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.     

大肠癌前哨淋巴结微转移的检测及其临床意义

为探讨大肠癌前哨淋巴结（SLN）微转移（MM）的检测方法及其临床意义,我们对64例行根治性手术的DukesB期大肠癌患者SLN进行定位;应用常规HE染色联合免疫组化SIP法染色,对定位成功的122枚SLN中细胞角蛋白20（CK20）及端粒酶进行检测,并分析其表达与I临床病理因素的相关性。结果显示：（1）SLN定位成功61例（95．3％）,共获取SLN122枚。（2）定位成功的61例中,有6例9枚SLN常规HE染色阳性;余55例113枚SLNHE染色阴性,其中免疫组化染色CK20阳性15例（27．3％）,端粒酶阳性12例（21．8％）,两者联合检测SLNMM阳性21例（38．2％）。（3）DukesB期大肠癌患者SLNMM（＋）组癌的复发转移率明显高于同期SLNMM（-）组（P〈0．05）,生存率明显降低（P〈0．05）;而与DukesC期复发转移率及生存率比较,差异无统计学意义（P〉0．05）。（4）SLNMM（-）组患者的复发转移率、生存率与同期DukesC期患者比较,差异有统计学意义（P〈0．05）。（5）DukesB期大肠癌患者SLNMM的发生与患者年龄、性别及肿瘤侵犯肠管周径、生长方式、生长部位均无显著相关,而与肿瘤分化程度及大小、外周血癌胚抗原（CEA）值显著相关。结果表明,应用免疫组化法联合检测CK20和端粒酶,可提高大肠癌SLNMM的检出率;大肠癌SLNMM的检出能精确大肠癌的Dukes分期,有助于指导术后的辅助治疗和预后判断。     

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±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。     

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。     

淋巴结转移率对结直肠癌患者预后的影响

为探讨淋巴结转移率（rN）对结直肠癌患者预后的影响,回顾分析362例结直肠癌患者的临床病理资料和随访情况,分析rN与结直肠癌患者预后的关系。结果显示,患者3年、5年生存率与rN分期有关,P〈O．05。结果表明,rN分期可帮助评估结直肠癌患者的预后。     

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.     

壶腹周围癌淋巴结微转移的检测及其意义

目的探讨壶腹周围癌淋巴结微转移的检测及其意义。方法采用免疫组化法检测60例壶腹周围癌根治术患者HE染色阴性的淋巴结（220枚）中CK7、CK18及CK19的表达，并结合临床资料及随访结果进行分析。结果60例患者中有17例共43枚淋巴结有微转移；CK19、CK7及CK18的微转移检出率分别为19．55％（43／220）、14．55％（32／220）及11．36％（25／220）；CK19的微转移检出率高于CK7和CK18（P〈0．05）；CK7和CK19的检出率在临床Ⅲ、Ⅳ期高于Ⅰ、Ⅱ期（P〈0．05）；有微转移者比无微转移者的1年生存率低（P〈0．05）。结论壶腹周围癌淋巴结微转移可能是肿瘤转移的早期阶段。CK抗体是检测壶腹周围癌淋巴结微转移的有效指标，可为临床综合治疗与预后判断提供理论依据。     

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.     

CK在Ⅰ期非小细胞肺癌患者淋巴结中的表达及其临床意义

目的通过检测Ⅰ期非小细胞肺癌(NSCLC)患者淋巴结中细胞角蛋白(CK)的表达,确定微转移灶的存在及其与肿瘤复发、转移和预后的关系。方法以CK作为肿瘤标记物,应用免疫组化链霉亲生物素-生物素-过氧化酶复合物(Streptavidin biotin-peroxidase complex,SABC)法,检测根治术后常规病理HE染色阴性的33例Ⅰ期NSCLC患者的246枚淋巴结中的微转移灶。结果33例患者246枚淋巴结中有10例(30.3%)患者的12枚(4.9%)淋巴结中CK阳性表达。有或无CK阳性表达的患者复发转移率差异有统计学意义(80.0%vs.26.1%,χ2=7.015,P=0.016),CK阳性表达患者的中位生存期显著短于CK阴性表达者(21个月vs.60个月,P=0.016);Cox单因素风险模型(P=0.004)和多因素风险模型(P=0.004)均显示存在淋巴结微转移的期NSCLC患者预后不良。结论CK免疫组化染色可以作为检测和判定肺癌淋巴结微转移的有效方法。CK免疫组化染色检测淋巴结微转移与Ⅰ期NSCLC复发转移相关,有助于更加精确的分期,可以作为Ⅰ期NSCLC患者根治术后的一个预后指标,并为其综合治疗提供理论依据。     

