroyuki Ito c, Yoshihiro Miyata a, Haruhiko Nakayama c and Morihito Okada a, * Department of Surgical Oncology, Hiroshima University, Hiroshima, Japan b Department of Respiratory Medicine, Kanagawa Cancer Center, Yokohama, Japan c Department of Thoracic Surgery, Kanagawa Cancer Center, Yokohama, Japan * Corresponding author. Department of Surgical Oncology, Hiroshima University, Kasumi, Minami-ku, Hiroshima , Japan. Tel: ; Fax: ; morihito1217@hiroshima-u.ac.jp; morihito1217@gmail.com (M. Okada) Received 14 November 2014; received in revised form 20 January 2015; accepted 23 January 2015 Abstract OBJECTIVES: There is uncertainty as to which factors determine the aggressiveness of lung adenocarcinoma with a micropapillary pattern (MPP). The present study aimed to clarify the influence of a MPP on the malignant aggressiveness of clinical stage IA lung adenocarcinoma. METHODS: We retrospectively examined 347 consecutive patients with clinical stage IA lung adenocarcinoma who underwent complete resection. We defined MPP-positive as accounting for 5% of the entire tumour. RESULTS: Forty-eight (14%) and 299 (86%) patients were MPP-positive and negative, respectively. Lymphatic (P = 0.003) and vessel (P = 0.029) invasion as well as lymph node metastasis (P = 0.002) were more frequent in the MPP-positive than negative group. Five-year disease-free survival (DFS) rates were significantly lower in the MPP-positive than negative group (69.7 vs 89.3%, P < 0.001). Multivariate analysis for DFS showed that MPP (P = 0.048), lymphatic invasion (P = 0.003) and vessel invasion (P = 0.002) were independent poor prognostic factors. In addition, higher proportions (<5%, 5 30% and 30%) of MPP were associated with a poorer prognosis (89.3, 76.0, and 48.1%, respectively; P < 0.001). The prognosis of patients with MPP-positive tumours and negative tumours harbouring lepidic and solid predominant growth patents did not differ (100 vs 96.8%, P = 0.564; 66.7 vs 62.5%, P = 0.791, respectively). On the other hand, the prognosis tended to be poorer for patients with papillary predominant MPP-positive tumours than for those with negative tumours (62.5 vs 82.5%, P = 0.075). CONCLUSIONS: MPP has an effect on tumour malignancy and patients with tumours harbouring a higher ratio of MPP or papillary predominant subtypes have worse survival. Keywords: Lung cancer Micropapillary Prognosis INTRODUCTION Lung adenocarcinoma is the most common histological type of primary lung cancer and its incidence has recently increased [1]. The histological subtype of most lung adenocarcinomas is mixed rather than comprising a single subtype [2]. The mixed subtype has a wide spectrum of clinical, radiological, molecular and pathological heterogeneity [3] due to the complex heterogeneous mixture of histological subtypes. A new histological classification of lung adenocarcinoma was proposed by the International Association for the Study of Lung Cancer, the American Thoracic Society and the European Respiratory Society (IASLC/ATS/ERS) during 2011 [4]. Five distinctive subtypes of invasive lung adenocarcinoma were assigned to three groups based on prognosis: favourable (lepidic), intermediate (acinar and papillary) and poor (micropapillary and solid). The micropapillary subtype was a new addition to this classification and the micropapillary pattern (MPP) comprises small papillary structures without fibrovascular cores. This pattern is associated with aggressive clinical behaviour and it tends to present with extensive lymph node involvement and metastasis [5 13]. However, an optimal cut off value for the amount of MPP relative to clinical outcomes and which predominant subtypes are influenced on the aggressiveness by MPP status remain essentially unknown. Here, we retrospectively investigated the prognosis of patients with clinical stage IA lung adenocarcinoma according to MPP status and determined the malignant potential of various proportions of MPP and correlations with predominant subtypes. The Author Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.

