中性粒细胞—淋巴细胞比预测早期胃癌淋巴结转移的临床价值

目的分析中性粒细胞—淋巴细胞比(NLR)预测早期胃癌(EGC)淋巴结转移的临床价值,以期为EGC治疗方案的制订提供参考。方法回顾性分析在我院行胃癌根治术并经术后病理确诊为EGC的134例患者的临床资料,根据淋巴结是否转移分为阳性组和阴性组。收集EGC患者术前1周血液学指标并计算血小板—淋巴细胞比(PLR)和NLR;收集患者基本信息及术后病理信息,行单因素和多因素Logistic回归分析;通过受试者工作特征(ROC)曲线分析NLR预测EGC伴淋巴结转移阳性的诊断价值;分析术前NLR与患者一般资料及临床病理之间的相关性;Pearson相关性检验分析NLR与肿瘤大小的相关性;Kaplan-Meier(K-M)曲线及Log-rankχ2检验比较高NLR组和低NLR组患者术后生存状况。结果单因素分析结果显示,浸润深度、分化程度、肿瘤大小、PLR、NLR与淋巴结转移相关(P<0.05)。多因素Logistic回归分析结果显示,肿瘤大小≥2cm、浸润深度为黏膜下层、分化程度为低分化、NLR≥1.965是淋巴结转移的独立危险因素(P<0.05)。根据ROC曲线,NLR截断值为2.295,术前NLR预测淋巴结转移的灵敏性和特异性分别为82.6%和77.5%。根据截断值将所有患者分为低NLR组(NLR<2.295)90例和高NLR组(NLR≥2.295)44例,2组患者一般资料及临床病理相关因素分析结果显示,术前NLR与年龄、肿瘤大小、肿瘤大体类型显著相关(P<0.05)。术前NLR与肿瘤大小呈正相关(r=0.645,P<0.001)。术前高NLR组患者术后5年生存率明显低于低NLR组患者(P<0.05)。结论术前NLR对EGC患者发生淋巴结转移具有较高的预测价值,且对EGC患者预后的评估具有一定的临床参考价值。     

早期胃癌临床诊治的若干问题

胃癌是全球范围内死亡率最高的恶性肿瘤之一,而胃癌的早期发现和规范化治疗是改善胃癌患者的重要手段。随着医疗技术的发展,早期胃癌的检出率逐年提高,并且手术方式逐渐从传统开腹根治术向内镜切除和腹腔镜手术过渡。本课题组通过多年系列研究,联合国内外最新发现对早期胃癌临床生物学特征、分期系统评估和综合治疗方案等方面进行深入研究,为指导早期胃癌临床诊治提供科学依据。     

Gastric carcinoma with invasive micropapillary pattern and its association with lymph node metastasis

Ushiku T, Matsusaka K, Iwasaki Y, Tateishi Y, Funata N, Seto Y & Fukayama M
(2011) Histopathology  59 , 1081–1089
Gastric carcinoma with invasive micropapillary pattern and its association with lymph node metastasis Aims: This study aimed to characterize the clinicopathological features of invasive micropapillary carcinoma (IMPC) of the stomach. Methods and results: Seventeen cases of gastric IMPC were identified from histological reviews of 1178 consecutive cases. IMPC components occupied 10–90% of the entire tumours. Fifteen tumours showed invasion into the muscularis propria or deeper, whereas two tumours were limited to the submucosa. All 17 cases were associated with tubular or papillary adenocarcinoma. Lymphatic and venous invasion were identified more frequently in cases with IMPC components than in those without (P = 0.0023 and P = 0.0009, respectively). Nodal metastases were identified in 14 of 17 (82%) cases with IMPC components, whereas they were detected in 540 of 1161 (47%) cases with no IMPC components (P = 0.0053). Multivariate analysis demonstrated that the presence of IMPC was an independent predictor of nodal metastasis. Conclusions: Conservative treatments, such as endoscopic resection, should not be used for gastric carcinoma with IMPC components, as these cases are associated with a high propensity for lymphovascular invasion and nodal metastasis.     

