逆转录聚合酶链扩增与免疫组化在检测胃癌区域淋巴结微转移中的相关研究

目的：利用逆转录聚合酶链扩增检测胃癌常规病理检查阴性的淋巴结微转移的发生及与免疫组化结果的关系。方法：利用逆转录聚合酶链反应（RT—PCR）方法检测480枚胃癌胃周淋巴结癌胚抗原（CEA）mR-NA基因表达,同时比较RT—PCR与免疫组化方法的检测敏感性。结果：利用TT—PCR检测CEA mRNA是一种很敏感的方法。检测138例胃癌患者取材的480枚胃周淋巴结。免疫组化阳性率27．5％（132／480）。RT—PCR阳性率58．8％（282／480）,两组之间有显著性差异（P〈0．01）;RT—PCR阳性率随着病期进展而增大。结论：RT—PCR技术是比免疫组化更敏感的方法,可以预测胃癌病人淋巴结微转移,有效避免已有微小转移的患者被漏诊、误诊。     

子宫颈腺癌间质侵袭与小肠粘液抗原阳性淋巴结转移的关系

运用小肠粘液革抗（ＳＩＭＡ）免疫组化染色，观察４４例官颈腺癌中粘液间质侵袭与肿瘤淋巴结转移的关系及原发灶与转移灶内肿瘤细胞ＳＩＭＡ着色强度的对比。结果显示：宫颈腺癌中ＳＩＭＡ间质侵袭程度愈重则肿瘤淋巴结内转移的可能性愈大；肿瘤原发灶与转移灶内肿瘤细胞ＳＩＭＡ着色强度无明显差异。推测粘液间质侵袭是造成宫颈腺癌淋巴结内转移的重要原因；产生粘液的瘤细胞与非粘液产生的瘤细胞克隆，在淋巴结转移这一生物学特性上差别不大。     

应用基因芯片筛选胃癌淋巴转移相关基因及TLN1的初步研究

目的： 应用基因表达谱芯片筛选胃癌正常胃黏膜、胃癌原发灶和淋巴结转移灶的差异表达基因,并结合生物信息学方法筛选胃癌淋巴结转移相关基因,探讨TLN1与胃癌淋巴结转移的关系。方法：应用Affymetrix芯片筛选癌旁正常胃黏膜(A组)、胃癌原发灶(B组)和淋巴结转移灶(C组)的差异表达基因,利用队列试验的基因表达谱分析、基于聚类分析结果的基因功能（基于Gene Ontology分类）集群分析和Pathway分析等生物信息学方法对结果进行分析,并用RT-PCR检测TLN1 在胃癌原发灶和淋巴结转移灶的表达情况。结果：A、B、C 3组呈连续上调的差异表达基因278个,其功能主要集中在免疫应答、细胞黏附、磷酸盐转运、阴离子转移、细胞趋化和移动、信号转导等方面;连续下调的387个基因其功能主要集中在消化、糖类代谢、脂质代谢、蛋白代谢、一氧化氮复合物代谢、一氧化碳复合物代谢、细胞黏附等方面。Pathway分析显示在整合素介导的细胞黏附信号通路异常激活,THBS1、TLN1、CAPN3、ITGAX、SORBS1、CAPN6、CAPN9在3组中呈连续梯度改变。TLN1在癌旁非肿瘤胃黏膜、胃癌原发灶和淋巴结转移灶表达量分别为：0.0000342±0.0000711、0.1064±0.1251和0.2886±0.3529;在胃癌淋巴结转移灶显著高表达（P＜0.05）。结论：基因芯片技术结合生物信息学方法筛选胃癌淋巴转移相关基因,有助于找到胃癌淋巴道转移的关键基因或通路,为寻找肿瘤淋巴道转移的早期诊断指标及新的治疗靶点奠定了实验基础,本研究结果初步表明在整合素信号通路中扮演重要角色的TLN1基因异常表达与胃癌淋巴结转移密切相关。     