2 294 MATERIALS AND METHODS N. Tsubokawa et al. / European Journal of Cardio-Thoracic Surgery Analysis Study design Between April 2006 and December 2010, 552 consecutive patients underwent complete resection for clinical stage IA lung adenocarcinoma at Hiroshima University Hospital (Hiroshima, Japan) and Kanagawa Cancer Centre (Yokohama, Japan). Among them, 205 were excluded because they had multiple tumours or a history of previous lung surgery. Thus, data from 347 patients who underwent complete resection for clinical stage IA lung adenocarcinoma were analysed. Clinicopathological data were retrospectively collected from medical records. All patients were preoperatively assessed by high-resolution computed tomography (HRCT) and fluorescence deoxyglucosepositron emission tomography/computed tomography (PET/CT) and tumours were staged according to the tumor, lymph node, and metastatic Classification of Malignant Tumors, seventh edition [14]. Peripheral T1aN0M0 tumours were completely resected with appropriate surgical margins during sublobar resection. Ground-glass opacity tumours on HRCT were treated by wedge resection. All patients treated by lobectomy and segmentectomy also underwent systematic nodal dissection. If lymph node metastasis was confirmed on intraoperative frozen sections, the procedure was converted to standard lobectomy. All other patients underwent standard lobectomy. The Institutional Review Boards of the participating institutions approved this retrospective review of a prospective database and waived the requirement for informed consent from individual patients. Pathological investigation Surgically resected specimens were routinely fixed in 10% buffered formalin, serially cut into 5 7 mm thick slices and macroscopically assessed. Specimens were histologically diagnosed using haematoxylin eosin stain. Specimens that were equivocal by haematoxylin eosin staining were also immunohistochemically stained. According to the IASLC/ATS/ERS classification, three pathologists (one at Kanagawa Cancer Center and two at Hiroshima University) reviewed an average of 10 (range 5 15) slides per patient once again using comprehensive histological subtyping and recorded the ratio of histological components in 5% increments [4]. We defined MPP as cells growing in papillary tufts without fibrovascular cores that appeared detached or connected to alveolar walls [4 6] and occupied 5% of an entire tumour according to the IASLC/ATS/ERS classification [4]. The predominant subtypes in tumours were determined [4] as lepidic (including 56 patients with adenocarcinoma in situ and 15 with minimally invasive adenocarcinoma), acinar, papillary, micropapillary and solid. Visceral pleural invasion was taken as either present or absent and lymphatic and vascular invasion was considered present if at least one tumour cell cluster was visible in a blood or lymphatic vessel, respectively. Follow-up All patients who were treated by lung resection were followed up by a physical examination and chest radiography every 3 months, and chest and abdominal CT examinations every 6 months after the day of surgery for 2 years. Thereafter, the patients were assessed by a physical examination and chest radiography every 6 months, and then by annual chest CT examination. Summarized data are presented as numbers or as means ± standard deviation unless otherwise stated. Categorical and continuous variables were compared using χ 2 tests and unpaired t-tests, respectively. Overall survival (OS) was defined as the interval between lung surgery and the date of death or the last followup assessment. Disease-free survival (DFS) was defined as time from surgery to recurrence detected as signs or symptoms on routine follow-up radiography, death or last follow-up and assessed by univariate and multivariate analyses. Survival data were calculated using Kaplan Meier curves and compared using the log-rank test. P-values and hazard ratios (HRs) in univariate analysis were calculated using a Cox regression model. Variables that had P < 0.05 in univariate analyses were included in multivariate analyses using the Cox regression model. All data were statistically analysed using EZR (Saitama Medical Centre, Jichi Medical University), which is a graphical user interface for R (The R Foundation for Statistical