Immunohistochemically demonstrated lymph node micrometastasis and prognosis in patients with otherwise node-negative hilar cholangiocarcinoma

OBJECTIVE: To investigate whether immunohistochemically demonstrated lymph node micrometastasis has prognostic significance in patients with histologically node-negative (pN0) hilar cholangiocarcinoma. SUMMARY BACKGROUND DATA: The clinical significance of immunohistochemically detected lymph node micrometastasis recently has been evaluated in various tumors. However, no reports have addressed this issue with regard to hilar cholangiocarcinoma. METHODS: A total of 954 lymph nodes from surgical specimens of 45 patients with histologically node-negative hilar cholangiocarcinoma who underwent macroscopically curative resection were immunostained with monoclonal antibody against cytokeratins 8 and 18. The results were examined for relationships with clinical and pathologic features and with patient survival. RESULTS: Lymph node micrometastases were detected immunohistochemically in 11 (24.4%) of the 45 patients, being found in 13 (1.4%) of 954 lymph nodes examined. Of the 13 nodal micrometastases, 11 (84.6%) were found in the N2 regional lymph node group rather than N1. Clinicopathologic features showed no associations with lymph node micrometastases. Survival curves were essentially similar between patients with and without micrometastasis. In addition, the grade of micrometastasis showed no effect on survival. The Cox proportional hazard model identified microscopic venous invasion, microscopic resection margin status, and histologic differentiation as significant prognostic factors in patients with pN0 disease. CONCLUSIONS: Lymph node micrometastasis has no survival impact in patients with otherwise node-negative hilar cholangiocarcinoma. The authors do not recommend extensive lymph node sectioning with keratin immunostaining for prognostic evaluation.     

Lymph node micrometastasis and prognosis in patients with oesophageal squamous cell carcinoma

BACKGROUND: The purpose of this study was to investigate whether the presence of lymph node micrometastasis in pathological lymph node-negative (pN0) oesophageal squamous cell carcinoma had prognostic value. METHODS: Some 1840 lymph nodes were obtained from 50 patients with pN0 oesophageal squamous cell carcinoma who underwent curative resection of the primary tumour with systematic lymphadenectomy. These lymph nodes were examined immunohistochemically with anticytokeratin antibody (AE1/AE3). Lymph node micrometastases newly detected by immunohistochemistry were classified as micrometastasis. Additionally, lymph node micrometastases were classified into three stages: stage 1, one individual AE1/AE3-positive cell; stage 2, multiple individual positive cells; stage 3, one or multiple positive clusters. RESULTS: Micrometastases were detected in 20 patients (40 per cent). A higher stage of micrometastasis was associated with greater pathological tumour (pT) size (P = 0.023). Recurrent tumours developed in nine patients. However, the frequency of recurrence was similar in patients with, or without, micrometastasis (five of 20 and four of 30 patients respectively; P = 0.25). Twenty-three of 30 patients without micrometastasis survived, whereas 15 of 20 patients with micrometastasis were still alive (5-year overall survival 75 and 78 percent respectively, P = 0.91). Twenty-six of 30 patients without micrometastasis had no recurrence, whereas 15 of 20 patients with micrometastasis had no recurrence (5-year relapse-free survival 86 and 73 per cent respectively, P = 0.37). There was no significant difference in prognosis with respect to the stages of micrometastasis. Multivariate analysis also showed that micrometastasis was not an independent prognostic factor (P = 0.73). CONCLUSION: Immunohistochemical detection of lymph node micrometastasis may be an indicator of lymphatic dissemination of tumour cells. However, the presence of micrometastasis had no impact on the prognosis of node-negative patients with oesophageal squamous cell carcinoma.     

