Most Important Lymph Node Information in Gastric Cancer: Multivariate Prognostic Study

Background: In gastric cancer, the level and number of lymph node metastases is useful for predicting survival, and there are several staging systems for lymph node metastasis. The aim of this study was to compare the several lymph node classifications and to clarify the most important lymph node information associated with prognosis using multivariate analysis.Methods: A total of 106 patients with histologically node-positive gastric cancer treated by radical gastrectomy and extended lymph node dissection (D2, D3) were studied. The level of lymph node metastasis was categorized simply as Level I nodes (perigastric, No.1–6), Level II nodes (intermediate, No.7–9), and Level III nodes (distant, No.10–16), irrespective of the tumor location. The Level II nodes included lymph nodes along the left gastric artery, common hepatic artery, and celiac trunk.Results: Overall 5-year survival rate was 51%. Univariate analysis showed that 5-year survival rate was significantly influenced by the level of positive nodes (P < .01), total number of positive nodes (P < .01), number of positive Level I nodes (P < .01), and number of positive Level II nodes (P < .01), in addition to the tumor location (P < .05), tumor size (P < .05), gross type (P < .01), and depth of wall invasion (P < .01). Of these, independent prognostic factors associated with 5-year survival rate were the number of positive Level II nodes (0–1 vs. 2) (62% vs. 19%, P < .01) and the depth of wall invasion (within vs. beyond muscularis) (79% vs. 43%, P < .01).Conclusions: Among several staging systems for lymph node metastases, the number of positive Level II nodes provided the most powerful prognostic information in patients with node-positive gastric cancer. When there were two or more metastases in the Level II nodes, prognosis was poor even after D2 or D3 gastrectomy.     

Accurate Lymph Node Staging is of Greater Prognostic Importance Than Subclassification of the T2 Category for Gastric Adenocarcinoma

Background: Examination of 15 or more lymph nodes is necessary for accurate staging of gastric adenocarcinoma. This study examined whether prognostic discrimination is improved by distinguishing between pT2 tumors limited to the muscularis propria (MP) and those extending to subserosa (SS).Methods: A single-institution, prospectively maintained database for 1985–2000 was reviewed for patients who had had R0 resection of pT2 gastric carcinoma.Results: There were 161 patients with MP and 201 patients with SS. The prevalence of nodal metastasis was significantly lower with MP than with SS (47% vs. 66%, respectively; P < .001). As compared with MP, SS was associated with a similar prevalence of pN1 (44% vs. 43%) but a significantly higher prevalence of pN2 or pN3 (3% vs. 23%; P < .001). Five-year survival was significantly greater for patients with MP than with SS (64% vs. 49%; P = .005). On multivariate analyses, however, only the pN category and tumor site were independently significant prognostic factors. With accurate nodal staging, patients with MP or SS had similar survival in association with pN0 (90% vs. 86%) or pN1 (56% vs. 44%). pN2 or pN3 were mainly limited to SS tumors and these patients had poor survival (26% and 0%).Conclusions: For pT2 gastric adenocarcinoma, the depth of mural invasion was not an independently significant prognostic factor.     

Inadequacy of Lymph Node Staging in Gastric Cancer Patients: A Population-Based Study

Background In 1997, examination of at least 15 lymph nodes was recommended for adequate gastric cancer staging. However, the proportion of patients undergoing an adequate lymph node examination (LNE) has not been studied in a population-based manner. Methods We used Surveillance, Epidemiology, and End Results cancer registry data to assess LNE adequacy in adults with nonmetastatic gastric adenocarcinoma. We selected patients aged 18 through 80 years whose disease was diagnosed from 1998 through 2001 and who underwent at least partial gastrectomy. We evaluated the overall number of nodes, estimated the likelihood of adequate LNE (i.e., ≥15 nodes examined), and determined the influence of selected tumor and patient characteristics on LNE. Results In this 4-year period, 3593 patients met our study’s selection criteria. The median number of nodes examined was 10: 32% of patients underwent adequate LNE, and 9% of patients had no nodes examined. Node-positive patients were more likely to have undergone an adequate LNE than node-negative patients (42% vs. 23%; P < .0001). Younger age, female sex, and more radical surgery were associated with adequate LNE in both univariate and multivariate analysis (P < .0001). Geographical site was an important predictor; patients from one registry (Hawaii) were significantly more likely to have undergone adequate LNE than patients from all other registries (56% vs. 30%; P < .0001). Conclusions Our 4-year review of the Surveillance, Epidemiology, and End Results database revealed that only a third of patients with gastric cancer underwent adequate LNE, i.e., had the recommended minimum of 15 nodes examined for gastric cancer staging. Better results at one registry (Hawaii) indicate that substantial improvements could be made.     