Lymph Node Retrieval and Assessment in Stage II Colorectal Cancer: A Population-Based Study

Background: Adjuvant chemotherapy for patients with stage III (node-positive) colorectal cancer (CRC) reduces mortality by one third. Retrieval of an inadequate number of lymph nodes in the surgical specimen may result in incorrectly designating some patients as stage II (node negative), and consequently, such patients may not be offered appropriate chemotherapy. Recent National Cancer Institute guidelines suggest that a minimum of 12 nodes should be examined to ensure accurate staging.Methods: This population-based study identified stage II (T3N0 and T4N0) CRC cases by using CRC pathology reports (1997–2000) from the Ontario Cancer Registry. Patients aged 19 to 75 years were identified, and demographic, surgical, pathologic, and hospital data were extracted. Factors relating to the number of lymph nodes assessed were examined.Results: A total of 8848 CRC cases were reviewed, and 1789 stage II cases were identified. Seventy-three percent of cases were designated as node negative on the basis of assessment of <12 lymph nodes. Multivariate analysis showed that age, tumor size, specimen length, use of a pathology template, and academic status of the hospital were significant predictors of the number of lymph nodes assessed.Conclusions: A subset of patients with CRC in Ontario were assigned stage II disease on the basis of examination of relatively few lymph nodes.     

淋巴结转移范围较数目能更好地反映食管癌手术治疗的预后

目的为了完善食管癌淋巴结分级,探索食管癌淋巴结转移的理想分级方法。方法回顾性分析1985年1月至1989年12月期间236例胸段食管癌切除,且淋巴结清扫数目≥6枚的患者的临床病理及随访资料,采用Cox风险比例模型筛选风险因子,Log—rank检验对按淋巴结转移数目、距离、范围的分级进行生存分析。结果患者10年随访率为92．3％（218／236）,全组总的1年、5年、10年生存率分别为80．2％、43．1％和34．2％;其中112例（47．4％）有淋巴结转移,其5年生存率低于无淋巴结转移患者（14．8％ vs．66．6％;Х^2=77．18,P=0．000）。Cox回归分析：除了侵及深度、分化程度及有无淋巴结转移外,还有淋巴结转移个数、转移距离及转移范围均为影响预后的独立危险因素。单因素Log—rank检验：按转移淋巴结数分组时,总体生存率差异有统计学意义（Х^2=96．00,P=0．000）,但N2与N3组间生存率差异无统计学意义（P〉0．05）;按淋巴结转移距离分组,总体生存率差异有统计学意义（Х^2=79．29,P=0．000）,但S1,S2,S3组间生存率差异无统计学意义（P〉0．05）;按淋巴结转移范围分组（0,1和≥2野）,总体生存率差异有统计学意义（Х^2=87．47,P=0．000）,并且各组间生存率差异亦有统计学意义（Х^2=5．14,P=0．023）。结论按照淋巴结转移的范围（无转移、1野转移、≥2野转移）来修订食管癌TNM分期的N分级,更为合理并能更好地反映食管癌切除手术患者的预后。     

Sentinel Lymph Node Metastases Detected by Immunohistochemistry Only Do Not Mandate Complete Axillary Lymph Node Dissection in Breast Cancer