Clinical significance of lymph node micrometastasis in gallbladder carcinoma

BACKGROUND: This retrospective study was intended to define the clinical significance of lymph node micrometastasis in gallbladder carcinoma. METHODS: A total of 1136 regional lymph nodes taken from 63 consecutive patients undergoing radical resection were examined histologically. Micrometastasis was defined as a metastasis missed on routine histologic examination with hematoxylin-and-eosin but detected by immunohistochemical examination with an antibody against cytokeratins 8 and 18. RESULTS: None of 9 patients (0%) with pT1 disease and 19 of 54 patients (35%) with pT2-4 disease had nodal micrometastases. Univariate analysis identified nodal micrometastasis, type of radical resection, M classification, pT classification, perineural invasion, pTNM stage, timing of radical resection, lymphatic vessel invasion, and pN classification as significant variables. Multivariate analysis revealed that nodal micrometastasis (P =.0003) and type of radical resection (P=.0044) were independent prognostic factors. Nodal micrometastasis affected survival adversely, despite the absence (P=.0002) or presence (P <.0001) of overt nodal metastasis. Nodal micrometastasis correlated significantly with invasive characteristics: lymphatic vessel invasion, perineural invasion, and distant metastasis. CONCLUSIONS: Lymph node micrometastasis is the strongest independent predictor of worse survival regardless of the overt nodal status and may indicate aggressive tumor biology among patients undergoing curative resection for gallbladder carcinoma.     

中下段直肠癌预后与淋巴结微转移的关系

目的 观察淋巴结微转移对中下段直肠癌预后的影响.方法 应用CK-20免疫组织化学技术对56例中下段直肠癌患者共计661枚淋巴结检测微转移.结果 20例(35.7%)67枚(10.1%)淋巴结检出微转移.20例检出淋巴结微转移者中10例TNM分期提高:Ⅰ→ⅢA 3例,Ⅰ→ⅢC 2例,ⅡA→ⅢB 3例,ⅢA→ⅢC 2例.Kaplan-Meier生存分析显示,淋巴结微转移阳性患者半数生存期为(36.90±3.37)个月(95%置信区间:30.29～43.51个月),明显短于淋巴结微转移阴性者的(48.72±2.25)个月(95%置信区间:44.30～53.14个月),两者差异有统计学意义(P＜0.05).结论 中下段直肠癌淋巴结微转移检测有助于更准确地进行临床病理分期.淋巴结微转移阳性者预后较差.     

Impact of Lymph Node Micrometastasis in Patients with Pancreatic Head Cancer

Purpose The purpose of this study was to investigate the clinical significance of nodal micrometastasis in patients who underwent a curative operation for pancreatic cancer. Experimental Design Fifty-eight patients underwent a macroscopically curative resection with extended lymph node dissection for pancreatic cancer. The total number of resected lymph nodes was 1,058, and 944 histologically negative lymph nodes were subjected to immunohistochemical staining to detect occult micrometastases. Results Nodal micrometastases were detected immunohistochemically in 147 out of 944 resected histologically negative lymph nodes (15.6%). Forty-four of all 58 patients (75.9%) and 13 of the 23 histologically node-negative patients (56.5%) had nodal micrometastases. Nodal micrometastases existed in the N1 lymph node area most frequently, followed by the N2 and N3 lymph node areas. The distribution was similar to that of histologically metastatic lymph nodes. Ten out of 16 patients (62.5%) with histological N1, and 5 out of 16 patients (31.3%) with histological N2 had nodal micrometastases beyond the histological lymph node status. Three and 5-year survival rates of pN0 patients without lymph node nodal micrometastases were both 60.0%, while those with nodal micrometastases were 19.2% and 0%, respectively. There was statistically significant difference between the both groups (P = 0.041). Conclusions Nodal micrometastasis in pancreatic cancer existed in wider and more distant areas than histological lymph node status, and it was an unfavorable predictive factor, even in N0 patients.     

Clinical impact of micrometastasis of the lymph node in gastric cancer

Micrometastasis in regional lymph nodes has been observed immunohistochemically, but the biological and clinical roles of minute nodal invasion of carcinoma in gastric cancer remain unclear. We used the anti-cytokeratin (AE1/AE3) antibody to immunohistochemically detect nodal micrometastatic lesions that could not be identified by routine pathological examination. A total of 4203 lymph nodes were examined in 180 gastric cancer patients. Lymph node metastasis was found in 36 of the 180 patients by routine pathological evaluation. Immunohistochemically micrometastasis was detected in the lymph nodes of 19 node-negative patients. Micrometastasis was not detected in any of the mucosal gastric cancer patients who underwent lymph node dissection. Gastric cancer patients with more than six metastatic lymph nodes all had nodal micrometastasis. Patients with micrometastasis had a significantly poorer survival rate than those without micrometastasis (P < 0.05). Based on the present results the presence of lymph node micrometastasis may provide a more accurate indication for surgical outcome in gastric cancer patients at the same clinical stage.     