Computing, version ). RESULTS Clinicopathological features of patients with lung adenocarcinoma The median follow-up was 40.6 months. Table 1 summarizes the clinicopathological characteristics. Forty-eight (14%) and 299 (86%) patients had MPP-positive and negative clinical stage IA lung adenocarcinoma, respectively. Solid tumour sizes were larger on HRCT (1.48±0.86 vs 1.01±0.68, P < 0.001) and SUVmax on PET/CT was higher (3.02 ± 2.34 vs 2.19 ± 2.45, P = 0.029) in the MPP-positive than negative group. One hundred and ninety-two (55%), 55 (16%) and 99 (29%) patients underwent lobectomy, segmentectomy and wedge resection, respectively. Lymphatic invasion (27.1 vs 9.7%, P = 0.003), vessel invasion (27.1 vs 13.7%, P = 0.029) and lymph node metastasis (14.6 vs 4.7%, P =0.002) were more frequent in MPP-positive than negative patients. The pathological stages were IA, IB, IIA, IIB and IIIA in 277 (80%), 48 (14%) 11 (3%), 0 (0%) and 11 (3%) patients, respectively. Tumours were upstaged from clinical stage IA to pathological stage IB IIIA more frequently in the MPP-positive than negative group (41.7 vs 16.7%, P < 0.001). Survival according to a micropapillary presence Recurrence developed in 32 (9%) patients; 17 had local recurrence, 12 had distant metastases and three had local and distant metastases. Among 23 patients who died, 14 and nine were due to lung cancer and other diseases, respectively. Figure 1 shows the Kaplan Meier curves for survival according to the presence of MPP. The 5-year OS (Fig. 1A) and 5-year DFS (Fig. 1B) rates were significantly lower in the MPP-positive, than negative group (79.4 vs 91.7%, P = 0.042; and 69.7 vs 83.9%, P <0.001, respectively). Univariate analysis of DFS revealed that MPP as well as pleural, lymphatic and vessel invasion were significantly associated with a poor prognosis (All, P < 0.001). Multivariate analysis revealed that MPP [HR, 1.98; 95% confidence interval (CI), ; P = 0.048], as well as lymphatic invasion (HR, 2.96; 95% CI, ; P = 0.003) and vessel invasion (HR, 2.98; 95% CI, ; P = 0.002) were independent prognostic factors (Table 2). This study also showed that the prognosis was significantly poorer for

3 N. Tsubokawa et al. / European Journal of Cardio-Thoracic Surgery 295 Table 1: Clinicopathological characteristics All Micropapillary pattern P-value Positive Negative n = 48 (%) n = 299 (%) Age (years) < (19) 77 (26) (81) 222 (74) Sex Male (56) 122 (41) Female (44) 177 (59) Tumour size on HRCT cm (67) 178 (60) 3 cm (33) 121 (40) Solid size on HRCT a 1.07 ± ± ± 0.68 <0.001 SUVmax on PET/CT a 2.31 ± ± ± Surgical procedure Wedge resection (29) 85 (28) Segmentectomy 56 2 (4) 54 (18) Lobectomy (67) 160 (54) Pleural invasion (20) 33 (11) Lymphatic invasion (27) 29 (10) Vessel invasion (27) 41 (14) Lymph node metastasis 21 7 (15) 14 (5) a Values are shown as means ± SD. HRCT: high-resolution computed tomography; PET/CT: positron emission tomography/computed tomography; SD: standard deviation; SUVmax: maximum standardized uptake value. Figure 1: Kaplan Meier curves for overall (A) and disease-free (B) survival of patients with clinical stage IA lung adenocarcinoma according to the presence of micropapillary pattern. patients with MPP 5% than <5% who underwent wedge resection (5-year DFS, 51.4 vs 93.5%, P < 0.001), whereas this was not in those who underwent segmentectomy or lobectomy (5-year DFS, 76.7 vs 87.7%, P = 0.151). Influence of proportion of micropapillary pattern and predominant subtypes on survival outcomes Since MPP was selected as an independent prognostic factor, we investigated the malignant potential of MPP in clinical stage IA lung adenocarcinoma from the perspectives of MPP proportion and predominant subtypes. Figure 2 shows that the 5-year DFS rates of patients with MPP ratios 5%, 5 30% and 30% were 89.3, 76.0 and 48.1%, respectively. The prognosis was poorer among patients with tumours comprising 5 30% than 5% MPP, but better than those comprising 30% MPP (P = and P = 0.213, respectively). Survival was then investigated in MPP-positive and negative lung adenocarcinoma according to predominant subtypes. The prognosis was poorer for patients with solid-predominant MPP-negative tumours and with micropapillary-predominant MPP-positive tumours than for those with the other predominant subtypes (Fig. 3).