Correlation between microsatellite instability‐high phenotype and occult lymph node metastasis in gastric carcinoma

The aim of this study is to investigate the association of microsatellite instability (MSI) status with nodal status in gastric carcinoma (GC). MSI status was investigated in 623 consecutively resected GCs. To detect occult lymph node (LN) metastasis, immunohistochemistry (IHC) using antibodies against pan‐cytokeratin was performed in 391 node‐negative cases by initial histologic examination. MSI‐high (MSI‐H) phenotype was found in 68 GC cases (10.9%) and was significantly associated with increased patient age, antral location, intestinal type, absence of venous/perineural invasion, and expanding growth type (p < 0.05). When the nodal status was evaluated, the number of metastatic LNs of MSI‐H tumors tended to be lower than that of microsatellite stable/MSI‐low (MSS/L) tumors (1.49 ± 3.15 vs 4.37 ± 9.81; p = 0.052), but the MSI‐H phenotype was associated with the presence of lymphatic invasion (p = 0.036) and IHC‐positive occult LN metastasis (p = 0.007). By multivariate analysis, MSI‐H phenotype was significantly associated with IHC‐positive occult LN metastasis (Odds ratio, 2.654; p = 0.044). MSI status and occult LN metastasis were not prognostic factors by survival analysis. Our findings suggest that the relationship between MSI status and regional LN metastasis may have some clinical and biologic implications to be elucidated.     

血浆D-二聚体水平与乳腺癌腋窝淋巴结转移的相关性研究

目的：探讨血浆D–二聚体水平与乳腺癌腋窝淋巴结转移的关系,为预测乳腺癌腋窝淋巴结转移状态提供依据。方法：选取乳腺癌患者73例(乳腺癌组),乳腺良性疾病患者36例(良性疾病组)及健康体检女性50例(正常对照组),均检测D–二聚体水平,并结合患者临床及病理资料(肿瘤大小、病理分型、是否淋巴结转移、淋巴结转移个数、激素受体、癌基因等)进行综合分析。结果：乳腺癌组血浆D–二聚体水平明显高于其他两组,差异有统计学意义(P<0.01);乳腺良性疾病组与正常对照组D–二聚体水平比较,差异无统计学意义(P>0.05);腋窝淋巴结转移阳性患者D–二聚体水平高于腋窝淋巴结转移阴性患者,差异有统计学意义(P<0.01);肿瘤大小、病理类型、血浆D–二聚体水平与腋窝淋巴结转移个数显著相关(P<0.01);原发肿瘤的病理类型、血浆D–二聚体水平是腋窝淋巴结转移的危险因素(OR =7.464、6.470);血浆D–二聚体水平诊断乳腺癌腋窝淋巴结转移时的ROC曲线下面积(area under concentration-time,AUC)为0.689,以0.455μg/mL为最佳诊断分界点,灵敏度为52.3%,特异度为86.2%。结论：血浆D–二聚体水平与乳腺癌腋窝淋巴结转移状态及转移个数有关,其对判断乳腺癌腋窝淋巴结转移状态有一定临床价值。     

Expression of MMP-2 is associated with progression and lymph node metastasis of gastric carcinoma

