Anatomic Extent of Metastatic Lymph Nodes: Still Important for Gastric Cancer Prognosis

Background

Currently, gastric cancer staging systems do not consider the anatomic extent of metastatic lymph nodes (mLNs) as a prognostic factor. We therefore investigated the prognostic impact of the anatomic extent of mLNs on gastric cancer.

Methods

The prognoses of 4,043 gastric cancer patients who underwent curative resection were analyzed. Patients with mLNs in lymph node (LN) stations 1–6 (n = 1,980) comprised the perigastric LN-positive (PLN) group, and patients with mLNs in LN stations 7–12 and 14 (n = 2,063) were assigned to the extraperigastric LN-positive (ELN) group. Overall survival was estimated using the Kaplan–Meier method, and hazard ratios (HRs) were calculated by the Cox proportional hazard model.

Results

The ELN group exhibited worse survival than the PLN group (p < 0.001), although there were differences in their clinicopathological features. When patients were stratified according to tumor-node-metastasis stage, the ELN groups had unfavorable prognoses compared with the PLN groups (p < 0.05). There were significant differences in long-term survival when the nodal stage of the current staging systems were subdivided according to anatomic nodal extent (p < 0.05), although there was a strong association between the probability of having extraperigastric mLNs and N classification. In multivariate analysis using age, gender, tumor size, tumor location, histology, T classification, and the extent of mLNs as covariates, presence of extraperigastric mLNs was an independent prognostic factor (HR 1.89, 95 % CI 1.73–2.07), along with age, tumor size, tumor location, and T classification.

Conclusions

The anatomic extent of mLNs significantly affects patient prognosis. Including the anatomic extent of mLNs in the current staging system may predict gastric cancer prognosis more accurately in patients with the same stage of cancer.     

Detection and Prediction of Micrometastasis in the Lymph Nodes of Patients With pN0 Gastric Cancer

Background:The clinicopathologic significance of micrometastasis (MM) and tumor cell microinvolvement (TCM) in regional lymph nodes as identified by immunohistochemical staining for cytokeratin expression was evaluated in patients with node-negative gastric cancer.Methods:MM was defined as tumor cells with stromal reaction, and TCM was defined as individual tumor cells without stromal reaction. We investigated 1761 lymph nodes obtained from 67 gastric cancer patients whose diagnosis showed no lymph node metastasis by routine histological examination. The depth of tumor invasion was T1 (submucosa) in 33 patients and T2 (muscularis propria and subserosa) in 34 patients. The lymph nodes were examined immunohistochemically for the presence of tumor cells using anti-cytokeratin AE1/AE3 monoclonal antibody. Both the biopsy tumor specimens obtained prior to surgery and the resected primary tumors were immunostained with E-cadherin (E-cad) monoclonal antibody.Results:Thirty (1.5%) of the 1761 lymph nodes showed MM and/or TCM. MM with or without TCM was found in 10 patients, and TCM alone was found in 4 patients; 6 (18.2%) of the 33 patients with T1 tumor and 8 (23.5%) of the 34 patients with T2 tumor had occult lymph node metastasis. The 5-year survival rate was worse among those with MM with or without TCM, than among those without MM. Nearly all of the patients with MM and/or TCM had reduced or negative E-cad expression in the primary tumor.Conclusions:We demonstrated that the incidence of MM and/or TCM in the lymph nodes of patients with gastric cancer is quite high, and that such metastasis is associated with the prognosis of patients with pN0. Examination of E-cad expression in biopsy tumor specimens may be useful for predicting MM and/or TCM.     

Proposal of a New Classification for Stage III Colorectal Cancer Based on the Number and Ratio of Metastatic Lymph Nodes

Background

The objective of this retrospective study was to determine whether the current staging system for stage III colorectal cancer (CRC) is appropriate and to assess the value of the metastatic lymph node ratio (LNR) in predicting the prognosis of patients with stage III CRC.

Methods

From 2000 to 2006 inclusively, 245 patients with stage III CRC underwent curative resection. The follow-up was closed in March 2012. Kaplan–Meier survival curves and log-rank tests were used for the survival analysis.

