Abstract
Background: This study aimed to elucidate the intensive effect of the number of positive niduses in extranodal soft tissues (PNESTs) on the overall survival of gastric cancer (GC) patients after curative gastrectomy. Methods: The clinicopathological data of 961 GC patients were studied to determine whether increased number of PNESTs was a high-risk factor for the dismal prognosis of GC patients. Results: Survival analyses revealed that the number of PNESTs was negatively associated with the overall survival (OS) (P<0.001) and was an independent prognostic predictor (HR=1.360, P<0.001) for the 961 GC patients. The number of PNESTs, with the smallest BIC value (421.947, P=0.018), was identified as the most intensive independent predictor of prognosis for the 961 GC patients. Correlation analyses showed that the pT stage, pN stage, pTNM classification, tumor size, and type of gastrectomy were significantly related to the number of PNESTs, and that tumor size was the most closely relevant factor in all included GC patients. These findings revealed that increased number of PNESTs was suitable to evaluate the dismal prognosis of GC patients. Conclusions: The number of PNESTs is an important high-risk clinicopathological characteristic for improving the accuracy of prognostic evaluation of GC patients.
Keywords: Stomach, neoplasm, nidus, soft tissue, prognosis
Introduction
Gastric cancer (GC) is the second leading cause of cancer-related deaths worldwide for more than two decades, and the overall survival (OS) of GC patients remains dismal [1,2]. The number of lymph node metastasis of GC is the one of the most intensive prognostic predictors for the OS of patients after surgery [3,4]. To date, the prognostic evaluation for GC patients is commonly performed during the N stage, which is based on the positive nodal count, compared with the other categories of lymph node metastasis. However, many researchers stated that the positive niduses in extranodal soft tissues (PNESTs) should be redefined as an important prognostic predictor, owing to the involvement of primary tumor proliferation or the spreading of lymphatic system. According to recent reports, 10%-28% of GC specimens were revealed by the PNESTs through a routine pathological examination [5]. Tanabe et al. [6] reported that esophageal squamous cell carcinoma patients with PNESTs have a higher risk of recurrence, and PNESTs are the most intensive negative factor in evaluating the OS of patients after surgery. Furthermore, PNEST patients with 1-3 metastatic lymph nodes exhibited a lower 5-year survival rate and a significantly higher recurrence rate than the negative NEST (NNEST) patients with 1-3 metastatic lymph nodes. Conversely, Greenberg et al. [7] reported that oral tongue cancer PNEST patients with multiple positive lymph nodes have shorter median OS, lower disease-specific survival rate, and smaller disease-free interval than PNEST patients with a single positive lymph node. Therefore, the PNEST patients with the multiple positive lymph nodes were recommended to participate in the clinical trials to intensify their regional controlling and systemic therapy. A recent systematic review that includes 3250 GC patients showed that PNESTs are significantly associated with a higher risk of all-cause mortality, cancer-specific mortality, and disease recurrence compared with other clinicopathological characteristics [8].
Many investigators stated that PNEST should be used as a negative predictor of the OS of patients after gastrectomy; however, the specific contribution of PNESTs to the prognosis of GC remains unknown. Jiang et al. [9] found that the existence of PNESTs, which represents the aggressiveness of the tumor, is a significant independent predictor of reduced disease-free survival and OS in GC patients. Thus, PNESTs should be incorporated into the N stage to improve the accuracy of prognostic evaluation. Chen et al. [10] also reported that PNEST patients have more advanced primary tumor and worse prognosis than NNEST patients, which indicates that PNESTs should be considered as an essential supplementary to the TNM classification for GC.
The correlation between the number of PNESTs and the prognosis of GC patients is not yet explained in any formally published article. In the present study, we analyzed the clinicopathological data and follow-up records of GC patients to elucidate the detailed correlation between the number of PNESTs and the prognosis of GC patients. In addition, we aim to determine whether the number of PNESTs can be used as a novel variable in improving the precious staging of tumor and the accuracy of the prognostic evaluation for patients.