胃癌间质中肿瘤相关纤维母细胞CD34和SMA的表达及意义

目的探讨胃癌间质中肿瘤相关纤维母细胞CD34和SMA的表达及与胃癌侵袭性的关系。方法应用免疫组织化学PV6000通用型二步法检测75例胃癌组织及10例正常胃黏膜组织中间质纤维母细胞CD34和SMA的表达,并分析其与胃癌临床病理特征的关系。结果CD34在正常胃黏膜组织纤维母细胞中阳性表达率为80.0%（8/10）,而在胃癌组织纤维母细胞中仅6/75例呈阳性表达（8.0%）,两者比较差异有显著性（P〈0.01）。胃癌组织纤维母细胞中SMA阳性表达率为90.7%（68/75）,显著高于正常胃黏膜组（30.0%）（P〈0.01）。胃癌组织纤维母细胞中SMA表达与胃癌的Lauren分型及组织学分级无关（P〉0.05）,与临床分期和淋巴结转移有关（P〈0.05）,Ⅲ-Ⅳ期强阳性率（75.6%）明显高于Ⅰ-Ⅱ期（26.7%）（P〈0.01）,有淋巴结转移组的强阳性率（78.7%）明显高于无淋巴结转移组（17.9%）（P〈0.01）。结论与正常组织中纤维母细胞相比,胃癌中纤维母细胞表现为CD34（＋）表达的缺失,而转变为SMA（＋）的肌纤维母细胞的特征,两者的联合检测将可能作为肿瘤相关纤维母细胞较特异的标记;肿瘤相关纤维母细胞与胃癌的侵袭转移密切相关。     

胃癌间质反应的分型及免疫组化研究

根据癌组织中淋巴类细胞和纤维组织的反应程度把128例胃癌间质分为A、B、C三型。A型间质以所有癌细胞或癌性结构被大量的淋巴类细胞包围和边界明显为特征。C型间质主要为多量的纤维结缔组织。B型间质介于A和C型间质之间。A型间质胃癌无淋巴结转移,C型间质胃癌淋巴结转移达40.5%。UCHL,IgG,HLA—DR,AAT,ACT和含hCG,Serotonin,Gastrin等激素癌细胞的免疫组化分析认为这三型间质的形态学特征可以作为评价胃癌病人抗肿瘤免疫功能的形态学指标。     

单克隆抗体免疫组化法提高淋巴结转移性胃癌检出率的价值

本文用胃癌单克隆抗体mG_9免疫酶标组化法观察了58例胃癌淋巴结转移阳性率,发现免疫组化法能检出淋巴结内散在微小转移灶性癌细胞,从而提高了常规病理组织学对淋巴结转移的检出率。此外,MG_9阳性反应单核巨噬细胞似可作为淋巴结内癌早期转移的指标之一。     

层粘连蛋白及其受体在乳腺癌的表达与转移和预后的关系

目的观察层粘连蛋白（ｌａｍｉｎｉｎ,ＬＮ）和层粘连蛋白受体（ｌａｍｉｎｉｎｒｅｃｅｐｔｏｒ,ＬＮ－Ｒ）与乳腺癌转移和预后的关系。方法用ＬＳＡＢ免疫组化法,检测了１０９例乳腺癌原发灶和３７例淋巴结转移灶组织中ＬＮ和ＬＮ－Ｒ在癌细胞内表达的情况。结果有３２例（２９．４％）原发灶浸润性癌细胞内可见ＬＮ表达,５例（１３．７％）腋窝淋巴结转移灶中癌细胞内有ＬＮ表达。乳腺癌原发灶中有ＬＮ－Ｒ表达者占５５．０４％,淋巴结转移灶中ＬＮ－Ｒ表达占８３．７８％,后者明显高于前者（Ｐ＜０．０５）。６４例随访材料中单独ＬＮ表达者无１例死亡,而有ＬＮ－Ｒ表达者生存期明显短于无ＬＮ－Ｒ表达者（Ｐ＜０．００１）。经临床和病理多因素比例风险回归分析,显示淋巴结转移和ＬＮ－Ｒ是影响患者生存的独立因素,ＬＮ－Ｒ的风险度（４．３７５倍）大于淋巴结转移（２．８１０倍）。结论结果提示ＬＮ－Ｒ表达是导致乳腺癌患者死亡的重要生物学因素之一。     

乳腺微浸润癌的临床病理学特征及生物学特性

目的探讨乳腺微浸润癌（microinvasive carcinoma,MIC）的临床病理学特征及生物学特性和其病理诊断标准。方法回顾性研究40例MIC,按文献报道诊断标准分为两个亚型,并对病理学特征、分子生物学指标及预后进行比较。结果MIC占同期乳腺癌的1．5％,乳腺钼靶拍片85．0％的病例（34例／40例）显示不同程度的泥沙样钙化。粉刺型和高核分级的导管内癌更易形成间质浸润。淋巴结转移2．5％（1例／40例）。31例平均8个月随访显示无复发及转移。两亚型各指标比较结果差异均无显著性。结论MIC是一种少见、淋巴结转移率低、预后较好的恶性肿瘤。建议诊断标准：单个浸润灶时,最大径应〈2mm;出现几个浸润灶时,其中单个浸润灶的最大径应〈1mm,且几个浸润灶面积总和不应超过整个肿瘤组织面积的10％。     