AIMS: One important step in tumour invasion is the penetration of the basement membrane. Matrix metalloproteinases (MMPs) play a key role in the migration of normal and malignant cells through the basement membrane. The aim of this study was to investigate correlations between matrix metalloproteinase 2 (MMP-2) immunoreactivity and currently used classification systems and possible relationships between lymph node metastasis and MMP-2 expression. METHODS AND RESULTS: This prospective study analysed specimens obtained from 114 gastric cancer patients (mean age 64 years; range 33-86 years) who underwent gastrectomy with extended lymphadenectomy. All specimens were categorized according to UICC classification, WHO classification, tumour differentiation, Laurén classification, Ming classification and Goseki classification. Formalin-fixed paraffin-embedded tumour specimens were stained using an avidin-biotin complex peroxidase assay. MMP-2 expression in the tumour epithelium was studied by immunohistochemistry with semiquantitative (score 0-3) evaluation. The MMP-2 staining pattern was positive (score 1-3) in 93 (81.6%) specimens and negative (score 0) in 21 (18.4%) samples. No significant correlations were found between MMP-2 expression and other variables such as age, tumour differentiation, WHO, Lauren, Goseki, and Ming classifications. In contrast, the intensity of MMP-2 staining in tumour cells correlated significantly with depth of tumour infiltration (T-stage), lymph node metastasis (N-stage), distant metastasis (M-stage), and UICC stage. CONCLUSIONS: Expression of MMP-2 is strongly associated with tumour progression and lymph node metastasis in gastric cancer. Therefore MMP-2 staining may be clinically useful as predictor of tumour progression, especially for lymph node metastasis.     

早期胃癌淋巴结转移与病理特征相关性分析及手术方式选择

目的探讨影响早期胃癌（EGC）淋巴结转移的相关病理学因素,为EGC的手术方式选择提供参考。方法回顾性分析228例早期胃癌患者的临床病理特征及淋巴结转移情况,分析早期胃癌的大小、原发部位、大体分型、组织学分型、侵润深度及分化程度等与淋巴结转移的相关性以及手术方式的选择。结果 228例EGC患者中出现淋巴结转移31例（13.6%）,其中粘膜内癌10例（7.9%）,粘膜下癌21例（20.6%）。单因素分析发现EGC淋巴结转移与肿瘤大小、肿瘤侵润深度及分化程度相关（P〈0.01）,而与肿瘤的大体分型、组织学类型、肿瘤部位无关（P〉0.05）。多因素分析发现肿瘤直径大于2 cm、粘膜下癌及分化程度低是EGC淋巴结转移的独立危险因素。对于肿瘤直径小于2 cm、分化程度较高的粘膜内癌并无淋巴结转移的EGC,建议行内镜下粘膜切除术（EMR）或内镜粘膜下剥离术（ESD）治疗。结论肿瘤直径大于2 cm、粘膜下癌及分化程度低是EGC淋巴结转移的独立危险因素,淋巴结转移影响了早期胃癌手术方式。     

Tumor size of breast invasive ductal cancer measured with contrast-enhanced ultrasound predicts regional lymph node metastasis and N stage

Purpose: This study aimed to determine the role of breast invasive ductal cancer (BIDC) size measured with Contrast-enhanced Ultrasound (CEUS) in the prediction of regional lymph node metastasis (LNM) and N stage. Methods: One hundred and six consecutive patients with breast lesions underwent ultrasound imaging within 2 weeks before mastectomy and axillary lymph node dissection. The largest transverse (width) and anteroposterior (depth) diameter were measured under CEUS by using calipers. The correlation between tumor size and regional LNM metastasis and N stage was evaluated. Results: Univariate analysis showed the diameters measured with CEUS were associated with lymph node metastasis (P < 0.05). The tumor size could distinguish grouped N stage (all P < 0.05). Tumor area (TA) might be an indicator that can differentiate No BIDC from N1-3 BIDC (cutoff = 5.37 cm²), N0-1 BIDC from N2-3 BIDC (cutoff = 6.48 cm²), and N0-2 BIDC from N3 BIDC (cutoff = 8.23 cm²) with the sensitivity of 71%, 72% and 83%, respectively, and the specificity of 79%, 68% and 84%, respectively. Conclusions: The TA of BIDC measured with CEUS may be a predictor of regional LNM and N stage.     