Lymph node micrometastases in early gastric cancer and their impact on prognosis

Abstract While the presence of lymph node metastases in early gastric cancer (EGC) is the most significant prognostic factor, the relevance of lymph node micrometastases remains uncertain. The authors studied 5400 lymph nodes dissected from 300 patients treated surgically for EGC between 1976 and 1999, all of whom were histologically pN0. Micrometastases were defined as single or small clusters of neoplastic cells identifiable only by immunohistochemical methods. Lymph node micrometastases were observed in 30 of the 300 patients (10%). No significant correlation was observed between micrometastases and other clinicopathological characteristics. Analysis of overall survival showed no significant difference between positive or negative micrometastasis groups. The results of our study show that the presence of lymph node micrometastases in EGC does not influence patient prognosis. Electronic Publication     

CK19表达及其在结肠癌淋巴结微转移诊断中的应用

目的：研究用免疫组化方法检测CK19及其在结肠癌淋巴结微转移诊断中的应用与临床病理意义。方法：取材于50例结肠癌病人肿瘤组织及癌周淋巴结255枚,同时进行HE染色组织学检查和抗角蛋白19抗体的免疫组化检测。结果：50例结肠癌组织中CK19表达均为阳性。255枚淋巴结用HE染色检查阳性者56枚(22．0％),皆同时表达CK19阳性;另20枚淋巴结HE染色阴性,而CK19表达阳性。50例中有12例淋巴结中发现微转移,其中6例常规组织学检查属淋巴结转移阴性而免疫组化染色诊断表现为转移阳性。占常规病理检查淋巴结转移阴性者的21．4％(6／28)。随着肿瘤分期增加,淋巴结CK19表达阳性率亦增加。CK19表达阳性者预后较阴性者为差。结论：CK19免疫组化法是检测结肠癌淋巴结微转移的敏感而便捷的方法,而检测结肠癌微转移有助于判断肿瘤进展程度与预后。特别对在筛选组织学检查淋巴结阴性但存在微转移的病人有实用价值。     

Distribution of Lymph Node Metastasis Including Micrometastasis in Gastric Cancer with Submucosal Invasion

Abstract The purpose of this retrospective study was to analyze the distribution of lymph node metastases, including micrometastases, according to the location of the gastric cancer with submucosal invasion. A total of 118 patients with submucosal gastric cancer were enrolled in this study. The distribution of lymph node metastases was examined according to tumor location. Immunohistochemical examination using anti-cytokeratin antibody was performed to examine nodal micrometastases in 118 patients. Lymph node metastasis was found in 19.5% (23/118) of the patients. Significant differences were found for tumor size and depth, lymphatic invasion, and venous invasion for patients with and without nodal metastasis. The distribution of lymph node metastasis for tumors at upper or middle portions of the stomach was mainly found along the left gastric artery. The distribution of lymph node metastasis for tumors in the lower and lesser curvature varied. Immunohistochemical analysis found that 15 of 23 patients with lymph node metastasis found by histologic examination had micrometastases. The presence of two or more lymph node micrometastases was found in these 15 patients, and they were distributed in another stations, including distant nodes. The incidence of micrometastasis was 24.2% (23/95) in pN0 patients. Lymph node micrometastases were confined to regional nodes near the primary tumor. When planning minimally invasive treatment for submucosal gastric cancer, it is important to understand the distribution of lymph node metastasis, including micrometastasis, according to tumor location.     