Results

Survival time of patients with T3N1M0 was significantly better than that for patients in other subgroups of stage IIIB and similar to that of patients with stage IIIA disease. The greatest survival difference was found with 0.30 as the LNR cutoff point for patients with current stage III CRC. Survival time of patients with LNR ≤ 0.30 was significantly better than that of those with LNR > 0.30. rN1 included stage III patients with LNR ≤ 0.30, and rN2 included patients with LNR > 0.30. Survival time of patients with T4aN1(rN2)M0 staging was significantly worse than that for patients with T4aN1(rN1)M0 staging and similar to that of patients with stage IIIC CRC.

Conclusions

We propose an algorithm to incorporate LNR into the current American Joint Committee on Cancer staging system. In it the patients with T3N1M0 are excluded from the current stage IIIB and included in the stage IIIA group. Also, patients with T4aN1(rN2)M0 are excluded from the current stage IIIB group and included in the stage IIIC group.     

Poor Prognosis of Advanced Gastric Cancer with Metastatic Suprapancreatic Lymph Nodes

Background

Whether gastrectomy with D2 lymphadenectomy improves survival of patients with advanced gastric cancer (AGC) remains controversial. Few studies have described the pathological features of AGC with metastatic suprapancreatic lymph nodes (LN), which are the target of D2 lymphadenectomy. This study therefore aims to clarify the prognosis and clinical pathological features including the number and location of metastatic LN in AGC with metastatic suprapancreatic LN.

Methods

406 patients with AGC, who underwent gastrectomy with D2 lymphadenectomy from 1982 to 2007 at Oita University, were reviewed retrospectively with regard to presence or absence of metastatic suprapancreatic LN. The pathological factors associated with AGC with metastatic suprapancreatic LN were examined by univariate and multivariate analysis.

Results

Of 362 patients with AGC, 78 had suprapancreatic LN metastasis (21.5 %), differing significantly in terms of presence of vascular invasion and having a larger number of metastatic perigastric LN in comparison with only metastatic perigastric LN on univariate analysis. According to multivariate analysis, they were associated with presence of vascular invasion and a large number of total metastatic LN (more than two; N2≤). The overall 5-year survival rate of the AGC with perigastric LN metastasis (station 1–7) group was 37.9 % and of the AGC with suprapancreatic LN metastasis group was 12.8 %. There were significant differences in each group (P < 0.05).

Conclusions

Patients with AGC with metastatic suprapancreatic LN had a large number of total metastatic LN and poor prognosis, suggesting that it may be a systemic disease.     

胃癌第6组及其亚组淋巴结转移率和转移度的初步研究

目的检测胃幽门下(第6组)及其亚组淋巴结转移情况,以探讨临床合理清扫第6组淋巴结的价值。方法回顾性分析2006年1月至2009年12月期间我院80例接受根治性手术且有完整第6组及其3个亚组淋巴结送检资料的胃癌患者的临床病理资料,以胃网膜右静脉为参照将第6组淋巴结分为第6a、6b和6c亚组,计算第6组及其亚组淋巴结转移率和转移度,并对其淋巴结转移情况与胃癌临床病理特征和其他组(第7、8a和9组)淋巴结转移情况的关系进行logistic回归分析。结果 80例胃癌患者中第6组淋巴结转移率为41.3%(33/80),转移度为26.0%(108/415)。第6a亚组淋巴结转移率为7.5%(6/80),明显低于第6b亚组(16.3%,13/80)和第6c亚组(36.3%,29/80),P<0.001;第6a、6b和6c亚组淋巴结转移度分别为25.0%(8/32)、17.6%(13/74)和28.2%(87/309),差异无统计学意义(P=0.292)。第6a亚组阳性淋巴结与T分期(P=0.042)和N分期(P=0.006)有关;第6b亚组阳性淋巴结与N分期(P=0.002)和TNM分期(P=0.013)有关;第6c亚组阳性淋巴结与肿瘤分化程度(P=0.008)、T分期(P=0.003)、N分期(P=0.000)和TNM分期(P=0.000)有关。logistic回归分析显示:第6组淋巴结转移情况与第8a组淋巴结转移(P=0.023)和N分期(P=0.002)均有关;第6a亚组淋巴结转移与第8a组淋巴结转移有关(P=0.018);第6b亚组淋巴结转移与N分期有关(P=0.005);第6c亚组淋巴结转移与第8a组淋巴结转移(P=0.016)和N分期(P=0.004)均有关。结论胃癌手术中要彻底清扫第6组淋巴结,尤其要重视第6a和6b亚组淋巴结的清扫。     

