Lung cancer continues to be the leading cause of cancer

original article Why Do Pathological Stage IA Lung Adenocarcinomas Vary from Prognosis? A Clinicopathologic Study of 176 Patients with Pathological Stage IA Lung Adenocarcinoma Based on the IASLC/ATS/ERS Classification Jie Zhang, MD, MS,* Jie Wu, MD,* Qiang Tan, PhD, Lei Zhu, MD,* and Wen Gao, MD Background: Patients with pathological stage IA adenocarcinoma (AC) have a variable prognosis, even if treated in the same way. The postoperative treatment of pathological stage IA patients is also controversial. Methods: We identified 176 patients with pathological stage IA AC who had undergone a lobectomy and mediastinal lymph node dissection at the Shanghai Chest Hospital, Shanghai, China, between 2000 and 2006. No patient had preoperative treatment. The histologic subtypes of all patients were classified according to the 2011 International Association for the Study of Lung Cancer (IASLC)/ American Thoracic Society (ATS)/European Respiratory Society (ERS) international multidisciplinary lung AC classification. Patients 5-year overall survival (OS) and 5-year disease-free survival (DFS) were calculated using Kaplan Meier and Cox regression analyses. Results: One hundred seventy-six patients with pathological stage IA AC had an 86.6% 5-year OS and 74.6% 5-year DFS. The 10 patients with micropapillary predominant subtype had the lowest 5-year DFS (40.0%).The 12 patients with solid predominant with mucin production subtype had the lowest 5-year OS (66.7%). Univariate and multivariate analysis showed that sex and prognositic groups of the IASLC/ATS/ERS histologic classification were significantly associated with 5-year DFS of pathological stage IA AC. Conclusion: Our study revealed that sex was an independent prognostic factor of pathological stage IA AC. The IASLC/ATS/ERS classification of lung AC identifies histologic categories with prognostic differences that could be helpful in clinical therapy. Key Words: Lung, Adenocarcinoma, Classification, International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society, Pathologic tumor node metastasis Ia. (J Thorac Oncol. 2013;8: 1196-1202) Departments of *Pathology, Shanghai Lung Cancer Center, Thoracic Surgery, Shanghai Chest Hospital, Shanghai, China. Disclosure: The authors declare no conflict of interest. Address for correspondence: Wen Gao, MD, No. 241 West Huaihai Road, Xuhui District, Shanghai PRC. E-mail: gaowen5921@163.com Copyright 2013 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/13/0809-1196 Lung cancer continues to be the leading cause of cancer deaths in both men and women in the world. 1 Adenocarcinoma (AC) is the most common histologic type of primary lung cancer. 2 The correct diagnosis of lung cancer depends on the pathologic examination of cytologic or histologic specimens. It is a major focus of research to improve patient survival. The international multidisciplinary lung AC classification proposed by International Association for the Study of Lung Cancer (IASLC)/American Thoracic Society (ATS)/Europen Respiratory Society (ERS) 3 provided consistent terms and diagnostic criteria for AC subtypes. New concepts were introduced for surgical specimens, such as adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA). In the new classification, bronchioloalveolar carcinoma (BAC) was replaced by AIS for small solitary ACs with pure lepidic growth. MIA was described as small ( 3 cm) solitary ACs with predominant lepidic growth and invasion of 5 mm or lesser. Another important change included elimination of the mixed subtype AC. Invasive ACs were classified by predominant pattern after using comprehensive histologic subtyping with lepidic (formerly most mixed subtype tumors with nonmucinous BAC), acinar, papillary, solid, and micropapillary patterns. Each histologic subtype present in a tumor was estimated in 5% increments. According to the 2011 National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology for non small-cell lung cancer, stage pathologic tumor node metastasis (ptnm) Ia patients with complete resection are treated with observation. Adjuvant chemo- or radiotherapy was not recommended. The survival of pathological stage IA patients is theoretically much better than that of patients with other stages if they accept surgical therapy. However, previous reports show a relatively wide range of 5-year survival in pathological stage IA patients, from 77.0% to 94.4%. 4 6 Patients with stage IA AC undergoing the same treatments also had variable outcomes (recurrence, metastasis, and death). Important factors in predicting prognosis, such as histologic subtype, tumor size, and type of surgical therapy, may also predict survival. A consensus for postoperative treatment in pathological stage IA patients has not been reached. Yoshizawa et al. 7 validated the new AC 1196 Journal of Thoracic Oncology Volume 8, Number 9, September 2013

Journal of Thoracic Oncology Volume 8, Number 9, September 2013 Pathological Stage IA Adenocarcinomas Versus Prognosis classification with a North American data set that comprised 514 patients with stage I lung AC. Russell et al.8 also identified 210 patients with lung AC to confirm the utility of the new classification. Both reports demonstrated a correlation between AC subtype and patient survival, supporting the valuable prognostic role of the new classification. The prognostic impact of the new histologic classification still needs further validation. Against this background, we investigated the clinical utility of the new classification to predict patient outcome at the Shanghai Chest Hospital, Shanghai, China. PATIENTS AND METHODS Patient Selection The records of 176 patients with pathological stage IA AC, who had undergone a lobectomy with mediastinal lymph node dissection at the Shanghai Chest Hospital, from 2000 to 2006, were reviewed. No patient received preoperative treatment. Patients were excluded if they had adjuvant chemotherapy or radiotherapy. All patients were regularly followed up after surgery. Patients were examined on an outpatient basis at 3-month intervals for the first 2 years and at 6-month intervals thereafter. The follow-up evaluation included physical examination, blood examination, computed tomography scan of the chest and abdomen, brain magnetic resonance imaging, and bone scintigraphy. Distant metastasis at N3 lymph node was comfirmed by fine-needle aspiration and cytopathological diagnosis when clinically feasible. The median follow-up time for the entire group was 73 months (range, 10 147 months). Histologic Evaluation All specimens were categorized according to the IASLC/ ATS/ERS classification of lung AC. Tumors were classified as AIS (Fig. 1), MIA (Fig. 2), or invasive AC. Invasive AC was divided into lepidic predominant (Fig. 3), acinar predominant (Fig. 4), papillary predominant (Fig. 5), micropapillary predominant (Fig. 6), solid predominant (Fig. 7), invasive mucinous AC (Fig. 8), colloid AC subtypes (Fig.9), and fetal AC (Fig.10). The predominant pattern was defined as the pattern with the largest percentage. Two pathologists, blinded to patients outcome, independently reviewed all hematoxylin and eosin stained slides. If differences emerged on the same slide, the reviewers would reach a consensus during discussion and multihead microscopy examination. Visceral pleural invasion was assessed in all patients, using guidelines of the 7th edition of the TNM classification for lung cancer.9,10 All 176 patients were confirmed to have no visceral pleural involvement using elastic staining. FIGURE 1. Adenocarcinoma in situ, this tumor shows lepidic growth consisting of alveolar wall thickening by atypical pneumocyte proliferation. No invasive growth area is seen (Hematoxylin and Eosin, 100). Statistical analysis was conducted using SPSS version 17.0 (SPSS Inc., Chicago, IL). RESULTS Clinicopathological Characteristics Of the patients, 50.6% (89 of 176) were men and 49.4% (87 of 176) were women. The median age at presentation was 58 years (range, 30 79 years); 39.2% of patients had a right upper lobe tumor and 26.7% a left upper lobe tumor. The median tumor size was 1.9 cm (range, 0.5 3.0 cm). The most frequent histologic subtype was papillary predominant Statistical Analysis Overall survival (OS) or disease-free survival (DFS) in each separate histologic subtype was assessed using a Kaplan Meier analysis. Age, sex, location, tumor gross size, tumor invasive size, and prognostic groups of the IASLC/ATS/ ERS histologic classification were included in the univariate analysis. Multivariate analysis was performed for variables that were identified to be significant in the univariate analysis. FIGURE 2. Minimally invasive adenocarcinoma, this tumor consists of mostly lepidic growth but there is an invasive area not more than 5mm in diameter, with a papillary growth pattern (Hematoxylin and Eosin, 100). 1197

Journal of Thoracic Oncology Volume 8, Number 9, September 2013 Zhang et al. FIGURE 3. Lepidic predominant, this tumor consists of mostly lepidic growth but there is an invasive area more than 5 mm in diameter, with an acinar growth pattern (Hematoxylin and Eosin, 40). (40.9%, 72 of 176), followed by acinar predominant, MIA, lepidic predominant, solid predominant with mucin production, and micropapillary subtypes. These accounted for 22.7% (40 of 176), 9.1% (16 of 176), 7.9% (14 of 176), 6.8% (12 of 176), and 5.7% (10 of 176), respectively, of all patients. All AIS and MIA tumors were of the nonmucinous type (Table 1). Survival Analysis Five-year DFS was 74.6% (Table 2). The 10 patients with micropapillary predominant subtype had the lowest 5-year DFS (40.0%), followed by those with papillary predominant subtype (65.6%), solid predominant with mucin FIGURE 4. Acinar predominant, this tumor is composed of round-to-oval shaped glands consisting of atypical epithelial cells showing nuclear hyperchromasia and prominent nucleoli (Hematoxylin and Eosin, 200). 1198 FIGURE 5. Papillary predominant, this tumor shows a papillary pattern with cuboidal cells growing along the surface of fibrovascular cores (Hematoxylin and Eosin, 200). production (66.7%), and variants of invasive AC (66.7%). Five-year OS was 86.6%. The 12 patients with solid predominant with mucin production subtype had the lowest 5-year OS (66.7%), followed by patients with micropapillary predominant (80.0%), variants of invasive AC (83.3%), and acinar predominant (85.0%) (Table 2). On the basis of 5-year DFS, patients with different histologic subtypes were divided into three groups. The first group, AIS and MIA, had a 100% 5-year DFS. The second group, lepidic predominant and acinar predominant subtypes, had an 85.2% 5-year DFS. The third group, papillary predominant, micropapillary predominant, solid predominant with mucin production, and variants of invasive AC, had a 62.8% 5-year DFS. There was a significant difference in 5-year DFS among the three groups (p < 0.001) (Fig. 11). Patients with variants of FIGURE 6. Micropapillary predominant, this tumor shows glandular cells growing in small papillary tufts lacking fibrovascular cores (Hematoxylin and Eosin, 200).

Journal of Thoracic Oncology Volume 8, Number 9, September 2013 FIGURE 7. Solid predominant with mucin production, this tumor is composed of solid sheets of tumor cells with intracellular mucin production (Hematoxylin and Eosin, 200). invasive AC had a similar 5-year DFS to those with solid predominant with mucin production. In our series, only one patient had colloid AC. Surgical resection was performed in April 2000, followed by rapid progression and death in February 2001. Two patients with fetal subtype were alive without recurrence or metastases. One tumor was high grade and the other low grade. There was significant difference with respect to DFS among different histologic subtypes (p < 0.001). Women had a significantly greater 5-year DFS than men (81.2% versus 68.1%; p = 0.011) (Fig. 12). Neither age (p = 0.662) nor tumor location (p = 0.363) affected 5-year DFS. There was no correlation of DFS with either tumor gross size (p = 0.185) or tumor invasive size (p = 0.463). FIGURE 8. Invasive mucinous adenocarcinoma, this tumor shows tall columnar mucinous cells line along the alveolar walls with penetration of fibrous stroma (Hematoxylin and Eosin, 200). Pathological Stage IA Adenocarcinomas Versus Prognosis FIGURE 9. Colloid adenocarcinoma, this tumor consists of pools of mucin filling air spaces with well-differentiated malignant glands growing along the edges of the surrounding connective tissue (Hematoxylin and Eosin, 200). Cox Regression Univariate analysis and multivariate analysis in the Cox regression model both showed that sex (hazard ratio = 2.056; 95% confidence interval: 1.124 3.761; p = 0.019) and prognostic groups of the IASLC/ATS/ERS histologic classification (hazard ratio = 4.446; 95% confidence interval: 2.076 9.525; p < 0.001) were significantly associated with 5-year DFS (Table 3). DISCUSSION Patients with stage IA AC have had a variable 5-year survival, ranging from 77.0% to 94.4%.4 6 Our patients had FIGURE 10. Fetal adenocarcinoma, this tumor shows adenoid structure similar to endometrial glands, lined by pseudo-stratified epithelial cells containing glycogen vacuoles (Hematoxylin and Eosin, 200). 1199

Zhang et al. Journal of Thoracic Oncology Volume 8, Number 9, September 2013 TABLE 1. Clinicopathologic Characteristics of 176 Pathological Stage IA Adenocarcinoma Patients TABLE 2. Five-Year DFS and 5-Year OS in 176 Patients with Adenocarcinoma Clinicopathologic Characteristics Total Men Women Total Recurrence 5-Year DFS Death 5-year OS Sex 176 89 87 Age, yr Range 30 79 30 79 34 76 Median 58 59 58 Tumor gross size (cm) Range 0.5 3 Median 1.9 2 115 69 46 >2 61 20 41 Tumor invasive size a (cm) Median 1.8 1.8 106 60 46 >1.8 70 29 41 Tumor location RUL 69 37 32 RML 15 8 7 RLL 23 10 13 LUL 47 26 21 LLL 22 8 14 Predominant subtype AIS 6 4 2 MIA 16 6 10 Lepidic 14 10 4 Acinar 40 16 24 Papillary 72 32 40 Solid 12 10 2 Micropapillary 10 6 4 Variants b 6 5 1 a Adjusted for percentage of lepidic growth. b Variants of invasive adenocarcinoma includes invasive mucinous adenocarcinoma, colloid and fetal subtypes. RUL, right upper lobe; RML, right middle lobe; RLL, right lower lobe; LUL, left upper lobe; LLL, left lower lobe, AIS, adenocarcinoma in situ; MIA, minimally invasive adenocarcinoma. N n SD (%) n (%) AIS 6 0 100 0 100 MIA 16 0 100 0 100 Lepidic 14 2 0.094 85.7 0 100 Acinar 40 6 0.056 85 6 85 0.056 Papillary 72 26 0.057 65.6 14 85.5 0.042 Solid 12 4 0.136 66.7 4 66.7 0.136 Micropapillary 10 6 0.155 40 2 80 0.126 Variants a 6 3 0.192 66.7 1 83.3 0.152 a Variants of invasive adenocarcinoma include invasive mucinous adenocarcinoma, colloid and fetal subtypes. DFS; disease-free survival; AIS, adenocarcinoma in situ; MIA, minimally invasive adenocarcinoma; SD, standard deviation; OS, overall survival. impact of tumor size as a prognostic factor in stage Ia non small-cell lung cancer. 12 16 The current ptnm staging system does not consider histopathology or tumor differentiation. 17 Sakao et al. 5 reported that tumors with a BAC component exhibited less invasion and aggressive biological behavior, and that it was the size of the non-bac component that was prognostic. In 2011, the new IASLC/ATS/ERS classification of lung AC was proposed to identify histologic categories with prognostic differences. Yoshizawa et al. 7 reported the IASLC/ATS/ ERS histologic classification was predictive of prognosis in stage I AC (p = 0.038). Their data set revealed that AIS and MIA had a 100.0% 5-year DFS. Nonmucinous lepidic predominant, papillary predominant, and acinar predominant subtypes had 90.0%, 83.0%, and 84.0% 5-year DFS, respectively. Invasive mucinous AC, colloid adenocarcinoma, SD an 86.6% 5-year OS, and 74.6% 5-year DFS. The prognosis for patients with surgically resected stage IA AC could be improved. Multiple factors might influence their long-term survival and frequency of recurrence. Tsuneyo et al. 11 pointed out that lymph node metastases not observed during surgery could be identified during pathological examination. Patients without segmental lymph node sampling may be understaged, leading to incorrect treatment. The poor prognosis associated with stage IA AC implies that the current T descriptor (tumor size) does not completely reflect the biological behavior of the tumors. In our patients, neither tumor gross size nor invasive size had correlation with 5-year DFS. Yoshizawa et al. 7 pointed out that both tumor gross size (p = 0.04) and invasive size adjusted by the percentage of lepidic growth (p = 0.026) were poor prognostic factors in stage I AC. There is still, however, other conflicting evidence to support the FIGURE 11. Five-year disease-free survival in the three groups: AIS and MIA, lepidic and acinar predominant, papillary, micropapillary, and solid predominant (p < 0.001). AIS, adenocarcinoma in situ; MIA, minimally invasive adenocarcinoma. 1200

Journal of Thoracic Oncology Volume 8, Number 9, September 2013 Pathological Stage IA Adenocarcinomas Versus Prognosis FIGURE 12. There was a significant difference in 5-year disease-free survival between men and women (p = 0.011). solid predominant with mucin production, and micropapillary predominant subtypes had 75.0%, 71.0%, 70.0%, and 67.0% 5-year DFS, respectively. Our findings were similar to those of Yoshizawa et al., 7 with AIS and MIA being associated with good prognosis, and solid predominant with mucin production and micropapillary predominant subtypes associated with poor prognosis. We found the 5-year DFS in papillary predominant subtype (65.6%) to be significantly lower than that reported (83%) by Yoshizawa et al. 7. This suggested the papillary predominant and solid predominant with mucin production subtypes have poor prognosis. 18 We found that the micropapillary predominant subtype was apt to recur or metastasize early, similar to literature reports. 8,19 21 Patients with this diagnosis require further oncologic evaluation and clinical attention. Owing to their good prognosis, patients with AIS or MIA may be treated with a limited surgical resection (wedge resection or segmental resection). Whether a limited resection provides similar or better result as lobectomy is still questioned. 22 More study is needed to validate this. More attention should be directed on progression after surgery for patients with micropapillary predominant subtype, solid predominant with mucin production, and variants of invasive AC subtypes. The relatively poor prognosis (recurrence or metastasis) of the lepidic predominant adenocarcinoma predominant subtype in our study was likely caused by the invasive component such as papillary component. Sakurai et al. 23 and Tsuboi et al. 24 reported women with AC had a better prognosis than men for pathologic stage I disease. In our study, male patients had an obviously poorer prognosis than their female counterparts both in univariate and multivariate analyses. In summary, our study revealed that in pathological stage IA AC patients, neither tumor gross size nor invasive size was related to prognosis. Sex was an independent prognostic factor of pathological stage IA AC. The IASLC/ATS/ ERS classification of lung AC identifies histologic categories with prognostic differences that could be helpful in clinical therapy. Patients with poor prognostic histologic components, such as micropapillary or solid predominant with mucin TABLE 3. Univariate Analysis and Multivariate Analysis with 5-year DFS Characteristic No. of Patients 5-yr DFS Probability (%) Univariate p Value by Log-Rank Test Multivariate Analysis HR 95% CI p Overall 176 74.6 Age, yr 58 88 73.4 0.662 Not included in multivariable model >58 88 75.9 Sex Female 87 81.2 0.011 1 Male 89 68.1 2.050 1.121 3.750 0.020 Location Right 107 77.1 0.363 Not included in multivariable model Left 69 70.8 Tumor gross size 2 cm (T1a) 115 70.0 0.185 Not included in multivariable model >2 cm (T1b) 61 81.4 Tumor invasive size 1.8 cm 106 75.4 0.463 Not included in multivariable model >1.8 cm 70 73.3 Prognositic groups of the new classification d 176 <0.001 3.866 1.942 7.698 <0.001 The HR value means the relative risk when the histologic differentiation rises up a level. d As a grading indicator, prognostic groups of the new classification are taken as quantitative data in patients survival analysis. CI, confidence interval; DFS, disease-free survival; HR, hazard ratio. 1201

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