Prognostic effect of lymph node micrometastasis in patients with histologically node-negative gastric cancer

Background There is no consensus as to the impact of lymph node micrometastasis on survival of patients with gastric cancer. The aim of this study was to clarify the prognostic significance of lymph node micrometastasis in patients with histologically node-negative gastric cancer Methods Lymph nodes (n=2039) from 64 patients with histologically node-negative gastric cancer (T2, T3) were evaluated for micrometastasis. Three serial 5-μm sections of the resected lymph nodes were prepared for immunohistochemical staining with the anti-cytokeratin antibody CAM 5.2. Results Micrometastasis was found in 73 of 2039 nodes (4%) and 20 of 64 patients (32%). The 5-year survival rate was significantly lower for patients with lymph node micrometastasis than for those without lymph node micrometastasis (66% vs. 95%,P<.01). The 5-year survival rate was significantly lower when there were four or more positive micrometastatic nodes (94% vs. 29%,P <.01) and when there were extragastric micrometastatic nodes (89% vs. 53%,P<.01). Conclusions Lymph node micrometastasis was associated with poor outcome in patients with histologically node-negative gastric cancer. The number and the level of lymph node micrometastases are useful prognostic markers for deciding treatment strategies for additional therapy and follow-up.     

甲状腺滤泡状癌淋巴结微转移与中央组淋巴结处理的探讨

目的 从淋巴结微转移的角度探讨甲状腺滤泡状癌中央组(Ⅵ组)淋巴结处理的意义.方法 选择细胞角蛋白(CK-19)单克隆抗体,应用免疫组化SP法对68例326枚常规病理检查阴性的颈淋巴结(pN0)进行检测,确定其微转移情况并与临床及随访资料进行对比分析.结果 326枚pN0淋巴结中微转移阳性46枚,包括Ⅱ组4枚(4/42),Ⅲ组5枚(5/34),Ⅳ组5枚(5/49),Ⅴ组1枚(1/17),Ⅵ组31枚(31/184).在淋巴结微转移阳性的14例中6例(6/14)出现局部复发或远处转移,而54例微转移阴性病人中仅3例(3/54)复发或远处转移(P＜0.01).结论 甲状腺滤泡状癌Ⅵ组淋巴结是容易发生微转移的区域淋巴结;且淋巴结微转移与肿瘤复发及转移有密切关系.甲状腺滤泡状癌手术时应常规清扫Ⅵ组淋巴结.     

Immunohistochemically detected micrometastases in peribronchial and mediastinal lymph nodes from patients with T1, N0, M0 pulmonary adenocarcinomas

The T1, N0, M0 subset of stage I lung adenocarcinoma is a tumor that has a 5-year disease-free survival rate of 66% to 85%. To date, there has not been a rigorous immunohistochemically detected lymph node micrometastasis study composed of patients with identical stage and type of tumors, and in which standard histologic features were incorporated into multivariate analyses. We immunohistochemically examined the peribronchial and mediastinal lymph nodes from 80 consecutively accrued patients with T1, N0, M0 adenocarcinomas and bronchioloalveolar carcinomas unselected for distant metastasis, and an additional 39 patients with similar stage and type neoplasms who were selected for their development of metastases to evaluate the prevalence of micrometastases, their association with distant metastases, and their relationship with other pathologic prognostic features. All slides were stained with keratin AE1/3. Micrometastases were confirmed with Ber-Ep4. Three immunohistochemically detected lymph node micrometastases were identified in three of 80 consecutively accrued patients (4%). These three positive stains constituted 0.5% of the 573 stains required to immunohistochemically screen all of the lymph node blocks from these patients. Among the 39 patients who were selected because they developed distant metastases, three immunohistochemically detected lymph node micrometastases from three patients were identified, which constituted 8% of patients in this group and 1% of the 280 stains required to screen all of these patients' lymph nodes. Small vessel invasion, maximum tumor dimension, and immunohistochemically detected lymph node micrometastases were independently associated with metastases on multivariate analysis. Among patients who developed metastases, there was no significant difference in the disease-free survival rate between those with and those without immunohistochemically detected lymph node micrometastases. Given the low sensitivity in terms of the number of immunohistochemical stains performed, and the prognostic significance of standard histologic features, the use of immunohistochemical screening lymph nodes from all patients with T1, N0, M0 adenocarcinomas is questionable.     