4 296 N. Tsubokawa et al. / European Journal of Cardio-Thoracic Surgery Table 2: Findings from univariate and multivariate analyses of DFS Variable Univariate Multivariate HR 95% CI P-value HR 95% CI P-value Surgical procedure Limited resection/lobectomy Pathological tumour size 2 cm/ >2 cm Micropapillary 5%/<5% < Pleural invasion Yes/no < Lymphatic invasion Yes/no < Vessel invasion Yes/no < CI: confidence interval; HR: hazard ratio. Figure 3A shows that the 5-year DFS of patients with acinar and papillary predominant and with solid-predominant tumours were similar in the MPP-positive group (68.2, 62.5 and 66.7%, respectively). We then evaluated which predominant subtypes affected survival according to the presence or absence of MPP. Figure 4 shows that the survival rates of patients with MPP-positive and negative tumours harbouring a lepidic or a solid-predominant subtype did not differ (lepidic, 100 vs 96.8%, P = 0.564; solid, 66.7 vs 62.5%, P = 0.791). On the other hand, the prognosis tended to be poorer for patients with papillary predominant subtype of MPP-positive than MPP-negative tumours (62.5 vs 82.5%, P = 0.075). The results were similar for acinarpredominant subtype of MPP-positive and negative tumours, although the difference did not reach significance due to the small sample size (68.2 vs 84.2%, P = 0.324). Associations between proportion of micropapillary pattern and predominant subtypes in micropapillary pattern-positive tumours We investigated differences in predominant subtypes according to the presence and proportion of MPP (Fig. 5). The lepidicpredominant subtype was less prevalent (19 vs 56%), whereas the papillary-, acinar- and solid-predominant subtypes were more prevalent in the MPP-positive than negative group (23 vs 19%, 29 vs 16% and 13 vs 8%, respectively). The micropapillary-predominant subtype was identified in 13% of the MPP-positive group (Fig. 5A). The proportion of MPP was lower ( 10%) in seven patients (64%) of MPP-positive tumours with a lepidic-predominant subtype, and higher ( 10%) in 10 (71%), 8 (73%), and 4 (66%) patients of MPPpositive tumours with papillary-, acinar-, and solid predominant subtype, respectively. DISCUSSION The MPP was an independent predictive prognostic factor in clinical stage IA lung adenocarcinoma. In addition, we discovered that the MPP more negatively impacted survival when tumours had a higher proportion of MPP or papillary- or acinar-predominant Figure 2: Five-year disease-free survival curves for patients with clinical stage IA lung adenocarcinoma according to ratios of micropapillary patterns. subtypes. On the other hand, the prognosis of lepidic-predominant lung adenocarcinoma was favourable regardless of MPP. Although previous reports [5, 6, 8 13] also revealed that lung adenocarcinoma with MPP has a worse biological behaviour, the relationship between MPP and predominant subtype in early stage lung adenocarcinoma has remained unknown. This study revealed details of the relationship between MPP and predominant subtypes. MPP negatively influences the survival of patients with papillaryand acinar-predominant, but not lepidic- or solid-predominant subtypes. The survival of patients with MPP-positive tumours harbouring a papillary- and acinar-predominant subtype was similar to that of the solid-predominant subtype, because about 70% of patients in these groups had a higher ratio ( 10%) of MPP. On the other hand, since few patients with the lepidic-predominant subtype had a high proportion of MPP, the influence of MPP might be less significant than that in the papillary- and acinarpredominant subtypes. The 5-year DFS rates of solid-predominant, MPP-positive and negative tumours were similar. Since the survival of patients with the solid-predominant subtype was poor, MPP

5 N. Tsubokawa et al. / European Journal of Cardio-Thoracic Surgery 297 Figure 3: Five-year disease-free survival rates of patients with clinical stage IA lung adenocarcinoma according to predominant subtypes in the micropapillary patternpositive group (A) and the micropapillary-pattern negative group (B). Figure 4: Disease-free survival curves of clinical stage IA lung adenocarcinoma with predominant subtypes according to the presence of micropapillary pattern. A, B, C and D depict lepidic-, papillary-, acinar- and solid-predominant subtypes, respectively.

