Lymph node micrometastasis in node negative early gastric cancer

Aims

The clinical significance of lymph node micrometastasis for histologically node negative gastric cancer is not well documented. This study was to assess the incidence and to clarify the risk factors of lymph node micrometastasis in patients with node negative early gastric cancer (EGC).

Methods

We investigated the lymph node micrometastasis with using an anticytokeratin immunohistochemical stain in 90 patients with node negative EGC who underwent curative resection between 1991 and 2000.

Results

Among 3526 nodes from 90 patients, there were 17 cytokeratin immunohistochemical stain positive nodes from nine patients. The incidence of micrometastasis was higher in patients with lymphatic invasion (p = 0.012), venous invasion (p = 0.026) and larger tumor (p = 0.003). The independent risk factors for lymph node micrometastasis were lymphatic invasion (p = 0.004, RR = 22.915, 95% CI = 2.709 ∼ 193.828) and tumor size (p = 0.029, RR = 1.493, 95% CI = 1.042 ∼ 2.138). Although there were 10 deaths during the follow-up period of mean 67.6 months (1 month ∼ 147 months), there was no death from a cancer recurrence.

Conclusions

The incidence of lymph node micrometastasis in patients with node negative early gastric cancer was 10%, and the independent risk factors for micrometastasis were lymphatic invasion and tumor size.     

Assessment of lymph node micrometastasis in early gastric cancer in relation to sentinel nodes

Background The development of endoscopic resection and reduced surgical procedures has progressed in recent years. Lymph node micrometastases can be cited as one of the problems with reduced operations. In this study, we investigated clinicopathological findings and sentinel lymph nodes (SNs) for associations with micrometastases. We discuss the indications for endoscopic mucosal resection (EMR), reduced surgery, and sentinel node navigation surgery (SNNS) based on the results. Methods Immunostaining with anti-cytokeratin antibodies was used as the method of exploring for micrometastases. Comparisons and assessments were made in regard to the presence or absence of micrometastases and various clinicopathological factors. Results The relationship between the clinicopathological factors and micrometastases was investigated in 120 patients with pT1pN0 gastric cancer. Significant differences in depth of invasion (mucosal [m] versus submucosal [sm]) and histological type (differentiated versus undifferentiated) were observed in both univariate analysis and multivariate analysis. Micrometastases were observed in 32% of the sm cancers, and they were observed in group 2 lymph nodes (no. 7) in 8%. They tended to be more common in the undifferentiated type. The micrometastatic lymph nodes were restricted to blue nodes (BNs) and lymph nodes within the dye flow area of patent blue (used intraoperatively explore for SNs). Conclusion It is considered that the indications for current EMR and reduced surgery in early gastric cancer are valid from the standpoint of micrometastases. But if the SNNS that has been studied in recent years is introduced, the lymphatic basin dissection method seems valid only if the case is s-pN0 early cancer.     

Lymph node metastasis and preoperative diagnosis of depth of invasion in early gastric cancer

Background. No reports have, to date, focused on the relationship between preoperative determination of the depth of invasion and lymph node metastasis. The present study, under the leadership of the Japanese Gastric Cancer Association, was designed to form a basis for decision making in limited treatment for early gastric cancer (EGC). Methods. From eight major hospitals in Japan, 2672 gastric cancers whose preoperative depth of invasion was mucosal(M-cancer), and 6209 EGCs, consisting of 3584 mucosal(m-) and 2625 submucosal(sm-) cancers, were collected by questionnaire. All registered patients underwent gastrectomy with D1 or more extensive lymphadenectomy between 1985 and 1998. Results. The accuracy of preoperative diagnosis of depth of invasion of M-cancers was 80.2% (2144/2672). However, of the total of 2432 M-cancers in which no nodal involvement was observed intraoperatively (N0), histological examination of the resected specimens confirmed that lymph node metastasis was absent in 2353 (96.8%). The frequencies of lymph node metastasis in early gastric, m-, and sm-cancers were 8.9%, 2.5%, and 17.6%, respectively. Node involvement was associated with a higher frequency of undifferentiated than differentiated histology, as well as with greater tumor size. The incidences of lymph node metastasis in m-cancers with a diameter of less than 4 cm, and in sm-cancers with a diameter below 1 cm were 1.3% (37/2837) and 4.9% (4/82), respectively. These metastases rarely extended beyond the first tier. Conclusion. N0 and M-cancers, m-cancers less than 4 cm in diameter, and sm-cancers no larger than 1 cm in diameter may be appropriate indications for limited surgery. Received: January 23, 2001 / Accepted: March 15, 2001     