Impact of Regional Lymph Node Evaluation in Staging Patients With Periampullary Tumors

Background Two distinct lymph nodes reproducibly assessed by computed tomography for the evaluation of periampullary tumors are the common bile duct (CBD) node and the gastroduodenal artery (GDA) node. We examined whether radiographical enlargement of either lymph node predicts tumor resectability, nodal metastasis, or patient survival. Methods Ninety-four consecutive patients underwent attempted curative resection of periampullary tumors between September 2001 and June 2003. A single radiologist recorded in a retrospective, blinded fashion the short- and long-axis measurements of the CBD and GDA nodes. Results Sixty-one percent (n = 57) of tumors were resectable by pancreaticoduodenectomy. Overall, actual 6-, 12-, and 18-month survival was 87%, 68%, and 63%, respectively. Enlarged radiographical nodal size by either axis was not associated with the presence of metastasis to these lymph nodes or with reduced overall patient survival. Only a CBD node short-axis size >10 mm predicted unresectability (odds ratio, 3.2; P = .036). Liver metastasis and/or carcinomatosis were present in 43% of unresectable patients, and this was associated with decreased survival at both 1 year (25% vs. 77%; P < .001) and 18 months (19% vs. 72%; P <.001). A pathologic diagnosis of metastasis to the GDA node, but not the CBD node, was associated with a similarly decreased survival (1 year: 33% vs. 78%, P = .028; 18 months: 22% vs. 70%, P = .023). Conclusions For presumed periampullary malignancy, a CBD node short-axis size >10 mm predicts tumor unresectability. Metastatic disease to the GDA node, particularly for pancreatic adenocarcinoma, portends a poor prognosis equivalent to that of hepatic or peritoneal spread. Given these findings, radiographical CBD lymph node measurements may guide selection for performing laparoscopic staging with or without ultrasonography in conjunction with GDA nodal biopsy in patients with periampullary malignancy. Presented in part at the annual meetings of the American Hepato-Pancreatico-Biliary Association on April 15, 2005 and The Pancreas Club on May 15, 2005.     

Comparison of Four Staging Systems of Lymph Node Metastasis in Gastric Cancer

Background  

The classification of lymph node metastasis in patients with gastric cancer is still controversial. Our aim was to evaluate the relative merits of four staging systems of lymph node metastasis.     

胃癌淋巴管生成、淋巴管浸润及淋巴结微转移的临床意义

目的探讨胃癌淋巴管生成、淋巴管浸润及淋巴结微转移的临床意义。方法免疫组化法检测68例胃癌原发灶中D2-40的表达及其中51例胃癌的791枚淋巴结中CK20和CKpan的表达，结合患者的l临床病理特征进行综合分析。结果胃癌HE染色淋巴管浸润（LVI-HE）和D240染色淋巴管浸润（LVI-IM）的阳性率分别为66．2％（45／68）和76．5％（52／68），差异无统计学意义（P=0．118）。LVI-IM阳性率与肿瘤浸润深度（P=0．044）、TNM分期（P=0．003）及存在淋巴结转移（P=0．000）有关。68例胃癌平均淋巴管密度（LVD）为（18．19&#177;7．44）个／HP.LVD升高与LVI-HE阳性（P=0．040）、LVI—IM阳性（P=0．001）、静脉浸润（P=0．037）、TNM分期较晚（P：0．020）及存在淋巴结转移（P=0．001）有关系。LVD值≥15个／HP者近期生存率较LVD值≤14个／HP者明显降低（P=0．032）。51例胃癌HE染色和CK（CK20或CKpan）染色检出淋巴结转移率分别为74．5％（38／51）和88．2％（45／51），791枚淋巴结的转移淋巴结检出率由HE染色的32．0％（253／791）提高到CK染色的41．5％（328／791），P〈0．001。CKpan的微转移检出率明显高于CK20（P=0．003）。微转移淋巴结数量与肿瘤大小（P=0．001）、LVIHE（P=0．040）、肿瘤浸润深度（P=0．018）及TNM分期（P=0．012）有关。微转移淋巴结的检出使淋巴结转移站别及TNM分期迁移：7例N0→N1，6例N1→N2，1例N2→N3；4例Ⅰb→Ⅱ，4例Ⅱ→Ⅲa，3例Ⅲa→Ⅲb，1例Ⅲb→Ⅳ。结论D2-40及CK检测在诊断淋巴管浸润和淋巴结微转移上优于HE检查。CK20和CKpan的联合检查有利于发现微转移淋巴结。肿瘤TNM分期越晚，越易发生淋巴结微转移。LVI-IM、LVD及淋巴结微转移三者都与胃癌淋巴结转移有关。LVD值较高者近期生存率较低。     