Background: The significance of breast cancer sentinel lymph node (SLN) metastases detected only by immunohistochemistry staining (IHC) remains poorly understood. This study attempted to quantify the risk of non-SLN metastases.Methods: A prospectively collected database of 750 consecutive SLN biopsy procedures in breast cancer patients was reviewed. Medical records were reviewed to supplement the database.Results: SLNs were identified in 738 (98.4%) of these procedures in 723 patients. Of these, 151 patients (20.5%) had metastases detected by hematoxylin and eosin staining (H&E), and 33 (4.6%) of the 718 with known IHC staining results had metastases detected by IHC only. Twenty-eight (84.8%) of 33 patients with IHC-detected metastases underwent complete axillary lymph node dissection (CALND). The median primary tumor size was 2.0 cm among those undergoing CALND and 0.9 cm among the five patients treated without CALND (P = .10). Two of the 28 patients (7.1%) had additional metastases detected with CALND. These patients had a T3 or T4 invasive lobular primary tumor. Of 24 patients with T1 or T2 primary tumors and IHC-detected metastases who underwent CALND, none had additional metastases detected. Median follow-up was 14.5 months. All patients with IHC-detected SLN metastases were treated with adjuvant systemic therapy. None of the five patients with IHC-detected metastases not undergoing CALND has subsequently manifested clinical axillary disease.Conclusions: CALND could have been or was safely omitted in 29 of 29 patients with T1 or T2 primary tumors and metastases detected by IHC. Such patients should be counseled about this low risk before CALND is recommended.     

结直肠癌前哨淋巴结活检的研究进展

目的 了解前哨淋巴结(SLN)活检技术在结直肠癌领域的应用现状。方法 复习国外近5年的文献并加以综述。结果 SLN状态可以准确预测结直肠癌区域淋巴结群的肿瘤转移情况，对SLN行集中、细致的分析有助于发现传统病理学检查遗漏的微转移灶，从而使部分患者肿瘤分期上调。结论 结直肠癌SLN活检是一种切实可行的技术，有望为临床判断区域淋巴结群受累状况提供一种新的手段，从而有助于更准确的肿瘤分期。     

Colorectal Surgical Specimen Lymph Node Harvest: Improvement of Lymph Node Yield with a Pathology Assistant

Introduction  Adequate lymph node harvest from colorectal cancer specimens has become a standard of care, influencing both staging and survival. To improve lymph node harvests at our hospital, a pathology assistant was trained to meticulously harvest lymph nodes from colorectal cancer specimens. An analysis of trends in lymph node harvests over time is presented. Methods  The number of harvested lymph nodes from 391 consecutive colorectal cancer pathology reports was retrospectively reviewed from a single community hospital over 8 years (1999–2006). This spanned 4 years prior to the training of the pathology assistant and 4 years after. Results  From 1999–2002, the mean number of harvested lymph nodes varied from 12.2 to 14.4. The percentage of specimens achieving 12 lymph nodes was 50–67%. From 2003–2006, the mean number of harvested lymph nodes increased to 18.4–20.7, while the percentage of specimens achieving 12 lymph nodes was 83–87%. Both of these improvements achieved statistical significance with p values of <0.00001. Conclusions  Over time, lymph node harvests at our hospital dramatically improved. The training of a pathology assistant to harvest the lymph nodes from colorectal cancer specimens dramatically affected lymph node harvests and can be a crucial component of pathologic analysis of these specimens. Presented as a Poster at the SSAT/DDW, San Diego, CA, May 21 2008.     

Size of Residual Lymph Node Metastasis After Neoadjuvant Chemotherapy in Locally Advanced Breast Cancer Patients Is Prognostic