逆转录聚合酶链反应检测结直肠癌淋巴结微转移的临床意义

背景与目的:结直肠癌淋巴结微转移灶是否有预测预后价值目前尚有争议,本文对结直肠癌患者淋巴结微转移情况进行逆转录聚合酶链反应(RT-PCR)检测,研究微转移对临床分期和预后的影响。方法:用RT-PCR技术检测56例结直肠癌患者肠旁及系膜淋巴结中细胞角质蛋白CK20mRNA,揭示微转移灶的存在,并与常规病理苏木精伊红(HE)染色和免疫组化染色结果进行比较;分析HE染色和RT-PCR检测结果对判定临床病理分期和统计生存率的影响。结果:共检测432个淋巴结,HE染色、免疫组化染色和RT-PCR法淋巴结转移检出率分别为57.2%、62.3%和73.1%。HE染色和免疫组化的检出率无显著性差异(P>0.05),而HE染色和RT-PCR法检测结果有显著性差异(P<0.05)。56例患者中,按HE染色结果确定的PN0、PN1和PN2期,其5年无复发转移生存率分别为80%、60%和50%;通过RT-PCR技术检测,升级后的PN0、PN1和PN2期5年无复发转移生存率分别为100%、61.9%和55.6%,两种方法分析的结果有显著性差异(P<0.05)。结论:HE染色未确切指出淋巴结微转移癌;RT-PCR法检测CK20mRNA可以推断淋巴结微转移癌的存在,从而有助于确定结直肠癌临床分期和预测预后。     

Paraaortic lymph node micrometastasis and tumor cell microinvolvement in advanced gastric carcinoma

Background. Paraaortic lymph node dissection in advanced gastric carcinoma is controversial. The purpose of this study was to investigate the incidence and significance of micrometastasis (MM) or tumor cell microinvolvement (TCM) in these critical lymph nodes. Methods. A total of 2339 lymph nodes, including 390 paraaortic nodes, obtained from 47 patients with advanced gastric carcinoma were examined immunohistochemically, using cytokeratin antibody. Results. Lymph node metastasis was found in 95 of the 390 paraaortic nodes of 14 patients by routine histological examination. MM or TCM was immunohistochemically detected in 45 of the 295 negative paraaortic lymph nodes from 15 of 33 patients (MM, n = 5; TCM, n = 10). The 5-year-survival rate in the paraaortic node-negative group and cytokeratin-positive group was significantly higher that that of the hematoxilin and eosin-positive group. The total number of lymph node metastases by hematoxylin and eosin staining and the pathological lymph node compartments, by cytokeratin-positive nodes, were prognostic factors by multivariate analysis. Conclusions. We demonstrated a high rate of MM or TCM in the paraaortic lymph nodes and suggest that such harbored metastases are related to the prognosis of patients with advanced gastric carcinoma. On the basis of this study, a multi-institutional study should be considered. Received for publication on June 7, 1999; accepted on Sept. 30, 1999     

The significances of lymph node micrometastasis and its correlation with E-cadherin expression in pT1-T3N0 gastric adenocarcinoma

BACKGROUND: Recently, micrometastasis (MM) in the lymph node in gastric cancer has been detected by cytokeratin immunostaining. However, clinical significance of MM and its relationship with reduced expression of E-cadherin in primary lesion have not been well studied. METHODS: The 4,990 lymph nodes from 184 pT1~T3N0 patients from 1995 to 2000 at Korea University Hospital were immunostained with the anticytokeratin AE1/3 antibody for detection of micometastasis. The primary lesions were also immunostained for E-cadherin expression. RESULTS: MM in the lymph node of gastric cancer was found in 131 (2.6%) of total dissected nodes, and 31 of 184 patients (16.8%) were shown to have MM. The MM was significantly correlated with the depth of invasion, tumor size, operation method, Lauren classification, lymphovascular invasion and loss of E-cadherin expression in primary tumor. On multivariate analysis, the independent risk factors for MM were the depth of invasion and loss of E-cadherin expression. The patients with MM had significantly lower 5-year overall and disease free survival rate than those without MM. CONCLUSION: Lymph node MM in histologically node-negative gastric cancer was significantly correlated with poor 5-year survival rate. The determination of E-cadherin expression in primary gastric tumor may be useful in prediction of the MM.     