A Comprehensive Assessment of Accurate Lymph Node Staging and Preoperative Detection in Resected Pancreatic Cancer

Background

The current (seventh edition) American Joint Commission on Cancer (AJCC) Staging System for pancreatic ductal adenocarcinoma (PDAC) dichotomizes pathologic lymph node (LN) involvement into absence (pN0) or presence (pN1) of disease. The recently announced eighth edition also includes stratification on the number of positive nodes. Furthermore, LNs detected on preoperative imaging (CT, MRI, or endoscopic ultrasound—EUS) are considered to be pathologically involved in other gastrointestinal cancers. However, this is less well defined for PDAC. Therefore, the three aims of this study were to determine (1) whether the new AJCC staging system led to more accurate staging, (2) the number of nodes needed to be examined to detect pathologic involvement, and (3) if pN disease could be reliably detected on preoperative imaging in PDAC.

Methods

A retrospective review of all patients undergoing pancreatectomy at a single US academic center from January 1990 to September 2015. Pathology reports of resected specimens were reviewed to determine the total number of LNs examined and those positive for metastasis. CT, MRI, and/or EUS reports were used to determine the presence or absence of preoperatively detectable LN enlargement.

Results

Of the 490 surgical resections for PDAC, pN1 disease was detected in 59.4% (n = 291) and was positively correlated with the number of LNs pathologically examined (P < 0.001). Patients with pN1 disease had a shorter overall survival (OS) than those without nodal involvement (25.1 vs. 44.0 months; P < 0.001); however, OS was not different when stratifying by the number of nodes as on the eighth AJCC system. Pathologic examination of > 20 LNs in treatment naïve patients was optimal to detect pN1 disease and predict longer OS for those without nodal involvement (median survival > 41.1 months, P = 0.03 when compared to < 15 or 15–19 LNs examined). LNs were detected by CT, MRI, or EUS in 30.7% (103/335) of patients. The positive predictive value (PPV) of preoperative LN detection for pathologic involvement was 77.3% for treatment naïve patients and 84.2% for those without biliary obstruction.

Conclusions

Although the LN scoring in the seventh PDAC AJCC Staging System was sufficient to predict OS of our patients, more LNs than previously considered (20 vs. 15) were optimal to detect pathologic involvement. Preoperative LN detection was an accurate predictor of pN1 disease for treatment naïve patients without biliary obstruction.

     

Utility of a Prognostic Nomogram Designed for Gastric Cancer in Predicting Outcome of Patients with R0 Resected Duodenal Adenocarcinoma

Background There is little information to determine prognosis or to guide clinical care for patients with duodenal adenocarcinoma. We have hypothesized that survival following resection of duodenal cancer is similar to survival following resection of distal gastric cancer. We tested the utility of a nomogram created for determining disease-specific survival (DSS) after R0 resection of gastric cancer in estimating DSS for patients with resected duodenal cancer. Methods Review of a prospective database identified 106 patients who underwent R0 resection of duodenal cancer. Comparison was made to 459 patients with distal gastric cancer. The Student t test, Fisher exact test, Pearson chi-square test, and log-rank test were used to assess statistical significance. Concordance probabilities and calibration plots were used for nomogram validation. Results Duodenal cancers were more deeply invasive than gastric cancer (P < .01). The rate of lymph node positivity was not statistically different between the two tumors; however, there were differences in the rate of nodal positivity for certain depths of penetration. Younger age (P = .002), negative regional lymph nodes (P = .03), and tumors confined to the bowel wall or subserosa (P = .03) were associated with improved DSS for duodenal cancer. When applied to patients with duodenal cancer, the nomogram had a concordance probability of 0.70, and calibration appeared to be accurate. Conclusions A nomogram created for determining DSS after resection of gastric cancer predicts outcome for duodenal cancer patients and may prove to be useful for research and in guiding clinical care.     