Background The prognostic significance of micrometastasis after neoadjuvant chemotherapy for locally advanced breast cancer is unknown. We examined the residual lymph node metastasis size in patients after treatment with neoadjuvant chemotherapy to determine the relevance of metastasis size on outcome. Methods Stage II/III breast cancer patients treated with neoadjuvant chemotherapy at our institution from 1991 to 2002 were included. We examined the relationship of postneoadjuvant chemotherapy lymph node metastasis size and number with distant disease-free survival (DDFS) and overall survival (OS). Results In 122 patients with a median follow-up of 5.4 years, we found not only that patients with an increasing number of residual positive nodes had progressively worse DDFS and OS (P < .0001 for both) compared with patients with negative nodes, but also that the size of the largest lymph node metastasis was associated with worse DDFS and OS (P < .0001 for both) in both univariate and multivariate analysis. Compared with negative nodes, even lymph node micrometastasis (<2 mm) was associated with worsened DDFS and OS (adjusted P = .02 and P = .005, respectively). Conclusions Residual micrometastatic disease in the axillary lymph nodes after neoadjuvant chemotherapy is predictive of worse prognosis than negative nodes. In this study, the lymph node metastasis size and the number of involved lymph nodes were independent powerful predictors of DDFS and OS.     

Lymph Node Size and Metastatic Infiltration in Colon Cancer

Background: Detection of metastatic lymph nodes in colon cancer is essential for determining stage and adjuvant treatment modalities. Lymph node size has been used as one possible criterion for nodal metastasis. Although enlarged regional lymph nodes are generally interpreted as metastases, few data are available that correlate lymph node size with metastatic infiltration in colon cancer.Methods: In a prospective morphometric study, the regional lymph nodes from 30 colon specimens from consecutive patients with primary colon cancer were analyzed. The lymph nodes were counted and the largest diameter of each lymph node was measured and analyzed for metastatic involvement by histological examination.Results: A total of 698 lymph nodes were present in the 30 specimens examined for this study. A mean number of 23 (range, 19–39) lymph nodes was found in each specimen. Of these nodes, 566 (81%) were tumor-free and 132 (19%) contained metastases. The mean diameter of the lymph nodes free of metastases was 3.9 mm, whereas those infiltrated by metastases averaged 5.9 mm in diameter (P< 0.0001). Of the tumor-free lymph nodes, 528 (93%) measured < 5 mm in diameter, whereas 70 (53%) lymph nodes containing metastases measured < 5 mm in diameter.Conclusions: Lymph node size is not a reliable indicator for lymph node metastasis in colon cancer. A careful histological search for small lymph node metastasis in the specimen should be undertaken to avoid false-negative node staging.     

Sentinel Nodes Are Identifiable in Formalin-Fixed Specimens After Surgeon-Performed Ex Vivo Sentinel Lymph Node Mapping in Colorectal Cancer

Background In recent years, the technique of sentinel lymph node (SLN) mapping has been applied to colorectal cancer. One aim was to ultrastage patients who were deemed node negative by routine pathologic processing but who went on to develop systemic disease. Such a group may benefit from adjuvant chemotherapy.Methods With fully informed consent and ethical approval, 37 patients with primary colorectal cancer and 3 patients with large adenomas were prospectively mapped. Isosulfan blue dye (1 to 2 mL) was injected around tumors within 5 to 10 minutes of resection. After gentle massage to recreate in vivo lymph flow, specimens were placed directly into formalin. During routine pathologic analysis, all nodes were bivalved, and blue-staining nodes were noted. These later underwent multilevel step sectioning with hematoxylin and eosin and cytokeratin staining.Results SLNs were found in 39 of 40 patients (98% sensitivity), with an average of 4.1 SLNs per patient (range, 1–8). In 14 of 16 (88% specificity) patients with nodal metastases on routine reporting, SLN status was in accordance. Focused examination of SLNs identified occult tumor deposits in 6 (29%) of 21 node-negative patients. No metastatic cells were found in SLNs draining the three adenomas.Conclusions The ability to identify SLNs after formalin fixation increases the ease and applicability of SLN mapping in colorectal cancer. Furthermore, the sensitivity and specificity of this simple ex vivo method for establishing regional lymph node status were directly comparable to those in previously published reports.Presented at the British Society of Gastroenterology, Glasgow, United Kingdom, 2004; the American Society of Colon and Rectal Surgeons, Dallas, Texas, 2004; and the Association of Coloproctologists of Great Britain and Ireland, Birmingham, 2004.