多西他赛为主的三药方案治疗高龄低分化胃癌的效果观察

目的分析以多西他赛为主的三药方案治疗高龄低分化胃癌患者的临床效果。方法随机数表法将91例高龄低分化胃癌患者随机分组对照组(n=45)和观察组(n=46),对照组患者接受多西他赛^+奥沙利铂方案化疗,观察组患者接受多西他赛^+奥沙利铂^+替吉奥方案化疗,比较两组患者的外周血T淋巴细胞(包括CD8^+、CD4^+、CD3^+)水平、临床疗效、生存情况及不良反应发生情况。结果治疗前后,两组患者CD3^+、CD4^+和CD8^+水平比较,差异均无统计学意义(P﹥0.05);治疗后,两组患者CD3^+、CD4^+和CD8^+水平均高于本组治疗前,差异均有统计学意义(P﹤0.05)。观察组患者疾病控制率(DCR)为56.5%(26/46),与对照组患者的51.1%(23/45)比较,差异无统计学意义(χ^2=0.268,P﹥0.05)。两组患者肿瘤进展时间和生存时间比较,差异均无统计学意义(P﹥0.05)。观察组患者中性粒细胞减少、白细胞减少、血小板减少、疲劳、脱发的发生率均高于对照组患者,差异均有统计学意义(P﹤0.05)。结论多西他赛为主的二药、三药方案治疗高龄低分化胃癌的临床效果相当,但三药方案的不良反应较重,考虑到高龄患者的身体条件,采用以多西他赛为主的二药方案治疗更为合适。     

早期胃癌组织中上皮钙粘蛋白表达与淋巴结微转移及临床病理的关系

背景与目的:早期胃癌淋巴结微转移问题日益受到关注,胞浆角蛋白(cytokeratin,CK)染色是识别上皮源性恶性肿瘤细胞的重要方法,本研究拟探讨早期胃癌原发灶上皮钙粘蛋白(epithelial cadherin,E-cad)的表达情况与淋巴结内出现微转移之间的关系及临床意义.方法:用免疫组织化学染色的方法对162例早期胃癌患者的4 522枚淋巴结进行苏木精-伊红(HE)和胞浆角蛋白(cytokeratin,CK)染色,并对其中135例患者的原发灶切片进行E-cad染色,结合临床病理资料和随访结果进行分析.结果:HE染色发现的淋巴结转移率为6.8%(11/162),而CK染色发现的淋巴结转移率为26.5%(43/162),二者差异有统计学意义(P＜0.001).在151例HE染色未见淋巴结转移的患者中通过CK染色发现了32例(21.2%)有淋巴结微转移,且淋巴结微转移多见于原发灶直径大于1.0 cm,组织分化不良,肿瘤浸润较深的(如浸及粘膜下层),淋巴管和血管受累,以及E-cad低表达标本(P＜0.05).原发灶E-cad的低表达率为57.0%(77/135),与淋巴结出现微转移有密切关系,有淋巴结微转移患者的5年生存率比没有微转移者明显低(P＜0.01).结论:肿瘤直径大于1.0 cm,组织分化不良,较深的浸润,淋巴管或血管受累,以及E-cad低表达是早期胃癌患者出现淋巴结转移的高危因素.     

Immunohistochemical detection of lymph node microinvolvement in node-negative gastric cancer

Background. Despite curative resection of the primary tumor with extensive dissection of lymph nodes, some patients with node-negative gastric cancer die of local relapse or metastatic disease. Microinvolvement of regional lymph nodes may play an important role in the prognosis. Methods. To evaluate the incidence and prognostic implications of regional lymph node microinvolvement in node-negative gastric cancer, we retrospectively analyzed tissue samples from 51 patients operated on for primary gastric cancer. They had tumors that invaded beyond the muscularis propria, but without metastasis to the lymph nodes, shown by the conventional H&E staining method. The regional lymph nodes were examined immunohistochemically, using monoclonal antibodies against cytokeratin. Results. Microinvolvement was found in 4.8% of lymph nodes (67/1390) and in 43.2% of the patients (22/51). The clinical outcome of the patients with microinvolvement was not significantly different from those without it. However, no patient died in the no-microinvolvement group, while three patients in the microinvolvement group died of recurrence. Conclusion. The incidence of microinvolvement in conventionally negative lymph nodes cannot be ignored, and detecting microinvolvement may be important for predicting recurrence of gastric cancer. Received for publication on April 26, 1999; accepted on Sept. 14, 1999     

早期胃癌淋巴结微转移检测的临床意义

目的探讨淋巴结微转移与早期胃癌临床病理特征及预后的关系。方法应用免疫组化方法对182例早期胃癌1631个淋巴结进行微转移检测。结果早期胃癌中4.1%的淋巴结、13.2%的患者存在淋巴结微转移。淋巴结微转移与年龄、性别、肿瘤大小、部位、大体类型、分化程度、浸润深度、淋巴管癌栓、癌旁黏膜萎缩、肠化、异型增生及预后无关。结论淋巴结微转移检测对早期胃癌预后判断价值有限。     

Prognostic influence of immunohistochemically detected lymph node micrometastasis and histological subtype in pN0 oesophageal cancer

Introduction

Differences in frequency and clinical impact of lymph node micrometastasis between histological subtypes of oesophageal cancer have not been determined.