Morphological Distribution of Metastatic Foci in Sentinel Lymph Nodes with Gastric Cancer

Background The TNM classification defines micrometastasis (MM) and isolated tumor cells (ITC) in lymph nodes (LN). Sentinel node (SN) navigation surgery has been introduced in gastrointestinal cancer. Few reports have examined the morphological distribution of MM and ITC of SN in gastric cancer. The purpose of this study was to clarify the clinical significance of the morphological distribution of cancer cells in SNs according to metastasis (MA), MM, and ITC. Methods All dissected LNs obtained from 160 consecutive patients with mapped SNs arising from cT1–2 N0 tumors were examined. Metastasis in these LNs was examined by histology and cytokeratin staining. The distribution of MA, MM, and ITC was classified as marginal sinus (MS), intermediate sinus (IS), parenchymal (PA), and diffuse types (DF). Results Nodal metastases were detected in 65 SNs from 30 patients and MA, MM, and ITC accounted for 53.9%, 21.5%, and 24.6%, respectively. MS, IS, PA, and DF accounted for 57%, 6%, 17%, and 20.0%, respectively. Patients with metastasis of non-MS had more nodal metastasis in non-SNs (P = .025) and had nodal metastasis in second tier (P = .009), compared with the patients with metastasis of MS. The incidence of metastasis in non-MS was higher in tumors larger than 40 mm than those smaller than 40 mm (P = .011). Conclusion When performing SN navigation surgery in gastric cancer, we should keep in mind that the patients with tumor larger than 40 mm in size and nodal metastasis of non-MS may have non-SN metastasis and nodal metastasis in second tier.     

The Microanatomic Location of Metastatic Breast Cancer in Sentinel Lymph Nodes Predicts Nonsentinel Lymph Node Involvement

Background The majority of sentinel node (SN) positive breast cancer patients do not have additional non-SN involvement and may not benefit from axillary lymph node dissection (ALND). Previous studies in melanoma have suggested that microanatomic localization of SN metastases may predict non-SN involvement. The present study was designed to assess whether these criteria might also be used to be more restrictive in selecting breast cancer patients who would benefit from an ALND. Methods A consecutive series of 357 patients with invasive breast cancer and a tumor-positive axillary SN, followed by an ALND, was reviewed. Microanatomic SN tumor features (subcapsular, combined subcapsular and parenchymal, parenchymal, extensive localization, multifocality, and the penetrative depth from the SN capsule) were evaluated for their predictive value for non-SN involvement. Results Non-SN metastases were found in 136/357 cases (38%). Microanatomic location and penetrative depth of SN metastases were significant predictors for non-SN involvement (<0.001); limited penetrative depth was associated with a low frequency of non-SN involvement with a minimal of 10%. Conclusions Microanatomic location and penetrative depth of breast cancer SN metastases predict non-SN involvement. However, based on these features no subgroup of patients could be selected with less than 10% non-SN involvement.     

胃周阳性淋巴结数目是胃癌的一个预后指标

目的：研究胃周阳性淋巴结数目在胃癌预后中的意义。方法：将１２４例经组织学证实为淋巴结阳性者作为研究对象,分析胃周转移淋巴结数目与临床病理特征及生存率的关系。结果：１２４例胃周淋巴结阳性胃癌患者总的５年生存率为４８．３％,胃周阳性淋巴结超过６个的患者５年生存率明显下降（Ｐ＜０．０１）。与胃周阳性淋巴结≥７个的胃癌相比,阳性淋巴结数≤６个的胃癌常小于４ＣＣ（Ｐ＜０．００５）,多呈大体局限型（Ｐ＜０．０２５）,未侵及浆膜（Ｐ＜０．０１）,巨淋巴结转移多局限于胃周淋巴结（Ｐ＜０．００５）。结论：胃周阳性淋巴结数目与肿瘤进展和生存率相关,是淋巴结阳性胃癌的一个简便有用的预后指标。     

Detection of Metastatic Lymph Nodes Using 5-Aminolevulinic Acid in Patients with Gastric Cancer

Background

Precise diagnosis of lymph node metastases is essential to select therapeutic strategy for patients with gastric cancer, and rapid intraoperative diagnosis is useful for performing less invasive surgery. In this study, we focused on a known photosensitizer, 5-aminolevulinic acid (5-ALA), and examined the feasibility of 5-ALA-induced protoporphyrin IX (PpIX) fluorescence to detect metastatic foci in excised lymph nodes of patients with gastric cancer.