Materials and methods
Patients
The eligible participants in this study include patients aged 20 years or older who underwent surgical resection for GC at the Gastric Cancer Surgery Division, Tianjin Medical University Cancer Hospital from March 2003 to December 2011. Patients were selected according to the eligibility criteria: 1) patients with histologically proven primary cancer of the stomach; 2) patients without a history of gastrectomy or other malignancies; 3) patients without any non-curative surgical factors (such as distant metastasis, positive peritoneal cytology, or peritoneal dissemination); 4) patients with non-esophagogastric junction tumor; 5) patients with pathologically negative resection margins (R0 resection); and 6) patients who remained alive during the initial hospital stay and during the first postoperative month. After applying these criteria, 961 GC patients were included in the study.
Surgical management
All patients underwent standard R0 resection. Primary tumors were resected en bloc using lymphadenectomy (D1, D2, or D2+) according to the guidelines of the Japanese Gastric Cancer Association [11]. Limited lymphadenectomy (D1) entails the removal of the perigastric nodes only, whereas extended lymphadenectomy (D2 or D2+) involves the removal of both perigastric and extragastric nodes. The choice of surgical procedure for gastrectomy (total gastrectomy or subtotal gastrectomy) was according to the attending surgeon’s preference and was based on the gastric cancer treatment guidelines in Japan [12].
Follow-up evaluation
After undergoing curative surgery, all patients were required to follow up every 3 or 6 months for 2 years and annually thereafter until death. The median follow-up time for the entire cohort was 39 months (range of 2-138 months). The follow-up evaluation of all the patients included in this study was completed in December 2016. The OS rate was calculated from the day of surgical resection until the time of death or final follow-up. Ultrasonography, computed tomography scans, chest X-rays, and endoscopy were performed at every visit.
Statistical analysis
To determine the most appropriate cut-off values for continuous data variables, such as tumor size and the number of PNESTs, the cut-point survival analysis [13] was adopted. According to the result of the cut-point survival analysis, the number of PNESTs intervals were as follows: NNEST (PNEST=0), the number of PNESTs between 1 and 2 (1≤PNESTs≤2), and the number of PNESTs of more than 3 (PNESTs≥3). Various clinicopathological factors were analyzed using the method of Kaplan and Meier, and the log-rank test was used to determine the univariate significance. The multivariate analysis includes factors that were potentially important for the univariate analysis (P<0.05). Models of logistic regression or Cox proportional hazards were used for the multivariate analysis. Hazard ratios and 95% confidence intervals were generated. Akaike information criterion (AIC) and Bayesian IC (BIC) values for each category were calculated to measure the discriminatory ability within the Cox proportional hazard regression model. Smaller AIC or BIC value indicates a better model for predicting outcomes [14,15]. Significance was defined as P<0.05. All statistical analyses were performed using SPSS 22.0 software.
Results
General information
Analysis was performed on the data from 961 gastric cancer patients, including 688 men (71.6%) and 273 women (28.4%). The mean age of the patients was 60.13 ± 11.53 years (range of 20-84 years). The median OS of the patients after curative surgery was 28 months. PNESTs with a mean number of 0.7 ± 1.37 (range 0-13) per patient were dissected for the histopathological examination after surgery. All patients were divided into three categories according to the number of PNESTs: 608 patients had a NNEST (PNEST=0), 288 patients had the number of PNESTs between 1 and 2 (1≤PNESTs≤2), and 65 patients had the number of PNESTs of more than 3 (PNESTs≥3).