Annexin A7在胃癌及转移灶中的表达及意义

目的：研究Annexin A7在胃癌及转移灶中的表达及其临床意义。方法：采用免疫组织化学SP法检测20例正常胃黏膜、60例胃癌原发灶及30例淋巴结转移灶中Annexin A7的表达情况,并比较其与胃癌的不同病理类型、不同分化程度等的关系。结果：Annexin A7在胃癌中阳性率为53.3%,明显高于正常胃黏膜中的25.0%（P<0.05）;在淋巴结转移灶中的阳性率为76.7%,明显高于原发灶的53.3%（P<0.01）。Annexin A7在管状腺癌、黏液腺癌及印戒细胞癌的阳性率分别为63.6%,27.5%及20.0%,其表达在管状腺癌与黏液腺癌之间有统计学差异（P<0.05）。Annexin A7的表达在性别、年龄、肿瘤大小、分化程度及早晚期分组中的差异均无统计学意义（P>0.05）。 结论：Annexin A7高表达在胃癌发生和转移中可能起重要作用;并且其在胃管状腺癌中的表达高于黏液腺癌。     

胃癌淋巴结隐匿性微转移的病理形态及免疫组织化学分析

肿瘤的转移是恶性肿瘤的重要生物学行为,常是导致患者死亡的重要原因,确定淋巴结有无癌转移对肿瘤的治疗和预后有重要意义。近年来,不少学者采用多种技术手段研究不同类型肿瘤淋巴结隐匿性转移,多数学者认为淋巴结隐匿性转移者其复发率较未有转移者高。胃癌淋巴结隐匿性转移,尤其是淋巴结隐匿性微转移在临床病理诊断中易漏诊。我们收集76例胃癌根治标本探讨其胃癌淋巴结隐匿性微转移的病理形态学及免疫组化特征。     

Intraoperative cytologic evaluation of sentinel lymph nodes in patients with breast carcinoma by scrape preparation

Intraoperative evaluation of sentinel lymph nodes (SLNs) in patients with breast carcinoma allows surgeons to complete axillary lymph node dissection in one procedure if any SLN shows metastasis. The accuracy of intraoperative pathological diagnosis is critical for decision-making. The purpose of this study was to evaluate our rapid intraoperative cytologic diagnosis of SLN through comparing with the final surgical pathologic diagnosis of the corresponding lymph nodes. A total of 454 SLNs from 159 consecutive female patients with a preoperative diagnosis of breast carcinoma over 3-year period were included in this study. After gross examination of each bisected lymph node, a scrape preparation was prepared for each submitted lymph node and was stained by the rapid Papanicolaou method. The intraoperative cytologic diagnosis was compared with the final surgical pathologic diagnoses. The overall sensitivity of intraoperative cytology was 52.5% with specificity of 100%. There were 17 false-negative cases. Of them, six nodes had isolated tumor cells, seven nodes had micrometastasis (0.2-2 mm), and four nodes had macrometastasis (>2 mm). There were no interpretive errors identified. The size of metastasis and tumor grade appeared to be significant factors in detecting metastasis by cytology. In addition, subsequent non-SLN involvement was 9% in patients with micrometastasis versus 50% in patients with macrometastasis (P < 0.05). Our study shows that the intraoperative cytologic evaluation of SLNs in breast carcinoma is a reasonably accurate method. The majority of false-negative cases were due to micrometastasis and isolated tumor cells.     

Interval sentinel lymph nodes in melanoma: a digital pathology analysis of Ki67 expression and microvascular density