Methods

A total of 144 lymph nodes obtained from 14 gastric cancer patients were examined. The patients were administered 5-ALA orally before surgery. Excised lymph nodes were cut in half and observed by fluorescence microscopy. The diagnostic results were compared to those of the routine histopathological examination.

Results

Observed red fluorescence of PpIX was identical to the metastatic focus, with 84 % accuracy. Twelve non-metastatic lymph nodes showed unexpected PpIX accumulation to lymphoid follicles, but these could be discriminated based on their characteristic fluorescence patterns. With incorporation of this morphological consideration, this method demonstrated good diagnostic power with 92.4 % accuracy. On the quantitative analysis using the signal intensity ratio of red to the sum of red, green, and blue (R/(R + G + B) ratio) as an index corresponding to red fluorescence of PpIX, metastatic lymph nodes showed significantly higher value than non-metastatic lymph nodes (p < 0.0001). The area under the curve was calculated as 0.832 throughout Receiver operating characteristic analysis.

Conclusions

Our results demonstrated that 5-ALA-induced fluorescence diagnosis is a simple and safe method and is a potential candidate for a novel rapid intraoperative diagnostic method applicable to clinical practice.     

胃癌淋巴结转移的CT分组定位诊断法

目的：评价CT对胃癌淋巴结转移的诊断价值以及临床应用价值。方法：采用分组定位诊断方法，通过识别CT上作为标志的血管、脏器以确定各组淋巴结所在位置，将CT观察结果与手术所见和病理检查结果相比较，得出CT对各组淋巴结诊断的准确性、特异性、敏感性。结果：CT检查胃癌转移淋巴结准确率较高的为第3、7、9、1、16组等，敏感性较高的为第3、1、7、9、16组等，特异性较高的为第3、7、9、12、1、16组等。结论：分组定位诊断法全面评价了CT对胃癌各组淋巴结转移的诊断性能，将此方法的特点与临床病理、淋巴结转移规律相结合，对提高术前分期准确性、选择合理的治疗方法具有一定价值。     

Adjustment of N Stages of Gastric Cancer by the Ratio Between the Metastatic and Examined Lymph Nodes

Background  The present study attempted to determine whether N stage could be adjusted for the differences in survival rates based on the ratio between the examined and metastatic lymph nodes (LN ratio). Methods  Five hundred and twenty-nine patients with both >15 lymph nodes examined and ≥ N1 after R0 resection were enrolled in the present study. To determine the cutoff LN ratio, the ratios at each N stage were compared at intervals of 10% with the log-rank test of Kaplan–Meier estimates of the survival curves. Results  The 5-year survival rate of patients with N1 was 71.7%. Those of N2 patients with LN ratio of <60% (n = 116) and ≥60% (n = 3) were 37.0% and 0%, respectively. Those of N3 patients with LN ratio of <30% (n = 32), between 30% and 60% (n = 67), and ≥60% (n = 26) were 31.0%, 16.3%, and 0%, respectively. Thus, adjusted N2 was obtained from the sum of N2 < 60% and N3 < 30%. N3 with an LN ratio between 30% and 60% was regarded as adjusted N3. N2 and N3 patients with an LN ratio of ≥60% were regarded as adjusted T4. The 5-year survival rate in patients with adjusted N2, N3, and N4 were 35.7%, 16.3%, and 0%, respectively. Multivariate analysis showed adjusted N stage and tumor depth were significant independent prognostic factors. Conclusions  The results of this study suggest that, since stage migration can be induced in the N staging system, such stage migration can be adjusted by the LN ratio based on the survival rate.     