Significant factor characteristics associated with OS of GC after curative surgery
According to the univariate analysis, the following 10 clinicopathological characteristics were significantly associated with OS after the curative surgery for the 961 patients enrolled in the study: pT stage (according to the 7th-edition TNM classification), pN stage (according to the 7th-edition TNM classification), pTNM classification (according to the 7th-edition TNM classification), tumor size, tumor location, type of gastrectomy, extent of lymphadenectomy, Lauren classification, and the number of PNESTs (Figure 1; Table 1). According to the multivariate analysis (Cox proportional hazards model with Bootstrap procedure), the number of PNESTs was an independent prognostic predictor (HR=1.360, P<0.001) for the 961 GC patients; other qualifying predictors include the pT stage (HR=1.219, P<0.001), pN stage (HR=1.294, P<0.001), tumor location (HR=1.080, P=0.020), type of gastrectomy (HR=0.796 , P<0.001), and extent of lymphadenectomy (HR=0.839, P<0.001) (Table 1).
Figure 1.
Survival curve of patients according to the number of PNESTs subgroups.
Table 1.
Survival analysis of the 961 gastric cancer patients
| Characteristics | Cases | 5-YSR (%) | χ2 value | Univariate P value | Multivariate P value | Hazard ratio (95% CI) | |
|---|---|---|---|---|---|---|---|
| Age | 2.695 | 0.101 | |||||
| ≤65 yrs | 614 | 28.7 | |||||
| ≥66 yrs | 347 | 27.5 | |||||
| Gender | 0.068 | 0.769 | |||||
| Male | 688 | 27.9 | |||||
| Female | 273 | 27.5 | |||||
| pT stage | 72.410 | <0.001 | <0.001 | 1.219 (1.095-1.357) | |||
| T1a | 9 | 66.7 | |||||
| T1b | 17 | 64.7 | |||||
| T2 | 99 | 55.6 | |||||
| T3 | 53 | 37.7 | |||||
| T4a | 742 | 23.0 | |||||
| T4b | 41 | 6.0 | |||||
| pN stage | 177.161 | <0.001 | <0.001 | 1.294 (1.215-1.377) | |||
| N0 | 306 | 45.8 | |||||
| N1 | 191 | 28.8 | |||||
| N2 | 236 | 21.2 | |||||
| N3a | 159 | 11.9 | |||||
| N3b | 69 | 13.0 | |||||
| pTNM classification | 188.866 | <0.001 | |||||
| Ia | 21 | 71.4 | |||||
| Ib | 62 | 59.7 | |||||
| IIa | 43 | 39.5 | |||||
| IIb | 224 | 42.0 | |||||
| IIIa | 162 | 24.7 | |||||
| IIIb | 228 | 18.9 | |||||
| IIIc | 221 | 8.1 | |||||
| Tumor size | 35.045 | <0.001 | |||||
| ≤4 | 359 | 37.3 | |||||
| >4 | 602 | 22.1 | |||||
| Tumor location | 22.272 | <0.001 | 0.020 | 1.080 (1.012-1.151) | |||
| Upper third | 291 | 24.7 | |||||
| Middle third | 89 | 32.6 | |||||
| Lower third | 381 | 34.9 | |||||
| >2/3 stomach | 200 | 21.0 | |||||
| Type of gastrectomy | 62.247 | <0.001 | <0.001 | 0.796 (0.727-0.871) | |||
| Total | 255 | 15.7 | |||||
| Proximal subtotal | 252 | 25.0 | |||||
| Distal subtotal | 454 | 36.1 | |||||
| Extent of lymphadenectomy | 17.562 | <0.001 | <0.001 | 0.839 (0.779-0.903) | |||
| Less than D2 | 428 | 22.4 | |||||
| D2 or D2+ | 533 | 32.1 | |||||
| No. of examined lymph nodes | 0.026 | 0.872 | |||||
| ≤15 | 525 | 27.6 | |||||
| ≥16 | 436 | 28.0 | |||||
| Lauren classification | 10.678 | 0.005 | |||||
| Intestinal | 262 | 34.0 | |||||
| Diffuse | 636 | 24.2 | |||||
| Mixed | 23 | 26.1 | |||||
| PNEST | 93.974 | <0.001 | |||||
| Negative | 608 | 36.2 | |||||
| Positive | 353 | 13.3 | |||||
| The number of PNESTs | 120.904 | <0.001 | <0.001 | 1.360 (1.201-1.541) | |||
| 0 | 608 | 36.2 | |||||
| 1-2 | 288 | 15.6 | |||||
| 3 or more | 65 | 7.7 | |||||
5-YSR 5-year survival rate.