Outcome of Histologically Node-negative Esophageal Squamous Cell Carcinoma

The outcome of node-negative esophageal carcinoma and the prognostic significance of lymph node micrometastasis remain unknown. The aim of this retrospective study was to clarify these two points. A series of 98 patients who underwent curative operation for histologically node-negative (pN0 in TNM classification) esophageal carcinoma were enrolled in the study. We reviewed the cause of death of these patients. The survival curves were calculated and compared after stratifications according to clinicopathologic parameters. Lymph node micrometastasis in the patients with recurrences was examined using immunohistochemical staining of cytokeratin. Their ages ranged from 45 to 83 years (mean 64.3 years). There were 83 men and 15 women. Altogether, 54 patients were still alive, and 44 had died. A total of 9 patients died from recurrence of their esophageal carcinoma, 33 died from other causes (pneumonia 11, extraesophageal carcinoma 7, and so on), and 2 died from unknown causes. Eight patients had locoregional recurrences, and two patients had distant recurrences. The overall survival rate for the 98 patients was 58.2%. The survival for patients with pT2 or pT3 tumors was significantly worse than for those with pTis or pT1 tumors (p = 0.02, log-rank test). Other clinicopathologic factors did not affect the prognosis. Immunohistochemical study found no lymph node micrometastasis in 365 lymph nodes resected from the patients with recurrences. Only the depth of tumor invasion affected the outcome of patients with node-negative esophageal carcinoma. Altogether, 75% of patients died of other causes without recurrence, with the two main causes of death being pulmonary complications and extraesophageal carcinoma in these patients. Lymph node micrometastasis was not associated with recurrence in this series.     

Clinical value of genetically diagnosed lymph node micrometastasis for patients with oral squamous cell carcinoma

BACKGROUND: The purpose of this study was to investigate the incidence and clinical significance of genetically diagnosed lymph node micrometastasis for patients with oral squamous cell carcinoma (SCC). METHODS: A total of 495 lymph nodes obtained from 21 patients with primary oral SCCs that had p53 mutations were examined for corresponding p53 mutations in lymph nodes using mutant allele-specific amplification (MASA). RESULTS: Among 476 histologically negative nodes, 44 were scored as positive for metastasis by MASA. All 19 histologically positive lymph nodes were genetically positive. Four of the 10 pN0 cases and nine of the 11 pN-positive cases had genetically positive micrometastases. Four patients who had five or more genetically positive lymph nodes located in three or more levels, three with disease staged as pN0 or pN1, died of cancer. CONCLUSIONS: These results indicate that a high rate of micrometastasis in cervical lymph nodes of oral SCCs and patients with multiple or lower neck spread of micrometastases have a poor prognosis; they should be treated with postoperative adjuvant therapy.     

Outcome of histologically node-negative esophageal squamous cell carcinoma

The outcome of node-negative esophageal carcinoma and the prognostic significance of lymph node micrometastasis remain unknown. The aim of this retrospective study was to clarify these two points. A series of 98 patients who underwent curative operation for histologically node-negative (pN0 in TNM classification) esophageal carcinoma were enrolled in the study. We reviewed the cause of death of these patients. The survival curves were calculated and compared after stratifications according to clinicopathologic parameters. Lymph node micrometastasis in the patients with recurrences was examined using immunohistochemical staining of cytokeratin. Their ages ranged from 45 to 83 years (mean 64.3 years). There were 83 men and 15 women. Altogether, 54 patients were still alive, and 44 had died. A total of 9 patients died from recurrence of their esophageal carcinoma, 33 died from other causes (pneumonia 11, extraesophageal carcinoma 7, and so on), and 2 died from unknown causes. Eight patients had locoregional recurrences, and two patients had distant recurrences. The overall survival rate for the 98 patients was 58.2%. The survival for patients with pT2 or pT3 tumors was significantly worse than for those with pTis or pT1 tumors (p = 0.02, log-rank test). Other clinicopathologic factors did not affect the prognosis. Immunohistochemical study found no lymph node micrometastasis in 365 lymph nodes resected from the patients with recurrences. Only the depth of tumor invasion affected the outcome of patients with node-negative esophageal carcinoma. Altogether, 75% of patients died of other causes without recurrence, with the two main causes of death being pulmonary complications and extraesophageal carcinoma in these patients. Lymph node micrometastasis was not associated with recurrence in this series.     