次级淋巴组织趋化因子在胃癌淋巴结转移中的作用

目的：研究次级淋巴组织趋化因子（secondary lymphoid tissue chemokine,SLC)在胃癌淋巴结中的表达，以进一步阐明胃癌淋巴转移的机制。方法：用逆转录聚合酶链反应（RT－PCR）测定29例胃癌组织淋巴结中SLC mRNA的表达。结果：胃癌转移淋巴结中SLC mRNA的表达均显著低于相应的正常胃黏模组织，但其表达与病人的临床病理特征并不相关。结论：在胃癌转移淋巴结中，SLC的表达明显受抑，后者可能在胃癌的淋巴结转移中起了重要作用，提高淋巴结中SLC的表达可能成为控制胃癌转移和复发的又一关键途径。     

Revisiting the Concept of Lymph Node Metastases of Pancreatic Head Cancer: Number of Metastatic Lymph Nodes and Lymph Node Ratio According to N Stage

Background

Some suggest that metastatic lymph node ratio (LNR) may be prognostic of survival in patients with pancreatic cancer. However, this phenomenon was confused by inclusion of node-negative patients in the analysis. The present study was designed to evaluate the prognostic impact of metastatic LNR and the absolute number of metastatic LNs in patients resected for pancreatic cancer.

Methods

Data were collected from 398 patients who underwent curative surgery for pancreatic head cancer at Seoul National University Hospital. Long-term survival was analyzed according to LNR and absolute number of metastatic LNs.

Results

Of the patients, 227 (57.0 %) had LN metastasis. The mean numbers of total retrieved and metastatic LNs were 19.5 and 1.9, respectively, and the mean LNR was 0.11. Median overall survival (OS) of patients was significantly higher in N0 than in N1 patients after curative resection (25.4 vs. 14.8 months, p < 0.001). Median OS was significantly lower in patients with 1 than in those with 0 positive LNs (17.3 vs. 25.4 months, p = 0.001). Among N1 patients, those with 0 < LNR ≤ 0.2 had comparable prognosis than those with >0.2 LNR (median OS 17.2 vs. 12.8 months, p = 0.096), and the number of metastatic LNs did not correlate with median OS (p = 0.365).

Conclusions

The presence of a single positive metastatic LN was associated with significantly poorer OS in patients with pancreatic cancer. When LN metastasis was present, the number of metastatic LNs and LNR had limited prognostic relevance.     

Outcome of Patients With Proximal Gastric Cancer Depends on Extent of Resection and Number of Resected Lymph Nodes

Background: Studies have shown that the survival of patients with gastric adenocarcinoma is related to the number of regional lymph nodes with metastases. The probability of identifying node-positive cancers increases with the number of lymph nodes resected and examined. It has been recommended that at least 15 lymph nodes be removed and examined for adequate staging. Prospective randomized studies have shown the lymph node yield is much greater with the D2 resection than the D1. This study evaluated the relative contribution of both the number of resected lymph nodes and the extent of gastric resection (D1/D2) on the outcome of patients with proximal gastric cancer.Methods: The medical records of 114 patients with adenocarcinoma of the proximal stomach, who underwent a curative gastric resection, were reviewed. Patients were stratified into four groups, i.e., two groups, D1/D1.5 and D2/D2.5, based on the extent of resection, and two groups based on the number of lymph nodes removed, fewer than 15 lymph nodes and 15 or more lymph nodes. Survival was determined by the method of Kaplan-Meier and differences compared by the log-rank test. Multivariate analysis was performed by using the Cox model.Results: The number of resected lymph nodes had no effect on the survival of the group as a whole. A significant improvement in survival was noted for patients with a D2 or greater resection. The median survival of patients with 15 or more lymph nodes resected improved from 25 months to 42 months when treated with an extended resection, (D2 or D2.5). Resection of 15 or more lymph nodes alone, or combined with an extended resection, resulted in a statistically significant improvement in survival for patients in American Joint Committee on Cancer Staging (AJCC) stage II.Conclusions: Both resection of 15 or more lymph nodes and extended lymphadenectomy contributed to the survival advantage observed in patients with AJCC stage II gastric cancer. The D2 gastric resection prolonged the median survival time and improved the 5-year survival rate for patients with 15 or more resected lymph nodes.Presented at the 52nd Annual Meeting of the Society of Surgical Oncology, Orlando, Florida, March 4–7, 1999.