6 298 N. Tsubokawa et al. / European Journal of Cardio-Thoracic Surgery Figure 5: Ratios of predominant subtypes according to the presence of micropapillary pattern. might have minimally affected survival even though most patients had a high proportion of MPP. In addition, MPP was detected less frequently in the lepidic-predominant subtype and more frequently in the papillary- and acinar-predominant subtypes. A previous study has also significantly associated a non-lepidic, papillary-predominant subtype with MPP [8] although this study cohort was heterogeneous because it included all stages of lung adenocarcinoma. Lung adenocarcinoma with MPP seems to be associated with a high degree of aggressiveness, advance stage, lymph node metastasis and lymphovascular invasion [7, 13, 15, 16]. The prognosis of patients with lung adenocarcinoma is poor regardless of an early clinical stage [6, 11]. Miyoshi et al. [6] found that clinical stage I lung adenocarcinoma was pathologically up-staged more frequently in MPP-positive than negative tumours because of lymph node and lung micrometastasis. Our study also found significantly more frequent upstaging in the MPP-positive than negative group. Discrepancies between clinical and pathological stages are considered a characteristic feature of adenocarcinoma with MPP. A higher proportion of MPP in the entire tumour was associated with a poor prognosis. Previous studies [8, 9, 17, 18] have also found that a greater proportion of MPP in tumours is associated with poor survival, which might be attributable to the aggressive behaviour of MPP. Kamiya et al. [8] identified a loss of vascularity, cell matrix contact and fewer preserved intercellular junctions in MPP tufts. These cells have most likely acquired resistance to anoikis and have facilitated anchorage-independent growth. Therefore, a higher MPP ratio in a tumour is likely to be associated with a higher frequency of micrometastasis. Thus, the ratio of MPP in a tumour is an important prognostic factor. Zhan et al. [19] also reported that micropapillary-predominant tumours were more likely to recur than non-micropapillary-predominant adenocarcinoma with a MPP. However, the optimal cut-off values with which to discriminate the presence of MPP, or the extent to which MPP determines a poor prognosis remains controversial. Many investigators have classified tumours as MPP-positive when the ratio of MPP is 5% of the entire tumour [20]. We also used 5% as the cut-off value according to the new IASLC/ATS/ERS classification. The survival rates were significantly worse for the group with >5% MPP than with <5%, indicating that 5% is reasonable as a cut-off value. We established 30% as the optimal cut-off to determine a poor prognosis based on published reports [18, 21] and found that the prognosis was poorer in the group with lung adenocarcinoma and 30% MPP than with 5 30% MPP. A high ratio of MPP is defined as 50% in some studies [8, 9, 17]. If the cut-off MPP ratio was taken as >40%, only micropapillarypredominant subtypes would remain. We already showed that survival was the poorest for the micropapillary, among all predominant subtypes. Since we aimed to determine cut-off values including not only micropapillary, but also other predominant subtypes, cut-off values of 40 and 50% were not applied in the present study. Nitadori et al. [22] reported that MPP 5% was associated with increased risk of recurrence in a group that underwent limited resection and increased risk of local recurrence when the surgical margin was <1 cm. Even small tumours with MPP might require segmentectomy with an adequate surgical margin or lobectomy. However, to pre- or intraoperatively determine whether tumours have MPP and to determine the optimal extent of resection for their tumours is difficult. Especially, the ratio of MPP that is significantly associated with prognosis could not be obtained from intraoperative frozen sections. One review [23] noted that most previous articles describing intraoperative analyses of frozen sections focused on the predictive value for non-invasive tumours and did not discuss the predominant subtypes of invasive tumours. In addition, the data are not yet sufficient to suggest that completion lobectomy or adjuvant chemotherapy should proceed after initial sublobar resection of tumours with MPP; therefore, further investigations and more data are required. The present study had some limitations, including those imposed by the nature of its retrospective design. Secondary epidermal growth factor receptor (EGFR) mutation status was unknown. Some previous studies have found frequent EGFR mutations in lung adenocarcinoma with MPP [2, 20, 24, 25]. Although biologically aggressive, MPP but could be controlled with EGFR-tyrosine kinase inhibitors [20]. In summary, the survival of patients with clinical stage IA lung adenocarcinoma with MPP was poor. In addition, MPP impacted survival more negatively when a tumour harboured a higher ratio of MPP or papillary- or acinar-predominant subtypes. Although a larger study is required, we postulate that lung adenocarcinoma with MPP, especially at a higher ratio, can require adjuvant therapy regardless of the stage and will require further resection if limited resection is initially performed.