Efficacy of Different Technical Procedures for Sentinel Lymph Node Biopsy in Gastric Cancer Staging

BACKGROUND: The clinical impact of sentinel lymph node biopsy (SLNB) in gastric cancer is controversial. We performed a prospective trial to compare different methods: radiocolloid method (RM), dye method (DM), and both methods simultaneously (dual method, or DUM) for reliability and therapeutic consequences. METHODS: RM and DM were applied in 35 gastric cancer patients. After endoscopic peritumoral injection of (99m)Tc-colloid and Patent Blue V, the positions of all blue sentinel lymph nodes (SLNs) were recorded, and the SLNs microscopically examined by hematoxylin and eosin, step sections, and immunohistochemistry. RESULTS: RM, DM, and DUM identified the SLNs in 34 (97%) of 35 patients. The sensitivity for the prediction of positive lymph node status for RM was 22 (92%) of 24, for DM 16 (66%) of 24, and for DUM 22 (92%) of 24. In 7 of 17 (RM), 5 of 15 (DM), and 7 of 17 (DUM) patients classified as N0 by routine hematoxylin and eosin staining, micrometastases or isolated tumor cells were found in the SLN (upstaging) after focused examination. If only a limited lymph node dissection of the SLN basins would have been performed in patients, residual lymph node metastases were left in 9 of 24 (RM), in 7 of 34 (DM), and in 5 of 24 (DUM) of patients with node-positive disease. CONCLUSIONS: Use of RM was superior. DUM did not further increase the sensitivity. A limited lymph node dissection-i.e., lymphatic basin in patients with SLN-positive disease-is associated with a high risk of residual metastases. Patients with negative SLNs may be selected for a limited surgical procedure if they meet certain criteria.     

Impact of Solitary Involved Lymph Node on Outcome in Localized Cancer of the Esophagus and Esophagogastric Junction

Node-positive esophageal cancer is associated with a dismal prognosis. The impact of a solitary involved node, however, is unclear, and this study examined the implications of a solitary node compared with greater nodal involvement and node-negative disease. The clinical and pathologic details of 604 patients were entered prospectively into a database from1993 and 2005. Four pathologic groups were analyzed: node-negative, one lymph node positive, two or three lymph nodes positive, and greater than three lymph nodes positive. Three hundred and fifteen patients (52%) were node-positive and 289 were node-negative. The median survival was 26 months in the node-negative group. Patients (n = 84) who had one node positive had a median survival of 16 months (p = 0.03 vs node-negative). Eighty-four patients who had two or three nodes positive had a median survival of 11 months compared with a median survival of 8 months in the 146 patients who had greater than three nodes positive (p = 0.01). The survival of patients with one node positive [number of nodes (N) = 1] was also significantly greater than the survival of patients with 2–3 nodes positive (N = 2–3) (p = 0.049) and greater than three nodes positive (p < 0001). The presence of a solitary involved lymph node has a negative impact on survival compared with node-negative disease, but it is associated with significantly improved overall survival compared with all other nodal groups.     

Gastric Cancer: Establishing Predictors of Biologic Behavior with Use of Population-Based Data

Background Tumor thickness and nodal status are important predictors of survival following curative resection for gastric cancer. Lymphovascular invasion (LVI) is a potential predictor of biological behavior. The relationship between LVI and tumor thickness (T status) has not been established in population-based studies.Methods Clinicopathological and survival data of 577 patients at nine centers, from between 1991 and 1997, was collected from patient records and a Provincial Cancer Registry. The primary endpoint of the study was death. A secondary analysis of a node-negative subgroup examined the significance of LVI with respect to T status.Results The population disease-specific survival was 28%. In a multivariate analysis, T, N, M, esophageal margin, tumor morphology, and residual tumor category were independent predictors of survival. LVI was documented in 58% of resected tumors. LVI correlated with advancing T and N status but was not significant in a multivariate population model. Subgroup analysis of node-negative gastric cancer found T status and LVI to be independent predictors of survival. LVI was associated with a 5-year survival of 8%, versus 43% among patients in whom it was absent (P < .001).Conclusions T status and N status were the most important independent predictors of survival in a population-based study of gastric cancer. LVI correlated with advancing N and T status. Multivariate analysis of node-negative patients showed LVI and T status are independent predictors of survival.     