淋巴结微转移检测对胃癌病理分期的影响

目的 分析淋巴结微转移对胃癌pN分期的影响。方法 采用CK-20 mRNA逆转录聚合酶链反应（RT-PCR）技术对2003年12月至2004年4月间行手术切除的30例胃癌患者共计850枚淋巴结扩增检测微转移。结果 应用苏木精-伊红染色法淋巴结转移检出率为27．1％（233／850），而RT-PCR法淋巴结转移的检出率则为36．5％（310／850）；两种方法比较，P〈0．01，差异有统计学意义。77枚淋巴结检出有微转移（12．5％，77／617）。有7例（23．3％）患者的肿瘤TNM分期提高，分别为IB→Ⅱ、IB→ⅢA、Ⅱ→ⅢA、ⅢA→ⅢB、ⅢA→Ⅳ各1例，ⅢB→Ⅳ2例。结论 RT-PCR法可以显著提高淋巴结转移的检出率，有助于更准确地进行临床病理分期。     

一种新的胃癌淋巴结分期方案

目的比较AJCC/UICC 1997年第五版胃癌TNM分期中的N分期与以淋巴结转移度为标准的新N分期. 方法行D2或D3术式的胃癌(皆无远处转移)标本用透光法摘取淋巴结,分别按2种方法分期,新法中N1为淋巴结转移度0.01%～10.00%, N2为10.01%～25.00%,N3为＞25.00%.全组随访,资料经统计学处理. 结果本组78例患者共取得淋巴结5388 枚,平均每例69枚(范围30～157枚).全组淋巴结转移率75.64%(59/78).新分期N0、N 1、N2、N3期患者3年生存率分别为100%、68.42%、7.58%、6.78%(χ2=35.85 0,P<0.01, r=0.95). 结论淋巴结转移度是一相对数,在预后的判断上,优于淋巴结转移数目.     

Molecular biological markers and micrometastasis in resected non-small-cell lung cancer

OBJECTIVES: Recent advances in molecular biology and genetics have created new diagnostic and treatment possibilities in clinical oncology. We evaluated the usefulness of molecular biological factors in primary tumor and micrometastasis in the bone marrow and pathological negative (pN0) lymph nodes as prognostic parameters in non-small-cell lung cancer (NSCLC) patients. METHODS: Pathological specimens were collected from 129 NSCLC patients to analyze molecular biological markers, including K-ras, p53, Rb, p16, loss of heterozygosity (LOH) at 3p, vascular endothelial growth factor (VEGF), and telomerase activity. Bone marrow samples from 250 NSCLC patients and pN0 lymph nodes from 85 of these patients were collected for micrometastasis detection by immunohistochemistry against cytokeratin. RESULTS: p53 abnormalities and 3p LOH were significantly associated with reduced patient survival in adenocarcinoma, whereas VEGF expression was significantly associated with reduced survival in a squamous cell carcinoma histological subtype by univariate or multivariate analysis. We identified micrometastatic tumor cells in bone marrow of 78 (31.2%) of 250 patients and in pN0 lymph nodes of 26 (30.6%) of 85 patients. Both bone marrow and lymph nodal micrometastases were associated with decreased survival among patients with stage I, however, only lymph nodal micrometastasis had a significant impact on survival. CONCLUSIONS: Molecular biological features of primary tumor and micrometastatic status appear useful in defining groups of patients with a poor prognosis who could benefit from adjuvant systemic treatment.     

Lymph Node Micrometastases in Patients With Early Gastric Cancer: Experience With 139 Patients

Background:Although lymph node metastases in patients with early gastric cancer (EGC) is an important prognostic factor, the prognostic relevance of lymph node micrometastases is still uncertain.Methods:The authors studied 1488 lymph nodes, which were histologically confirmed as pN0, dissected from 139 patients who were treated for EGC between 1976–1994. Micrometastases were defined as a single or small cluster of neoplastic cells identifiable only by immunohistochemical methods.Results:Lymph node micrometastases was observed in 24 of the 139 patients (17%). No significant correlation was observed between micrometastases and other clinicopathological characteristics. Analysis of overall survival showed no significant difference between the micrometastases positive and negative groups.Conclusion:The results of our study show that the presence of lymph node micrometastases in EGC does not have an influence on patient prognosis.