Significant factors associated with the number of PNESTs after curative surgery for GC
According to the multinomial logistical regression analysis, the number of PNESTs, with the smallest BIC value (421.947, P=0.018), was the most intensive independent predictor of prognosis for the 961 GC patients (Table 2). Furthermore, according to the correlation analyses between the number of PNESTs and other characteristics of the patients, the factors associated with the number of PNESTs include the pT stage, pN stage, pTNM classification, tumor size, and type of gastrectomy (Table 3). Tumor size was identified as the most closely relevant factor to the number of PNESTs in all included GC patients.
Table 2.
Akaike information criterion (AIC) and Bayesian information criterion (BIC) values test of prognosis characteristics for the gastric cancer patients
| AIC value | BIC value | -2 Log likelihood value | P | |
|---|---|---|---|---|
| pT stage | 401.396 | 430.604 | 389.396 | <0.001 |
| pN stage | 413.790 | 442.998 | 401.790 | <0.001 |
| Tumor location | 387.245 | 416.453 | 375.245 | 0.743 |
| Type of gastrectomy | 398.781 | 427.989 | 386.781 | 0.001 |
| Extent of lymphadenectomy | 401.234 | 430.441 | 389.234 | <0.001 |
| The number of PNESTs | 392.739 | 421.947 | 380.739 | 0.018 |
TNM tumor-node-metastasis.
Table 3.
Correlation analyses between the number of positive niduses in extranodal soft tissues (PNESTs) and other characteristics of the 961 gastric cancer patients
| Characteristics | Cases | The number of PNESTs | χ2 value | P value | ||
|---|---|---|---|---|---|---|
|
|
||||||
| 0 | 1-2 | 3 or more | ||||
| Age | 0.752 | 0.686 | ||||
| ≤65 yrs | 614 | 383 | 187 | 44 | ||
| ≥66 yrs | 347 | 225 | 101 | 21 | ||
| Gender | 2.552 | 0.279 | ||||
| Male | 688 | 445 | 196 | 47 | ||
| Female | 273 | 163 | 92 | 18 | ||
| pT stage | 79.806 | <0.001 | ||||
| T1a | 9 | 8 | 1 | 0 | ||
| T1b | 17 | 0 | 0 | 0 | ||
| T2 | 99 | 94 | 5 | 0 | ||
| T3 | 53 | 41 | 11 | 1 | ||
| T4a | 742 | 432 | 252 | 58 | ||
| T4b | 41 | 16 | 19 | 6 | ||
| pN stage | 155.874 | <0.001 | ||||
| N0 | 306 | 267 | 34 | 5 | ||
| N1 | 191 | 125 | 55 | 11 | ||
| N2 | 236 | 131 | 87 | 18 | ||
| N3a | 159 | 59 | 82 | 18 | ||
| N3b | 69 | 26 | 30 | 13 | ||
| pTNM classification | 183.859 | <0.001 | ||||
| Ia | 21 | 21 | 0 | 0 | ||
| Ib | 62 | 59 | 3 | 0 | ||
| IIa | 43 | 38 | 5 | 0 | ||
| IIb | 224 | 190 | 28 | 6 | ||
| IIIa | 162 | 101 | 53 | 8 | ||
| IIIb | 228 | 121 | 87 | 20 | ||
| IIIc | 221 | 78 | 112 | 31 | ||
| Tumor size | 33.783 | <0.001 | ||||
| ≤4 | 359 | 268 | 79 | 12 | ||
| >4 | 602 | 340 | 209 | 53 | ||
| Tumor location | 8.835 | 0.183 | ||||
| Upper third | 291 | 189 | 85 | 17 | ||
| Middle third | 89 | 56 | 25 | 8 | ||
| Lower third | 381 | 252 | 108 | 21 | ||
| >2/3 stomach | 200 | 111 | 70 | 19 | ||
| Type of gastrectomy | 23.324 | <0.001 | ||||
| Total | 255 | 134 | 91 | 30 | ||
| Proximal subtotal | 252 | 166 | 74 | 12 | ||
| Distal subtotal | 454 | 308 | 123 | 23 | ||
| Extent of lymphadenectomy | 1.778 | 0.411 | ||||
| Less than D2 | 428 | 261 | 137 | 30 | ||
| D2 or D2+ | 533 | 347 | 151 | 35 | ||
| No. of examined lymph nodes | 3.463 | 0.177 | ||||
| ≤15 | 525 | 346 | 146 | 33 | ||
| ≥16 | 436 | 262 | 142 | 32 | ||
| Lauren classification | 6.760 | 0.149 | ||||
| Intestinal | 262 | 180 | 68 | 14 | ||
| Diffuse | 636 | 381 | 205 | 50 | ||
| Mixed | 14 | 8 | 1 | |||
Discussion