7 N. Tsubokawa et al. / European Journal of Cardio-Thoracic Surgery 299 ACKNOWLEDGEMENTS The authors thank Tomoyuki Yokose, Kei Kushitani and Yukio Takeshima for reviewing the pathological sections. Funding This study was supported by the Japan Society for the Promotion of Science Kakenhi ( to T.M and to M.O.) Conflict of interest: none declared. REFERENCES [1] Molina JR, Yang P, Cassivi SD, Schild SE, Adjei AA. Non-small cell lung cancer: epidemiology, risk factors, treatment, and survivorship. Mayo Clin Proc 2008;83: [2] Motoi N, Szoke J, Riely GJV, Seshan VE, Kris MG, Rusch VW et al. Lung adenocarcinoma: modification of the 2004 WHO mixed subtype to include the major histologic subtype suggests correlations between papillary and micropapillary adenocarcinoma subtypes, EGFR mutations and gene expression analysis. Am J Surg Pathol 2008;32: [3] Travis WD, Garg K, Franklin WA, Wistuba II, Sabloff B, Noguchi M et al. Evolving concepts in the pathology and computed tomography imaging of lung adenocarcinoma and bronchioloalveolar carcinoma. J Clin Oncol 2005;23: [4] TravisWD,BrambillaE,NoguchiM,NicholsonAG,GeisingerKR,YatabeY et al. International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society International Multidisciplinary Classification of Lung Adenocarcinoma. J Thorac Oncol 2011;6: [5] Amin MB, Tamboli P, Merchant SH, Ordonez NG, Ro J, Ayala AG et al. Micropapillary component in lung adenocarcinoma: a distinctive histologic feature with possible prognostic significance. Am J Surg Pathol 2002; 26: [6] Miyoshi T, Satoh Y, Okumura S, Nagakawa K, Shirakusa T, Tsuchiya E et al. Early-stage lung adenocarcinomas with a micropapillary pattern, a distinct pathologic marker for a significantly poor prognosis. Am J Surg Pathol 2003;27: [7] Aida S, Shimazaki H, Sato K, Sato M, Deguchi H, Ozeki Y et al. Prognostic analysis of pulmonary adenocarcinoma subclassification with special consideration of papillary and bronchioloalveolar types. Histopathology 2004; 45: [8] Kamiya K, Hayashi Y, Douguchi J, Hashiguchi A, Yamada T, Izumi Y et al. Histopathological features and prognostic significance of the micropapillary pattern in lung adenocarcinoma. Mod Pathol 2008;21: [9] Makimoto Y, Nabeshima K, Iwasaki H, Miyoshi T, Enatsu S, Shiraishi T et al. Micropapillary pattern: a distinct pathological marker to subclassify tumours with a significantly poor prognosis within small peripheral lung adenocarcinoma (</=20 mm) with mixed bronchioloalveolar and invasive subtypes (Noguchi s type C tumours). Histopathology 2005;46: [10] Ninomiya H, Hiramatsu M, Inamura K, Nomura K, Okui M, Miyoshi T et al. Correlation between morphology and EGFR mutations in lung adenocarcinomas significance of the micropapillary pattern and the hobnail cell type. Lung Cancer 2009;63: [11] Roh MS, Lee JI, Choi PJ, Hong YS. Relationship between micropapillary component and micrometastasis in the regional lymph nodes of patients with stage I lung adenocarcinoma. Histopathology 2004;45: [12] Sanchez-Mora N, Presmanes MC, Monroy