Methylene blue-assisted lymph node dissection in combination with ex vivo sentinel lymph node mapping in gastric cancer

Aims:  Lymph node (LN) stage is still the strongest prognostic marker in potentially curable gastric cancer. Accuracy of histopathological lymph node assessment depends on the number of investigated LNs and detection rate of metastases and micrometastases. The aim was to perform a feasibility study employing intra-arterial methylene blue injection – a novel method to improve LN harvest – and ex vivo sentinel LN mapping.
Methods and results:  A total of 33 cases were enrolled, including 14 retrospective cases that served as a control group. The methylene group showed a highly significant improved mean LN harvest compared with unstained cases, with 38 ± 14 versus 21 ± 10 LNs ( P  < 0.001), respectively. The detection rate of ex vivo sentinel mapping was 88%. No skip metastases occurred.
Conclusion:  Both techniques have the potential to improve the accuracy of histopathological LN staging and can be combined successfully.     

超声对乳腺癌腋下淋巴结转移状态评估价值的研究进展

超声技术作为术前评估乳腺癌腋下淋巴结转移(axillary lymph node metastasis,ALNM)状态最常用的方法,可通过二维灰阶图像、血流表现、弹性成像、超声造影等手段根据淋巴结的形态、纵横比、皮质状态、淋巴门表现、血流情况等指标预测淋巴结转移与否.但超声技术受众多影响因素如腋下淋巴结的大小、位置、腋窝深度、医师经验、超声仪器分辨率不同等的限制,其检出率及准确率仍未达到令人满意的水平.因此,如何提高超声对乳腺癌ALNM的评估效能成为亟需解决的问题.     

Depressed-type of early colon cancer with extensive lymph node metastasis

Early colorectal cancer (ECC) is defined as invasive tumor limited to the colonic and rectal mucosa or submucosa, regardless of the presence or absence of lymph node metastasis. The incidence of lymph node metastasis in ECC ranges from 0 to 15.4%, and risk factors include depth of submucosal invasion, growth patterns (polypoid or non-polypoid), histologic subclassification, and lymphatic invasion. Of non-polypoid growth patterns, the depressed types of colorectal cancer have higher malignant potential than polypoid types, even for small sizes. Unfortunately, this type is also difficult to detect on colonoscopic examination. In this report, we describe a case of depressed type ECC with extensive lymph node metastasis without regional lymph node involvement.     

Establishment of lymph node metastatic model for human gastric cancer in nude mice and analysis of factors associated with metastasis

The actual mechanisms responsible for lymph node metastasis in gastric cancer are still unclear. To investigate the mechanisms of lymph node metastasis in gastric cancer, we established a lymph node metastatic model for human scirrhous gastric carcinoma. Lymph node metastasis had frequently developed after orthotopic implantation of OCUM-2M LN derived from a scirrhous gastric cancer cell line, OCUM-2M, which had low capacity for lymph node metastasis. We elucidated the different characteristics including binding ability, migratory capacity and immunoresponses induced by the cell surface molecules of these two cell lines. The binding ability to Matrigel and migratory capacity of OCUM-2M LN cells were significantly greater than those of OCUM-2M cells. On flow cytometric analysis, both OCUM-2M and OCUM-2M LN cells strongly expressed HLA-I (99.5 and 97.1%) and LFA-3 (76.6 and 99.2%) in level of expression between the two cell lines, but neither cell line expressed HLA-II (0.0 and 0 .0%), B7-1 (0.0 and 0.0%) or B7-2 (0.4 and 0.3%). ICAM-1 expression in OCUM-2M LN cells was weaker (0.7%) than that in OCUM-2M cells (36.8%). Strong adhesiveness and cytotoxicity of mononuclear lymphocytes for OCUM-2M cells were observed in adhesion and cytotoxic assays, both of which were significantly decreased by the addition of anti-ICAM-1 antibodies. On the other hand, the adhesiveness and cytotoxicity of OCUM-2M LN cells were significantly less than those of OCUM-2M cells, and were not affected by the addition of anti-ICAM-1 antibodies. These findings suggest that decreased ICAM-1 expression in a new gastric cancer cell line with a high rate of lymph node metasta-sis may in turn decrease immune responses mediated through LFA-1-dependent effector cell adhesion, and that this escape from the immunosurveillance system may be one of the factors inducing lymph node metas-tasis. In conclusion, we established a gastric cancer cell line, OCUM-2M LN, with a high rate of lymph node metasta sis. An in vivo lymph node-metastatic model with this cell line should be useful for analysing the mech-anism and therapeutic approach of lymph node metastasis. © Rapid Science Ltd.     