Alakus et al. [16] stated that PNEST is an independent negative predictor of prognosis in GC patients. Recently, Jiang et al. [9] also reported that PNEST is closely associated with cancer cell aggressiveness, and the presence of PNEST represents a statistical significance to the OS of GC patients after curative resection. In this study, we further revealed that the count of PNESTs is potentially an independent prognostic factor for GC patients. Thus, PNESTs should be meticulously validated for the subtle discriminations of the survival curves of various subgroups of GC patients. In theory, the quantitative division of PNESTs reflects the biological behavior of the cancer cells, including migration, invasion, proliferation, chemotaxis, and lymphangiogenesis. Therefore, Etoh et al. [17] previously proposed that PNEST should be adopted in the TNM staging system to improve the accuracy of the prognostic prediction of GC.
Although the TNM classification is the optimal indicator in evaluating the prognosis of GC patients, further studies showed that the prognosis of GC is interfered by a variety of clinicopathological characteristics [18,19]. A large variation of the incidence (between 10% and 28%) of PNEST was reported in several retrospective investigations [5,17]. However, no consensus was formed about the rational explanation for the mechanisms of the germination of PNEST in GC patients.
Two principal explanations are considered as the potential mechanisms of PNESTs in cancer cases. First, cancer cells depart from the primary lesion and then disseminate in the soft tissues via the lymphatic vessels, blood circulation, or serosal penetration. This explanation of germination of PNESTs is the oretically applicable to patients with systematic spreading or distant metastasis, which indicates that the prognoses of patients are dismal. Furthermore, cancer cells are detected in the perigastric lymph nodes in minor patients with GC. With the continuous proliferation of cancer cells, some perigastric nodes are damaged and the normal configuration is destroyed; thus, the pathologists might mistakenly identify the positive lymph nodes as PNESTs (Figure 2). Positive lymph nodes are false PNESTs but are also significantly associated with the prognosis of GC patients.
Figure 2.
False PNESTs: With the continuous proliferation of cancer cells, some perigastric nodes were destroyed and the normal configuration was disrupted; thus, the positive lymph nodes were mistakenly identified as PNESTs.
In the present study, we showed a significant correlation between PNESTs and pN stage in the GC patients, revealing the necessity to include the prognostic evaluation abilities of various counts of PNESTs in the quantitative analysis. Similar conclusions were proposed by Etoh [17].
In this study, we initially analyzed the contribution and clinical applicability of the count of PNESTs in the accurate evaluation of the OS of GC patients. Among the clinicopathological variables, the count of PNESTs was the most intensive predictor in accurately evaluating the OS of all included GC patients after surgery. The results of multinomial logistical regression analysis also showed that the count of PNESTs effectively improved the accuracy of OS prediction of patients by using the BIC value calculation. As a comprehensive clinicopathological factor in evaluating the OS of GC patients, the number of PNESTs generally helps in the accurate assessment of the patients’ prognosis and in the selection of the potential optimal treatment for patients. In the present study, all included patients were strictly selected in accordance with the standard R0 resection plus lymphadenectomy. Therefore, we believe our results provide some positive information for future studies. The limitation of the present study is the relatively small number of patients. A subsequently large scale and multi-center clinical study will be conducted to further confirm the correlation between the number of PNESTs and the prognosis of GC patients.