The presence of interval sentinel lymph nodes in melanoma is documented in several studies, but controversies still exist about the management of these lymph nodes. In this study, an immunohistochemical evaluation of tumor cell proliferation and neo-angiogenesis has been performed with the aim of establishing a correlation between these two parameters between positive and negative interval sentinel lymph nodes. This retrospective study reviewed data of 23 patients diagnosed with melanoma. Bioptic specimens of interval sentinel lymph node were retrieved, and immunohistochemical reactions on tissue sections were performed using Ki67 as a marker of proliferation and CD31 as a blood vessel marker for the study of angiogenesis. The entire stained tissue sections for each case were digitized using Aperio Scanscope Cs whole-slide scanning platform and stored as high-resolution images. Image analysis was carried out on three selected fields of equal area using IHC Nuclear and Microvessel analysis algorithms to determine positive Ki67 nuclei and vessel number. Patients were divided into positive and negative interval sentinel lymph node groups, and the positive interval sentinel lymph node group was further divided into interval positive with micrometastasis and interval positive with macrometastasis subgroups. The analysis revealed a significant difference between positive and negative interval sentinel lymph nodes in the percentage of Ki67-positive nuclei and mean vessel number suggestive of an increased cellular proliferation and angiogenesis in positive interval sentinel lymph nodes. Further analysis in the interval positive lymph node group showed a significant difference between micro- and macrometastasis subgroups in the percentage of Ki67-positive nuclei and mean vessel number. Percentage of Ki67-positive nuclei was increased in the macrometastasis subgroup, while mean vessel number was increased in the micrometastasis subgroup. The results of this study suggest that the correlation between tumor cell proliferation and neo-angiogenesis in interval sentinel lymph nodes in melanoma could be used as a good predictive marker to distinguish interval positive sentinel lymph nodes with micrometastasis from interval positive lymph nodes with macrometastasis subgroups.     

Keratin immunohistochemistry does not contribute to correct lymph node staging in patients with invasive lobular carcinoma

Studies suggest that immunohistochemistry improves rate of detecting sentinel lymph node metastases and is needed for adequate staging in invasive lobular carcinoma. Our study evaluates the use of cytokeratin immunohistochemistry in detecting sentinel lymph node metastases and its effect on staging patients with invasive lobular carcinoma. Material from 76 patients with invasive lobular carcinoma was reviewed. Cytokeratin immunostaining was performed on negative nodes, and deposits were classified as macrometastasis (>2.0 mm), micrometastasis (>0.2-2 mm), or isolated tumor cells (相似文献   

Multiparameter flow cytometry as a tool for the detection of micrometastatic tumour cells in the sentinel lymph node procedure of patients with breast cancer

AIM: To investigate whether multiparameter flow cytometry (MP-FCM) can be used for the detection of micrometastasis in sentinel lymph nodes (SLNs) in breast cancer. METHODS: Formalin fixed, paraffin wax embedded sentinel lymph nodes (n = 238) from 98 patients were analysed. For each lymph node, sections for haematoxylin and eosin (H&E) staining and immunohistochemistry (IHC) for cytokeratin (MNF116) were cut at three levels with a distance of 500 microm. The intervening material was used for MP-FCM. Cells were immunostained with MNF116, followed by an incubation with fluorescein isothiocyanate (FITC) labelled goat antimouse immunoglobulin. DNA was stained using propidium iodide. From each lymph node 100,000 cells were analysed on the flow cytometer. RESULTS: Thirty eight of the 98 patients with breast carcinoma showed evidence of metastatic disease in the SLN by one ore more of the three methods. In 37 of 38 cases where metastatic cells were seen in the routine H&E and/or IHC, more than 1% cytokeratin positive cells were detected by MP-FCM. In 24 patients, metastatic foci were more than 2 mm (macrometastasis) and in 14 these foci were smaller than 2 mm (micrometastasis). In three of these 14 cases, MP-FCM revealed positive SLNs, although this was not seen at first glance in the H&E or IHC sections. After revision of the slides, one of these three remained negative. However, MP-FCM analysis of the cytokeratin positive cells showed an aneuploid DNA peak, which was almost identical to that of the primary breast tumour. Duplicate measurements, done in 41 cases, showed a 99% reproducibility. In five of 14 patients with micrometastasis, one or two metastatic foci were found in the non-SLN. However, in 15 of 24 macrometastases multiple non-SLNs were found to have metastatic tumour. All micrometastases except for the remaining negative one mentioned above showed only diploid tumour cells, despite the fact that their primary tumours contained both diploid and aneuploid tumour cells. In primary tumours with more than 60% aneuploid cells, predominantly aneuploid macrometastasis were found, whereas diploid primary tumours only showed diploid micrometastases or macrometastases in their SLN. Aneuploid SLN macrometastases were associated with non-SLN metastases in five of seven patients, whereas diploid cases showed additional non-SLN metastases in only seven of 16 patients. CONCLUSION: In all cases, MP-FCM was sufficient to detect micrometastatic tumour cells in a large volume of lymph node tissue from SLNs. In some cases it was superior to H&E and IHC staining. Approximately 30% of SLN micrometastases are accompanied by additional non-SLN metastases. The size of the aneuploid fraction (> 60%) in the primary tumour may influence the risk of having both SLN and non-SLN metastases.     