Lymphangiogenesis in breast cancer is associated with non-sentinel lymph node metastases in sentinel node positive patients

Axillary lymph node dissection (ALND) is not suggested in breast cancer patients with negative sentinel lymph node (SLN) biopsies, and SLN is the only positive node in 40-70% of the remaining cases. To distinguish a subgroup in which ALND would be omitted, we investigated the role of lymphangiogenesis in primary breast cancer as a risk factor for distal lymph node involvements in patients with positive SLNs. 86 patients were included in this study. The frequency of proliferative lymphatic endothelial cells (LECP%) was evaluated in each specimen after immunohistochemical double staining for D2-40 and Ki-67. Larger primary tumor size, increased number of positive SLNs, lymphatic vessel invasion and LECP% were significantly associated with non-SLN metastases in the univariate analysis, but only LECP% retained significance in the multivariate model. A positive correlation between LECP% and lymphatic vessel invasion was also revealed. Our study confirmed the important role of lymphangiogenesis in tumor spread, and suggested that LECP% is a promising predictor for additional axillary lymph node involvements.     

Reduced expression of the cell-cycle inhibitor p27Kip1 is associated with progression and lymph node metastasis of gastric carcinoma

AIMS: p27Kip1 (p27), a cyclin-dependent kinase inhibitor, plays an important role as inhibiting the progression of the cell cycle. Decreased expression of p27 is associated with high histological grade and aggressiveness of several human tumours. We aimed to evaluate the role of p27 in the progression and metastasis of gastric carcinoma. METHODS AND RESULTS: We analysed the expression of p27 in 67 primary gastric carcinomas and 31 lymph node metastases by immunohistochemistry. Reduced expression of p27 was found more frequently in advanced gastric cancer (40.9%) than in early gastric cancer (15.6%) (P < 0.001). Decreased p27 expression correlated with large tumour size, high histological grade, lymphatic invasion, advanced stage, deep invasion, lymph node metastasis and recurrence. The expression of p27 showed an inverse correlation with the Ki67 labelling index. There was a significant reduction of p27 expression in metastatic tumour cells in lymph nodes (mean positive cells: 3. 7%) when compared to the corresponding primary gastric carcinomas (mean positive cells: 8.1%) (P = 0.008). CONCLUSIONS: Alterations of p27 expression may play an important role in the progression and metastasis to lymph node of tumour cells in human gastric carcinoma.     

HLA antigens are candidate markers for prediction of lymph node metastasis in gastric cancer

We investigated the association between human leucocyte antigen (HLA) antigens and lymph node metastasis in 724 gastric cancer patients. Among patients who had poorly differentiated adenocarcinoma with or without HLA-DR4 antigen, lymph node metastasis was detected in 80.8 and 54.9%, respectively (relative risk (RR)=3.5, P = 0.0005, corrected P = 0.0285). It was more common in patients with a family history of cancer death (RR = 7.7). Among signet ring cell carcinoma patients with or without HLA-1152 antigen, lymph node metastasis was detected in 57.7 and 19.7%, respectively (RR =5.6, P=0.0001, corrected P=0.0086). It was more common in patients who were smokers (RR = 8.3). Our findings suggest that HLA-DR4 and HLA-1152 antigens are associated with lymph node metastasis in gastric cancer.     