Prognostic Significance of Level and Number of Lymph Node Metastases in Patients with Gastric Cancer

BACKGROUND: To present data that provide some insight into the appropriateness of a nodal grouping category and its relation to survival in patients with gastric cancer. METHODS: We reviewed data of 777 patients with advanced gastric cancer who had undergone curative gastrectomy to investigate the prognostic significance of level and number of lymph node metastases. RESULTS: The prognosis of patients with gastric cancer was well correlated with the level and number of lymph node metastases. Multivariate analysis indicated that the level and number of lymph node metastases were independent prognostic indicators. Moreover, the number of lymph node metastases was an independent prognostic factor in N1, N2, and N3 patients. The most statistically significant difference in disease-specific survival was observed at a threshold of 11 lymph node metastases, yielding a chi2 value of 42.88, a hazard ratio of 2.523, at a 95% confidence interval of 1.913, 3.329 (P < .0001) by Cox proportional hazard model. On the basis of this result, patients were divided into two groups as follows: marked lymph node metastasis group (number of positive nodes > or =11) and slight lymph node metastasis group (number of positive nodes < or =10). The prognosis of patients with marked lymph node metastasis was statistically significantly worse than that with slight lymph node metastasis in N1, N2, and N3 patients. CONCLUSIONS: Both level and number were indispensable for evaluating lymph node metastasis. Therefore, addition of the number of positive nodes to the N category defined by the Japanese Classification of Gastric Carcinoma may be a useful strategy in the N staging classification in gastric cancer.     

胃癌中MMP-2表达与TNM分期和淋巴结转移的相关性研究

目的研究胃癌组织中基质金属蛋白酶-2(MMP-2)的表达与胃癌TNM分期和淋巴结转移的关系.方法用免疫组织化学半定量方法检测135例胃癌组织中MMP-2的表达,统计分析其与TNM分期等的相关性.结果MMP-2的表达与WHO、Lauren和Ming病理分型和淋巴结转移有相关性(P＜0.05),而与Borrmann病理分型、TNM分期中的远处转移(M)、癌组织浸润深度以及分化程度无相关性(P>0.05).本组中的早期胃癌28例,有9例表达MMP-2,其中7例伴有淋巴结转移,占早期胃癌伴淋巴结转移者8例中的87.5%.结论胃癌细胞表达MMP-2与肿瘤的浸润性生长方式和淋巴结转移密切相关;检测MMP-2可作为术前预测早期胃癌有无淋巴结转移和判断预后的辅助指标.     

Impact of Splenectomy for Lymph Node Dissection on Long-Term Surgical Outcome in Gastric Cancer

Background:In the treatment of gastric cancer, splenectomy is performed for effective lymph node dissection around the splenic artery and splenic hilum. The purpose of this study was to clarify the long-term outcome of splenectomy in the treatment of gastric cancer.Methods: The effect of splenectomy on recurrence and prognosis was examined in a retrospective analysis of 665 patients who had undergone curative total gastrectomy for gastric carcinoma from 1987 to 1996. The risk factors associated with recurrence and prognosis were investigated by univariate and multivariate analysis.Results: The splenectomy group showed more advanced lesions and a higher recurrence rate than the spleen-preserved group. However, after adjusting for the TNM (tumor, node, metastasis) stage, there was no significant difference in recurrence rate and pattern between the two groups. Logistic regression analysis revealed that gross type, serosal invasion, and nodal metastasis were independent risk factors for recurrence while splenectomy was not. When comparing patients with the same TNM (tumor, node, metastasis) stages, no significant difference in the 5-year survival rates was apparent. Multivariate analysis demonstrated that age, serosal invasion, and nodal metastasis were independent prognostic factors whereas splenectomy was not.Conclusions: These data suggest that splenectomy for lymph node dissection in gastric cancer is not effective regarding long-term patient prognosis.     