Eight-year experience with the intraoperative frozen section examination of sentinel lymph node biopsy for breast cancer in a North-Italian university center

Sentinel lymph node biopsy (SLNB) completely changed the impact of breast surgery on patients psycho-physical wellness, reducing morbidity associated with complete axillary lymph node dissection (CALND) while granting an adequate breast cancer staging. We reviewed our experience with the SLNB in a University Clinic. We collected data about all breast cancer patients submitted to SLNB from 2002 to 2010, and analyzed them with R (version 2.15.2), considering significant p<0.05. We performed 615 SLNBs on 607 patients, with a mean age of 59.86 (±10.76). Sentinel node detection rate resulted 99,7%, with a mean number of biopsied nodes of 1.64 (±0.67), axillary localization in 98% of cases, and negative intraoperative histological finding in the 86.2% of cases. Prevalence of ITCs, micrometastasis, macrometastasis and pericapsular metastasis resulted respectively 0.6%, 4.9%, 7.5% and 8.8%. Among women who received CALND, mean number of examined nodes was 16.36 (±6.19) and mean number of metastatic non-sentinel nodes was 0.97 in case of micrometastasis, 2.65 in case of macrometastasis, and up to 9.88 when pericapsular invasion was described. To conclude, our data confirm the role of nodal metastasis size in the prediction of non-sentinel node involvement, but further studies are required in order to better assess the role of ITCs and micrometastasis in the diagnostic and therapeutic management of breast cancer, with the final aim to reduce the surgical complications of axilla demolition when unnecessary.     

Clinical implications of immunohistochemically demonstrated lymph node micrometastasis in resectable pancreatic cancer

The purpose of this study was to determine the clinical significance of nodal micrometastasis detected by immunohistochemistry in patients that had undergone curative surgery for pancreatic cancer. Between 2005 and 2006, a total of 208 lymph nodes from 48 consecutive patients with pancreatic cancer that had undergone curative resection were immunostained with monoclonal antibody against pan-ck and CK-19. Micrometastasis was defined as metastasis missed by a routine H&E examination but detected during an immunohistochemical evaluation. Relations between immunohistochemical results and clinical and pathologic features and patient survival were examined. Nodal micrometastases were detected in 5 (29.4%) patients of 17 pN0 patients. Nodal micrometastasis was found to be related to tumor relapse (P = 0.043). Twelve patients without overt nodal metastasis and micrometastasis had better prognosis than 5 patients with only nodal micrometastasis (median survival; 35.9 vs 8.6 months, P < 0.001). The Cox proportional hazard model identified nodal micrometastasis as significant prognostic factors. Although the number of patients with micrometastasis was so small and further study would be needed, our study suggests that the lymph node micrometastasis could be the predictor of worse survival and might indicate aggressive tumor biology among patients undergoing curative resection for pancreas cancer.     

Relationship between micropapillary component and micrometastasis in the regional lymph nodes of patients with stage I lung adenocarcinoma

AIMS: To determine whether a micropapillary component is a prognostic predictor, with particular reference to nodal micrometastasis, in patients with stage I lung adenocarcinomas. METHODS AND RESULTS: Thirty-five cases with stage I lung adenocarcinomas, obtained from lobectomies or pneumonectomies, and 434 dissected hilar and mediastinal lymph nodes, were retrospectively reviewed. A micropapillary component and nodal micrometastasis were found in 16 (45.7%) and 14 (40%) of the 35 cases, respectively, with nodal micrometastasis in 24 (5.5%) of the 434 lymph nodes, in an immunohistochemical study using an anti-cytokeratin antibody. Ten (62.5%) of the 16 cases with a micropapillary component, and four (21.1%) of the remaining 19 cases, showed nodal micrometastases (P = 0.014). Kaplan-Meier survival curves demonstrated that there was no significant difference between the cases with and without a micropapillary component (P = 0.28). However, the 5 years' survival of the cases with and without nodal micrometastases were 71.4% and 35.7%, respectively (P = 0.03). CONCLUSIONS: A micropapillary component may be a manifestation of aggressive behaviour, as shown by frequent micrometastasis, for stage I lung adenocarcinomas.     

Comparison of pathologist-detected and automated computer-assisted image analysis detected sentinel lymph node micrometastases in breast cancer.