Methods

1204 lymph nodes from 32 squamous cell carcinomas and 54 adenocarcinomas with complete resection and pN0 status were re-evaluated using a serial sectioning protocol including immunohistochemistry. Intra-nodal tumour cells were classified as micrometastases (0.2–2 mm) or isolated tumour cells (<0.2 mm).

Results

There was no significant difference in the frequency of micrometastases between adenocarcinoma and squamous cell carcinoma (11.3% vs. 3.1%, p = n.s.). In the squamous cell carcinoma group, Kaplan–Meier curves showed a significantly prolonged 5-year survival (p = 0.02) and disease free interval (p < 0.01) for immunohistochemically node negative versus node positive patients. In patients with adenocarcinoma, no such difference (p = n.s. and p = n.s., respectively) was seen. In patients who did not undergo pre-treatment, those with adenocarcinoma had a significant 5-year survival (65% vs. 53%; p = 0.03) and disease free interval (83% vs. 58%; p < 0.05) advantage over those with squamous cell carcinoma. After pre-treatment, no difference between the histological subtypes was detected.Regression analysis did not reveal any factors that significantly affected overall survival in node negative patients. However, four factors did significantly influence disease free interval: pre-treatment (HR 3.3 [95% CI 1.2–9.1], p = 0.02); micrometastasis (HR 5.3 [95% CI 1.4–19.7], p = 0.01); UICC stage II vs. 0/I (HR 2.2 [95% CI 1.1–4.4], p = 0.03); and adenocarcinoma (HR 0.3 [95% CI 0.1–0.9], p = 0.03).

Conclusion

The difference in frequency and clinical impact of immunohistochemically detected micrometastasis may indicate that adenocarcinoma and squamous cell carcinoma should not be treated as one entity.     

Applicability of endoscopic submucosal dissection for undifferentiated early gastric cancer: Mixed histology of poorly differentiated adenocarcinoma and signet ring cell carcinoma is a worse predictive factor of nodal metastasis

Background

Endoscopic submucosal dissection (ESD) is not considered an appropriate treatment for undifferentiated early gastric cancer (UEGC) due to the higher risk of nodal metastases. We aimed to investigate predictive factors for nodal metastases in UEGCs, determine whether the tumor histology is an independent factor for it, and explore whether ESD is applicable for UEGC.

Signet ring cell percentage in poorly cohesive gastric cancer patients: A potential novel predictor of survival

Background and objectivesSignet ring cells (SRC) are widely acknowledged as a prognostically unfavorable histotype amongst poorly cohesive gastric cancer. In this study we evaluated the impact of SRC percentage on the clinical, pathological and prognostic features of these tumors according to the classification by the European Chapter of the IGCA.MethodsWe retrospectively reviewed records of patients with poorly cohesive gastric cancer that underwent surgery between 1995 and 2016, whose tissue specimens were available in a biological bank. All slides were put under revision, patients were reclassified into three groups according to the proportion of signet ring cells: “pure” SRC (containing ≥90% of SRCs), Poorly Cohesive-Not Otherwise Specified (PC–NOS) (containing ≤10% of SRCs), and PC-NOS/SRC (containing <90% but >10% of SRCs). The clinicopathological factors between different types were analyzed and prognostic differences were compared.ResultsAmong 143 enrolled patients, 51% were male and 49% were female. The mean (±SD) age at diagnosis was 61 ± 13.9 years. Eighty-seven patients (60.8%) were reclassified as PC-NOS, 56 (39.2%) as PC-NOS/SRC and none as “pure” SRC. Five-years overall survival was significantly higher in PC-NOS/SRC group (63.3%) compared with PC-NOS group (12.7%). The increase in mortality risk was more than four-fold in patients with PC-NOS pattern compared to those with PC-NOS/SRC (HR 4.32 [95% CI 2.5–7.4]. After adjustment for potential confounding factors, SRC pattern was still an independent predictor of survival.ConclusionsThe percentage of SRCs is inversely related to tumor aggressiveness, confirming the role of SRC pattern as an independent predictor of survival.     