胃癌不同部位淋巴结转移率及其临床意义的研究

目的探讨胃癌不同部位淋巴结转移的分布特点,旨在为合理的外科治疗提供依据。方法回顾性分析1995年1月至2004年12月期间在中国医科大学附属第一医院胃肠肿瘤外科实施手术的胃癌病例,分析各组淋巴结的转移率及其特点。结果 1 505例胃癌患者中,928例出现淋巴结转移,转移率为61.7%。上部癌(U)中转移率较高的淋巴结依次是No.1(32.9%)、No.3(28.7%)、No.2(20.4%)及No.7(18.6%);中部癌(M)中转移率较高的淋巴结依次是No.3(32.5%)、No.4(24.7%)、No.7(20.6%)及No.1(17.3%);下部癌(L)中转移率较高的淋巴结依次是No.6(33.7%)、No.3(31.3%)、No.4(25.6%)及No.7(21.5%)。结论胃周淋巴结转移根据胃癌的部位、浸润深度等,有着不同的特点。了解胃周淋巴结的转移规律能够获得pN分期无法提供的信息,对于正确评估胃癌的淋巴结转移程度、制订治疗方案及手术范围,具有重要的意义。     

Prognostic Score in Gastric Cancer: The Importance of a Conjoint Analysis of Clinical, Pathologic, and Therapeutic Factors

Background

This study was designed to establish a prognostic score for gastric cancer that takes into account factors related to the tumor, the patient, and the treatment.

Methods

Two hundred thirty patients with gastric adenocarcinoma admitted t o the Department of Abdominal Surgery at Hospital do Câncer A. C. Camargo (São Paulo) and treated by gastrectomy from January 1992 until December 1996 were included in this retrospective cohort. The prognostic score was created according to the variables identified in the multivariate analysis and by using the regression coefficients generated by the Cox regression.

Results

The 5-year overall survival rate was 44.5%. The final multivariate model identified six variables with a significant and independent effect on survival: sex, weight loss, lymphocyte count, tumor-node-metastasis staging, lymphadenectomy, and lymph node ratio. Patients were divided into four groups according to their scores, as follows: group 1, 0 to 3.0; group 2, 3.5 to 5.5; group 3, 6.0 to 8.5; and group 4, 9.0 to 14.0. The 5-year survival rates were 91.5%, 49.3%, 20.3%, and .0% for the score groups 1, 2, 3, and 4, respectively (P < .001). The score was superior in the assessment of prognosis when compared with tumor-node-metastasis staging alone.

Conclusions

It is possible to create a prognostic score that simultaneously includes factors related to the tumor, patient, and treatment, thus generating a more effective system in predicting the prognosis than the morphology-based staging systems.     

Prognosis of Lymph Node Metastasis in Soft Tissue Sarcoma

Background: We defined the tumor characteristics and prognosis of patients with regional lymph node metastasis (RLNM) from soft tissue sarcoma.Methods: All patients with RLNM from soft tissue sarcoma were identified from the Royal Marsden Hospital Sarcoma Unit prospective database from January 1990.Results: A total of 73 (3.4%) of 2127 patients had RLNM. Fifty-seven patients (78.1%) had RLNM as the first site of spread, and 16 patients (21.9%) presented with RLNM and distant metastasis synchronously. The most common histologies were rhabdomyosarcoma, epithelioid sarcoma, and angiosarcoma. There were 9 T1 and 36 T2 tumors, and tumor size was not available in 28 patients. There were 6 grade 1, 16 grade 2, and 51 grade 3 tumors. Forty-two patients presented with RLNM along with the primary tumor. Of the remaining patients, the median time to development of RLNM from diagnosis of the primary tumor was 13.5 months (95% confidence interval [CI], 1–100 months). The 1-year survival for patients with isolated RLNM was 77.49% (95% CI, 62.99%–86.88%), compared with 36.27% (95% CI, 13.32%–60.04%) for patients who presented with RLNM and distant metastasis (P = .005). The 1-year survival for metachronous and synchronous RLNM was 94.44% (95% CI, 66.64%–99.20%) and 67.54% (95% CI, 47.89%–81.12%), respectively (P = .05).Conclusions: Lymph node metastasis is rare. Patients who present with isolated RLNM have an improved survival compared with patients who present with regional and distant metastasis at diagnosis. Synchronous RLNM with the primary tumor have a poorer outcome than metachronous RLNM in the absence of distant metastasis.