Acknowledgements
Supported in part by grants from the Program of National Natural Science Foundation of China (NO. 81572372), National Precision Medicine Research Programme (2017YFC0908300), the Application Foundation and Advanced Technology Program of Tianjin Municipal Science and Technology Commission (NO. 15JCYBJC24800), National key research and development program of major chronic non-infectious disease prevention and control research (NO. 2016YFC1303200) and the National Key Clinical Specialist Construction Programs of China (NO. 2013-544).
Disclosure of conflict of interest
None.
References
- 1.Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin. 2012;62:10–29. doi: 10.3322/caac.20138. [DOI] [PubMed] [Google Scholar]
- 2.Kanda M, Kodera Y, Sakamoto J. Updated evidence on adjuvant treatments for gastric cancer. Expert Rev Gastroenterol Hepatol. 2015;9:1549–1560. doi: 10.1586/17474124.2015.1094373. [DOI] [PubMed] [Google Scholar]
- 3.Marrelli D, Morgagni P, de Manzoni G, Coniglio A, Marchet A, Saragoni L, Tiberio G, Roviello F Italian Research Group for Gastric Cancer (IRGGC) Prognostic value of the 7th AJCC/UICC TNM classification of noncardia gastric cancer: analysis of a large series from specialized Western centers. Ann Surg. 2012;255:486–491. doi: 10.1097/SLA.0b013e3182389b1a. [DOI] [PubMed] [Google Scholar]
- 4.Deng J, Zhang R, Pan Y, Wang B, Wu L, Jiao X, Bao T, Hao X, Liang H. Comparison of the staging of regional lymph nodes using the sixth and seventh editions of the tumor-node-metastasis (TNM) classification system for the evaluation of overall survival in gastric cancer patients: findings of a case-control analysis involving a single institution in China. Surgery. 2014;156:64–74. doi: 10.1016/j.surg.2014.03.020. [DOI] [PubMed] [Google Scholar]
- 5.Tanaka T, Kumagai K, Shimizu K, Masuo K, Yamagata K. Peritoneal metastasis in gastric cancer with particular reference to lymphatic advancement; extranodal invasion is a significant risk factor for peritoneal metastasis. J Surg Oncol. 2000;75:165–171. doi: 10.1002/1096-9098(200011)75:3<165::aid-jso3>3.0.co;2-5. [DOI] [PubMed] [Google Scholar]
- 6.Tanabe T, Kanda T, Kosugi S, Ikeda Y, Makino S, Komukai S, Ohashi M, Suzuki T, Hatakeyama K. Extranodal spreading of esophageal squamous cell carcinoma: clinicopathological characteristics and prognostic impact. World J Surg. 2007;31:2192–2198. doi: 10.1007/s00268-007-9204-2. [DOI] [PubMed] [Google Scholar]
- 7.Greenberg JS, Fowler R, Gomez J, Mo V, Roberts D, El Naggar AK, Myers JN. Extent of extracapsular spread: a critical prognosticator in oral tongue cancer. Cancer. 2003;97:1464–1470. doi: 10.1002/cncr.11202. [DOI] [PubMed] [Google Scholar]
- 8.Veronese N, Fassan M, Wood LD, Stubbs B, Solmi M, Capelli P, Pea A, Nottegar A, Sergi G, Manzato E, Carraro S, Maruzzo M, Cataldo I, Bagante F, Barbareschi M, Cheng L, Bencivenga M, de Manzoni G, Luchini C. Extranodal extension of nodal metastases is a poor prognostic indicator in gastric cancer: a systematic review and meta-analysis. J Gastrointest Surg. 2016;20:1692–1698. doi: 10.1007/s11605-016-3199-7. [DOI] [PubMed] [Google Scholar]