Recurrence in early gastric cancer with lymph node metastasis

Background  Early gastric cancer (EGC) has an excellent prognosis, but some patients with lymph node-positive disease will develop recurrence. In this study we investigated the risk factors for recurrence in this selected group of patients. Methods  The clinical and pathological records of 2368 patients who underwent gastrectomy for solitary EGC between 1980 and 1999 at the National Cancer Center Hospital, Tokyo, were examined. Two hundred and thirty-eight patients (10%) were lymph node-positive (positive for lymph node metastasis) and form the population of this study. Results  Nineteen (8%) of the 238 patients with lymph nodepositive disease developed recurrence. The most common site of recurrence was lymph node (37%), followed by liver (21%). The interval between surgery and the detection of recurrence ranged from 3 to 98 months, with a median of 26 months. Multivariate analysis demonstrated that the number of metastatic nodes was an independent risk factor for recurrence. Patients with seven or more metastatic nodes had the highest rate of recurrence, at 38%. Conclusion  The number of nodes positive for metastasis was the only independent risk factor for recurrence after curative surgery in patients with lymph node-positive early gastric cancer. These high-risk patients may obtain additional survival benefit if targeted with adjuvant chemotherapy.     

Long-term postoperative survival of a gastric cancer patient with numerous para-aortic lymph node metastases

Received on July 7, 1999; accepted on Oct. 12, 1999     

Predicting lymph node status in early gastric cancer

Accurate prediction of lymph node (LN) status is of crucial importance for appropriate treatment planning in patients with early gastric cancer (EGC). However, there is no definitive consensus yet on which patient and/or tumor characteristics are associated with LN metastasis. A systematic search for studies investigating the relationship between patient and/or tumor characteristics and LN metastasis in EGC was performed in PubMed/MEDLINE. Patient and/or tumor characteristics associated with LN metastasis were identified by meta-analyzing results of individual studies. Forty-five studies were included. Variables significantly associated with LN metastasis in gastric cancer limited to the mucosa were: age younger than 57 years, tumor location in the middle part of the stomach, larger tumor size, macroscopically depressed tumor type, tumor ulcerations, undifferentiated tumors, diffuse tumor type according to the Lauren classification, lymphatic tumor invasion, tumors with a proliferating cell nuclear antigen (PCNA) labeling index of more than 25%, and matrix metalloproteinase-9-positive tumors. Variables significantly associated with LN metastasis in gastric cancer limited to the submucosa were: female sex, tumor location in the lower part of the stomach, larger tumor size, undifferentiated tumors, increasing depth of submucosal invasion, lymphatic tumor invasion, vascular tumor invasion, increased submucosal vascularity, tumors with a PCNA labeling index of more than 25%, tumors with a gastric mucin phenotype, and vascular endothelial growth factor-C-positive tumors. We identified several variables associated with LN metastasis in EGC. These variables should be included in future research, in order to assess which of these variables remain as significant predictors of LN metastasis.     

结直肠癌淋巴结微转移对预后影响的意义

背景与目的:淋巴结微转移的预后价值尚无一致意见,本研究旨在探讨结直肠癌淋巴结微转移的预后意义。方法:收集江汉大学附属医院1988年～2001年结直肠癌根治性手术切除、有完整淋巴结检查资料的标本80例,其中直肠癌30例,结肠癌50例。经过溶脂法检查淋巴结共3869枚,平均每例48.36枚,经4μm间断连续切片、常规HE染色和免疫组化染色,确定有无淋巴结转移与微转移(微转移灶为瘤团直径<0.2mm或瘤细胞数<50个)。数据经SAS8.1统计学软件进行Cox模型回归分析及Spearman等级相关分析。结果:共检出转移淋巴结232枚(6%),微转移淋巴结39枚(1.01%)。直肠癌中淋巴结转移数与患者生存时间有关(χ2=9.94,P=0.0016);淋巴结微转移与淋巴结转移数(r=0.44,P=0.016)等病理学指标有关。结肠癌中淋巴结转移数(χ2=9.52,P=0.002)、AJCC淋巴结分期(χ2=5.73,P=0.0167)与患者生存时间有关,淋巴结微转移与Dukes’淋巴结分期(r=0.314,P=0.008)有关。结论:淋巴结微转移与结直肠癌预后相关,但不能作为独立的预后指标。