Sentinel lymph node biopsy in penile carcinoma

Sentinel lymph node (SLN) biopsy is a fairly new technique that is becoming the standard of care for regional lymph node staging of many solid tumors. This technique is based on the hypothesis of stepwise distribution of malignant cells in the lymphatic system. The absence of tumor cells in the first lymph node(s) in the lymphatic drainage of a tumor would indicate the absence of further spread in the regional lymph node basin(s). Therefore, this first lymph node is the guardian (sentinel) of the regional lymph node basin. To localize the sentinel node preoperatively, lymphoscintigraphy is usually performed after intradermal peritumoral injections of colloid particles labeled with technetium-99m. The tracer is transported through the lymphatic channels to the first draining nodes in the groins and is visible on the lymphoscintigram as hot spots. The main advantage of SLN biopsy in penile cancer is to decrease the treatment-related morbidity without compromising the survival benefit for the patient. Recent figures indicate a false-negative rate of 7%, with a complication rate of less than 5% for SLN biopsy. In conclusion, sentinel node biopsy of patients with penile cancer has evolved into a highly reliable procedure enabling the detection of lymph node invasion at the earliest possible time with minimal morbidity. With this technology at hand, which minimizes the treatment-related morbidity, there is hardly any place for standard lymphadenectomy in penile cancer patients.     

Membrane-type 1 matrix metalloproteinase enhances lymph node metastasis of gastric cancer

The mechanisms of the lymph node metastasis remain unclear. We demonstrate the role of MT1-MMP on the lymph node metastasis using in vivo experimental model of lymph node metastasis by orthotopic implantation of MT1-MMP transfected gastric cancer cell line in the stomach of nude rats. TMK-1 cell line without expression of MT1-MMP was transfected with the pcDNA3 plasmid containing a 3.4-kb MT1-MMP cDNA fragment by calcium phosphate method, and the transfected cell line was designated as TMK-MT. Western blot and RT-PCR analyses showed the specific bands corresponding to MT1-MMP in the TMK-MT cells. By gelatin zymography, the activated form (62-kDa) of MMP-2 was identified in the medium of TMK-MT cell line, but was not detected in TMK-1 cells. Six weeks after orthotopic implantation of TMK-1 and TMK-MT xenografts of nude mouse-subcutaneus tumor into the stomach of nude rats, gastric tumors were found in all the animals. Histologically, the lymphatic invasion was found in the submucosa of the TMK-MT gastric tumors. Lymph node metastasis was not detected in nude rats bearing TMK-1 gastric tumor (0/8). In contrast, lymph node metastasis was detected in five out of 8 rats, bearing TMK-MT gastric tumor. MT1-MMP immunoreactivity was found on the cell membrane and cytoplasm of TMK-MT cells not only in the lymph node metastasis but also in the stomach tumor. These results suggest that MT1-MMP overexpression induced by transfection of its gene may promote lymph node metastasis of transformed cells. This revised version was published online in July 2006 with corrections to the Cover Date.     

Benign glandular inclusion in obturator lymph node of a man treated for prostate carcinoma

Benign glandular inclusions in lymph nodes are extremely rare in men. Their identification is essential because it changes dramatically the prognosis and therapy of neoplasms. Described herein is the first case of benign glandular inclusion in an obturator lymph node dissected during a radical prostatectomy for treatment of prostate adenocarcinoma. A 60-year-old man underwent radical prostatectomy and obturator-hypogastric lymph node dissection for treatment of prostate adenocarcinoma. Benign glandular inclusion was found in microscopic examination. The lesion was characterized by two glandular spaces lined by a single, cuboid, benign epithelium localized in the sinus of one of four dissected lymph nodes. Immunohistochemistry showed mesothelial differentiation. Pathologists should be aware of benign glandular inclusion in obturator lymph nodes dissected during a radical prostatectomy for treatment of prostate cancer in order to avoid the incorrect diagnosis of metastatic disease.