- 9.Jiang N, Deng JY, Ding XW, Ke B, Liu N, Liang H. Node-extranodal soft tissue stage based on extranodal metastasis is associated with poor prognosis of patients with gastric cancer. J Surg Res. 2014;192:90–97. doi: 10.1016/j.jss.2014.05.053. [DOI] [PubMed] [Google Scholar]
- 10.Chen XL, Zhao LY, Xue L, Xu YH, Zhang WH, Liu K, Chen XZ, Yang K, Zhang B, Chen ZX, Chen JP, Zhou ZG, Hu JK. Prognostic significance and the role in TNM stage of extranodal metastasis within regional lymph nodes station in gastric carcinoma. Oncotarget. 2016;7:67047–67060. doi: 10.18632/oncotarget.11478. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Jaehne J, Meyer HJ, Maschek H, Geerlings H, Burns E, Pichlmayr R. Lymphadenectomy in gastric carcinoma. A prospective and prognostic study. Arch Surg. 1992;127:290–294. doi: 10.1001/archsurg.1992.01420030052010. [DOI] [PubMed] [Google Scholar]
- 12.Nakajima T. Gastric cancer treatment guidelines in Japan. Gastric Cancer. 2002;5:1–5. doi: 10.1007/s101200200000. [DOI] [PubMed] [Google Scholar]
- 13.Smith DD, Schwarz RR, Schwarz RE. Impact of total lymph node count on staging and survival after gastrectomy for gastric cancer: data from a large US-population database. J. Clin. Oncol. 2005;23:7114–7124. doi: 10.1200/JCO.2005.14.621. [DOI] [PubMed] [Google Scholar]
- 14.Cho YK, Chung JW, Kim JK, Ahn YS, Kim MY, Park YO, Kim WT, Byun JH. Comparison of 7 staging systems for patients with hepatocellular carcinoma undergoing transarterial chemoembolization. Cancer. 2008;112:352–361. doi: 10.1002/cncr.23185. [DOI] [PubMed] [Google Scholar]
- 15.Nitsche U, Maak M, Schuster T, Kunzli B, Langer R, Slotta-Huspenina J, Janssen KP, Friess H, Rosenberg R. Prediction of prognosis is not improved by the seventh and latest edition of the TNM classification for colorectal cancer in a single-center collective. Ann Surg. 2011;254:793–800. doi: 10.1097/SLA.0b013e3182369101. discussion 800-791. [DOI] [PubMed] [Google Scholar]
- 16.Alakus H, Holscher AH, Grass G, Hartmann E, Schulte C, Drebber U, Baldus SE, Bollschweiler E, Metzger R, Monig SP. Extracapsular lymph node spread: a new prognostic factor in gastric cancer. Cancer. 2010;116:309–315. doi: 10.1002/cncr.24764. [DOI] [PubMed] [Google Scholar]
- 17.Etoh T, Sasako M, Ishikawa K, Katai H, Sano T, Shimoda T. Extranodal metastasis is an indicator of poor prognosis in patients with gastric carcinoma. Br J Surg. 2006;93:369–373. doi: 10.1002/bjs.5240. [DOI] [PubMed] [Google Scholar]
- 18.Alici S, Kaya S, Izmirli M, Tuncer I, Dogan E, Ozbek H, Sayarlioglu H. Analysis of survival factors in patients with advanced-stage gastric adenocarcinoma. Med Sci Monit. 2006;12:CR221–229. [PubMed] [Google Scholar]
- 19.Orsenigo E, Carlucci M, Braga M, Tomajer V, Di Palo S, Tamburini A, Di Carlo V, Staudacher C. [Prognostic factors of gastric neoplasms: experience with 1,074 cases undergoing surgical treatment at a single center] Suppl Tumori. 2005;4:S86–87. [PubMed] [Google Scholar]