Sentinel lymph node biopsy has stimulated interest in identification of micrometastatic disease in lymph nodes, but identifying small clusters of tumor cells or single tumor cells in lymph nodes can be tedious and inaccurate. The optimal method of detecting micrometastases in sentinel nodes has not been established. Detection is dependent on node sectioning strategy and the ability to locate and confirm tumor cells on histologic sections. Immunohistochemical techniques have greatly enhanced detection in histologic sections; however, comparison of detection methodology has not been undertaken. Automated computer-assisted detection of candidate tumor cells may have the potential to significantly assist the pathologist. This study compares computer-assisted micrometastasis detection with routine detection by a pathologist. Cytokeratin-stained sentinel lymph node sections from 100 patients at the University of Vermont were evaluated by automated computer-assisted cell detection. Based on original routine light microscopy screening, 20 cases that were positive and 80 cases that were negative for micrometastases were selected. One-level (43 cases) or two-level (54 cases) cytokeratin-stained sections were examined per lymph node block. All 100 patients had previously been classified as node negative by using routine hematoxylin and eosin stained sections. Technical staining problems precluded computer-assisted cell detection scanning in three cases. Computer-assisted cell detection detected 19 of 20 (95.0%; 95% confidence interval, 75-100%) cases positive by routine light microscopy. Micrometastases missed by computer-assisted cell detection were caused by cells outside the instrument's scanning region. Computer-assisted cell detection detected additional micrometastases, undetected by light microscopy, in 8 of 77 (10.4%; 95% confidence interval, 5-20%) cases. The computer-assisted cell detection-positive, light microscopy-missed detection rate was similar for cases with one (3 of 30; 10.0%) or two (5 of 47; 10.6%) cytokeratin sections. Metastases detected by routine light microscopy tended to be larger (0.01-0.50 mm) than did metastases detected only by computer-assisted cell detection (0.01-0.03 mm). In a selected series of patients, automated computer-assisted cell detection identified more micrometastases than were identified by routine light microscopy screening of cytokeratin-stained sections. Computer-assisted detection of events that are limited in number or size may be more reliable than detection by a pathologist using routine light microscopy. Factors such as human fatigue, incomplete section screening, and variable staining contribute to missing metastases by routine light microscopy screening. Metastases identified exclusively by computer-assisted cell detection tend to be extremely small, and the clinical significance of their identification is currently unknown.     

Expression of urokinase-type plasminogen activator, stromelysin 1, stromelysin 3, and matrilysin genes in lung carcinomas.

We have previously shown that the extracellular-matrix-degrading enzymes, urokinase-type plasminogen activator (u-PA), stromelysin 1, stromelysin 3, and matrilysin, may play an important role in the transition from lung preneoplasia to invasive carcinoma. Using in situ hybridization and immunohistochemistry, we analyzed serial frozen sections for the expression of these enzymes in 89 lung carcinomas including 25 neuroendocrine (NE) carcinomas (10 small-cell lung carcinomas, 7 large-cell NE carcinomas, 1 atypical, and 7 typical carcinoids) and 64 non-small-cell, non-NE carcinomas (29 squamous and 7 basaloid carcinomas, 23 adenocarcinomas, and 5 large-cell carcinomas). Proteases, except matrilysin, were more often expressed in stromal than cancer cells. In non-small-cell, non-NE carcinomas, stromal co-expression of u-PA and stromelysin 3 was seen in 80 to 90% of the tumors and was highly correlated (P < 0.0001). Stromal u-PA and stromelysin 3 expression was linked to tumor size (P = 0.01 and 0.03, respectively) and lymph node involvement (P = 0.001 and 0.02, respectively). Epithelial expression of u-PA was correlated to tumor size (P = 0.04). Epithelial expression of stromelysin 3 predominated in squamous and basaloid carcinomas (P = 0.0005) and was inversely correlated to squamous differentiation (P = 0.018). Epithelial expression of matrilysin predominated in adenocarcinomas and large-cell carcinomas (P = 0.07). In NE carcinomas including small-cell lung carcinomas, stromal expression of u-PA was correlated to lymph node metastasis (P = 0.017). Epithelial expression of all enzymes were significantly less frequent in NE than in non-NE tumors. We conclude that 1) epithelial expression of matrix proteases in lung cancer is linked to cell phenotype (NE versus non-NE, squamous versus glandular) and 2) their stromal, rather than epithelial, expression influences local metastasis.