V, Moreno N, Lara-Martinez JMAladro MH et al. Micropapillary lung adenocarcinoma: a distinctive histologic subtype with prognostic significance. Case series. Hum Pathol 2008;39: [13] Cha MJ, Lee HY, Lee KS, Jeong JY, Han J, Shim YM et al. Micropapillary and solid subtypes of invasive lung adenocarcinoma: clinical predictors of histopathology and outcome. J Thorac Cardiovasc Surg 2014;147: e922. [14] Goldstraw P, Crowley J, Chansky K, Giroux DJ, Groome PA, Rami-Porta R et al. The IASLC Lung Cancer Staging Project: proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM Classification of malignant tumours. J Thorac Oncol 2007;2: [15] Nassar H. Carcinomas with micropapillary morphology: clinical significance and current concepts. Adv Anat Pathol 2004;11: [16] Koga K, Hamasaki M, Kato F, Aoki M, Hayashi H, Iwasaki A et al. Association of c-met phosphorylation with micropapillary pattern and small cluster invasion in pt1-size lung adenocarcinoma. Lung Cancer 2013;82: [17] Zhang J, Liang Z, Gao J, Luo Y, Liu T. Pulmonary adenocarcinoma with a micropapillary pattern: a clinicopathological, immunophenotypic and molecular analysis. Histopathology 2011;59: [18] Nagano T, Ishii G, Nagai K, Ito T, Kawase A, Takahashi K et al. Structural and biological properties of a papillary component generating a micropapillary component in lung adenocarcinoma. Lung Cancer 2010;67: [19] Zhang Y, Wang R, Cai D, Li Y, Pan Y, Hu H et al. A comprehensive investigation of molecular features and prognosis of lung adenocarcinoma with micropapillary component. J Thorac Oncol 2014;9: [20] Sumiyoshi S, Yoshizawa A, Sonobe M, Kobayashi M, Fujimoto M, Tsuruyama T et al. Pulmonary adenocarcinomas with micropapillary component significantly correlate with recurrence, but can be well controlled with EGFR tyrosine kinase inhibitors in the early stages. Lung Cancer 2013; 81:53 9. [21] Tsutsumida H, Nomoto M, Goto M, Kitajima S, Kubota I, Hirotsu Y et al. A micropapillary pattern is predictive of a poor prognosis in lung adenocarcinoma, and reduced surfactant apoprotein A expression in the micropapillary pattern is an excellent indicator of a poor prognosis. Mod Pathol 2007;20: [22] Nitadori J, Bograd AJ, Kadota K, Sima CS, Rizk NP, Morales EA et al. Impact of micropapillary histologic subtype in selecting limited resection vs lobectomy for lung adenocarcinoma of 2 cm or smaller. J Natl Cancer Inst 2013;105: [23] Van Schil PE, Asamura H, Rusch VW, Mitsudomi T, Tsuboi M, Brambilla E et al. Surgical implications of the new IASLC/ATS/ERS adenocarcinoma classification. Eur Respir J 2012;39: [24] Sun PL, Seol H, Lee HJ, Yoo SB, Kim H, Xu X et al. High incidence of EGFR mutations in Korean men smokers with no intratumoral heterogeneity of lung adenocarcinomas: correlation with histologic subtypes, EGFR/TTF-1 expressions, and clinical features. J Thorac Oncol 2012;7: [25] De Oliveira Duarte Achcar R, Nikiforova MN, Yousem SA. Micropapillary lung adenocarcinoma: EGFR, K-ras, and BRAF mutational profile. Am J Clin Pathol 2009;131: