Completely Resected N0 Non-Small Cell Lung Cancer: Prognostic Factors Affecting Long-Term Survival

Background. Although early stage non-small cell lung cancer (NSCLC) has an excellent outcome and correlated with good long-term survival, up to 15 percent of patients still relapse postoperatively and die. This study is conducted to identify prognostic factors that may affect the long-term survival in completely resected N0 NSCLC. Methods. Medical records of 124 patients with completely resected N0 NSCLC were retrospectively reviewed. Prognostic factors affecting long-term survival were analyzed by the Kaplan-Meier method and Cox proportional hazards analysis. Results. Overall five-year survival rate was 48 percent. Multivariable analysis revealed stage of disease, tumor necrosis, tumor recurrence, brain metastasis, adrenal metastases, and skin metastases as significant prognostic factors affecting long-term survival. The hazard ratio (HR) of tumor necrosis, tumor recurrence, brain metastasis, adrenal metastases, and skin metastases was 2.0, 2.3, 7.6, 4.1, and 8.3, respectively, and all P values were less than 0.001. Conclusions. Our study shows stage of disease, tumor necrosis, tumor recurrence, brain metastasis, adrenal metastasis, and skin metastasis as the independent prognostic factors of long-term survival in pathological N0 NSCLC. Early stage NSCLC patients without nodal involvement or presented with tumor necrosis should benefit from adjuvant chemotherapy, and sites of metastasis could predict the long-term survival as described.


Introduction
The curative treatment for early stage non-small cell lung cancer (NSCLC) patients without nodal involvement is surgery alone; however, some pathological characteristics may be associated with poor prognostic of long-term survival. Overall 5-year survival rates in completely resected stages IA and IB NSCLC range from 67 to 89% and from 57 to 75%, respectively; therefore, there are some poor prognostic factors that affect the overall survival despite presenting in the same stage [1][2][3][4]. Recently, some prognostic factors such as intratumoral blood vessel invasion (IVI), intratumoral lymphatic invasion (ILI), visceral pleural invasion, tumor size, and serum level of carcinoembryonic antigen (CEA), have been proposed in order to identify poor prognostic factors providing beneficial adjuvant chemotherapy for stage I NSCLC patients. Some studies showed that the strong poor prognostic factors in these patients are IVI and ILI [1,[5][6][7]. The purpose of this study is to identify prognostic factors associated with poor prognosis in overall survival in completely resected N0 NSCLC patients.

Patients and Methods
Between January 2008 and December 2011, 232 patients underwent anatomical resection (lobectomy, sleeve lobectomy, bilobectomy, and pneumonectomy) with systematic mediastinal lymph node dissection at Chiang Mai University Hospital, Chiang Mai, Thailand. One-hundred twentyfour patients were enrolled in this study because of no pathological lymph node involvement. We retrospectively reviewed these 124 cases from the medical recording system with regard to patient characteristics, signs and symptoms, tumor pathologic report, and follow-up status to examine the prognostic factors affecting the overall survival. In the preoperative evaluation, standard laboratory tests such as complete blood count (CBC), liver and renal function test, electrolyte, chest film, computed tomographic (CT) scan of the thorax including the upper abdomen, pulmonary function test, and bronchoscopy were performed on all of the patients. Bone scan and CT of the brain were obtained only in patients who had evidence of bone or brain metastasis. Patients with evidence of residual tumor at the resection margin (five patients) or who died within the first 28 days of the surgery (postoperative mortality) (three patients) or had single brain metastasis who underwent a craniectomy to remove tumor before pulmonary resection without nodal involvement (five patients) were all excluded. All of these patients did not received adjuvant chemotherapy.
The surgical procedures consisted of 114 lobectomies (91.9%) and 10 bilobectomies (8.1%). Systematic mediastinal lymph node dissection was performed in all cases, and all nodal stations were labeled according to the staging manual in thoracic oncology [8].
All excised specimens were formalin-fixed and sliced at ten-millimeter intervals. Histopathologic examination was performed by the same pathologist. Pathological staging was determined according to the IASLC TNM staging classification of NSCLC [9]. Histological subtypes of lung cancer were determined according to World Health Organization classification [10]. Visceral pleural invasion was defined as tumor extending beyond the elastic layer of the visceral pleura and/or exposed on the pleural surface but did not involve the parietal pleura. IVI and ILI were defined as tumor cells identifiable in the blood vessel lumen and lymphatic lumen, respectively. Tumor necrosis was defined as coagulative necrosis identifiable in the tumor. Tumor involvement of epineurium was defined as perineural invasion [11].
All patients were actively followed postoperatively for two weeks and for three-to six-month intervals for the first two years, and then yearly thereafter with a CT scan of the chest and upper abdomen. If patients developed signs or symptoms that correlated with tumor recurrence or metastasis, they would be worked up according to their signs or symptoms (i.e., CT brain or bone scan). Tumor recurrence was defined as evidence of tumor within the same lobe, the hilum, or the mediastinal lymph nodes (locoregional recurrence) or evidence of tumor in another lobe or elsewhere outside the hemithorax (distant recurrence). The interval to recurrence was defined as the interval between the time of the operation and the discovery of the recurrence by means of either imaging or cytopathological examination. Patients who developed brain metastasis were treated with whole brain radiation (multiple brain metastasis) or tumor excision (single brain metastasis and no other site of metastasis).
Standard chemotherapy and radiotherapy were used when having an indication.
The overall survival curves were estimated using the Kaplan-Meier method. Prognostic factors for overall survival were investigated univariately and multivariately by using a Cox multivariable regression model stratified by age. Univariable prognostic factors significant at the 0.05 level were considered for the multivariable models. Values of < 0.05 were considered significant. All tests were two-tailed and performed with commercial statistical software STATA version 11.0 (STATA Corp., CS, USA).
This study was reviewed and approved by the Research Ethics Committee, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.

Results
Patient's characteristic and pathological reports of patients are shown in Tables 1 and 2. The study cohort included 53 women and 71 men with a mean age of 61.8 years (range 24-83 years). Most common clinical presentation is chronic cough and hemoptysis. Forty-one percent of these patients are asymptomatic. Lobectomy is the most common procedure (91.9%). Histopathology was adenocarcinoma in 70 patients Univariable analysis demonstrated that there are eight significant prognostic factors which affect the overall survival ( < 0.05): age ≥ 70 years, staging of lung cancer, tumor necrosis, tumor recurrence, brain metastasis, adrenal metastasis, and skin metastasis (Table 3). No significant difference was seen for gender, smoking, histologic grading, histologic cell type, visceral pleural invasion, intratumoral blood vessel invasion, intratumoral lymphatic invasion, and other sites of metastasis.
Overall survival estimates curves by stage of NSCLC, tumor necrosis, tumor recurrence, brain metastasis, skin  Table 5. Patients who had any prognostic factor had significant shorter overall 2-year and 5-year survival than patients who did not have. There was only one patient that had adrenal metastasis, and this patient died within 2 months after diagnosed adrenal metastasis because one month after that he had lung metastasis and developed respiratory failure.

Discussion
The aim of this study was to identify independent prognostic factors of long-term survival in patients diagnosed early stage NSCLC (no nodal involvement) who underwent completely anatomical resection and mediastinal lymph node dissection. The principle findings were stage of disease or tumor size, tumor necrosis, tumor recurrence, brain metastasis, skin metastasis, and adrenal metastasis that are prognostic factors of poor long-term survival.
Regarding intratumoral blood vessel and lymphatic invasion, many previous studies showed that these factors have been considered as prognostic factors [12,20,21]. Yilmaz et al. [11] reported that lymphovascular invasion can show a higher risk of mortality in completely resected NSCLC. Pechet et al. [12] summarized that presentation of arterial invasion in stage I NSCLC patients was adversely associated with poor survival (hazard ratio (HR) of 3.5 and value < 0.001). Miyoshi et al. [21] and Shoji et al. [13] concluded that IVI was independent prognostic factor in pathological stage I NSCLC patients. In contrast, some studies did not show the relevant prognostic factors [22]. In our study, IVI and ILI have not been shown as prognostic factors. This study also did not demonstrate visceral pleural invasion as poor prognostic factor of overall survival like other previous studies [11,23]. Maximum tumor diameter is a valuable prognostic factor based on gross specimen [19]. In our study, stage of disease (only T is affected because no nodal involvement) is one of the poor prognostic factors. The overall survival of patients who diagnosed with stage II was significantly shorter than that of diagnosed with stage I. This result was the same as the study of Harada et al. [20] and other previous studies [24].
There were no previous studies demonstrating that the tumor necrosis was the poor prognostic factor. In our study, presenting tumor necrosis in stages IA, IB, IIA, and IIB was 12.1%, 33.3%, 66.7%, and 60.0%, respectively. As we have noticed, large tumors have more percentage of tumor necrosis than the small ones. One of the possible reasons why big  We already knew that tumor recurrence was poor prognostic factor of overall survival. Our results confirm that theory, however we found that brain metastasis, adrenal metastasis and skin metastasis were poor prognostic factors

ISRN Surgery
of overall survival comparing with other sites of tumor recurrence. There were no previous studies that show correlation between site of tumor recurrence and overall survival in completely resected early stage NSCLC patients.
Limitation of this study was retrospective nature and small sample size. Some prognostic factors that did not show poor prognostic factors may be because of small sample size. We also believe that large-scale studies are necessary to clarify the result of this study.

Conclusion
This study demonstrated that T stage of disease, tumor necrosis, tumor recurrence, brain metastasis, adrenal metastasis, and skin metastasis are poor prognostic factors of overall survival in completely resected early stage NSCLC patients. Patients who diagnosed more than pathologic stage IA or presented with tumor necrosis may gain survival benefits from adjuvant chemotherapy.