Angiogenesis is redundant for tumour growth in lymph node metastases

AIMS: Angiogenesis is essential for the growth of solid tumours. As the role of angiogenesis is unclear in the pathogenesis of primary lymph node (LN) tumours, we wondered whether neoangiogenesis was important in supporting and promoting the growth of tumours in LNs. METHODS AND RESULTS: We investigated 16 cases of squamous carcinoma involving oral cavity (n=9) and larynx/pyriform fossa (n=7), all of whom had lymph node metastases. Sections of the primary tumour, uninvolved mucosa, metastatic LN and nonmetastatic LN were double-immunostained with factor VIII-related antigen and MIB-1. Proliferating blood vessels, i.e. neoangiogenesis, was identified by coexpression of factor VIII-related antigen-stained blood vessels and MIB-1 staining of the endothelial cell nuclei. Counts were performed in an area of 4 mm2. Primary tumours (127-188.7), uninvolved mucosa (54-84.5) and metastatic LNs (123.5-167) had significantly lower vessel counts than nonmetastatic LNs (194-253.9) (P=0.003; P < 0.001; P < 0.001, respectively). With regard to neoangiogenesis, primary tumours (1.7-5) had significantly higher counts than uninvolved mucosa (0-0.4), nonmetastatic LNs (0-0.4) and metastatic LNs (0.9-2.4) (P < 0.001; P < 0.001; P=0.047, respectively). CONCLUSIONS: Our data suggest that because of the rich native vascularity of lymph nodes, neoangiogenesis is redundant for the growth of metastatic tumour.     

High-level cytoplasmic cyclin D1 expression in lymph node metastases from prostate cancer independently predicts early biochemical failure and death in surgically treated patients

Fleischmann A, Rocha C, Saxer‐Sekulic N, Zlobec I, Sauter G & Thalmann G N
(2011) Histopathology 58 , 781–789
High‐level cytoplasmic cyclin D1 expression in lymph node metastases from prostate cancer independently predicts early biochemical failure and death in surgically treated patients Aims: To test the prognostic significance of cyclin D1 in nodal‐positive prostate cancer. Methods and results: Nuclear and cytoplasmic cyclin D1 expression was evaluated in 119 nodal‐positive prostate cancer patients undergoing radical prostatectomy and extended lymphadenectomy. Cyclin D1 was correlated with various tumour features and biochemical recurrence‐free survival (bRFS), disease‐specific survival (DSS) and overall survival (OS). In the metastases, high‐level cytoplasmic cyclin D1 expression independently predicted poor outcome (5‐year bRFS, 12.5% versus 26.4%, P = 0.006; 5‐year DSS, 56.3% versus 80.7%, P = 0.007; 5‐year OS, 56.3% versus 78.7%, P = 0.011). These patients had a 2.62‐fold elevated risk of dying from prostate cancer as compared with patients with low‐level cytoplasmic cyclin D1 expression (P = 0.024). All other subcellular compartments of cyclin D1 expression in primary tumours and metastases were prognostically non‐significant. Conclusions: The subcellular location of cyclin D1 expression in prostate cancer is linked to specific clinical courses. Survival stratification according to biomarker expression in metastases indicates an important role for tumour sampling from these tissues.     

Early distant relapse in "node-negative" breast cancer patients is not predicted by occult axillary lymph node metastases, but by the features of the primary tumour

Early distant relapse occurs in a minority of node-negative breast cancer patients. Whether this poor prognosis can be predicted by the features of the primary tumour, or by the presence of occult metastases in the "negative" lymph nodes (LNs), remains a matter of debate. One hundred and four T(1-2)N(0)M(0) breast carcinoma patients were divided into two groups: group 1 (44%) showing early distant relapse with a median disease-free survival of 25 months, and group 2 (56%) showing no evidence of disease after a median follow-up of 91.5 months. All patients had received locoregional treatment only. All tumours were evaluated for medial/lateral location, histological type, size, grade, mitotic activity, fibrotic focus, necrosis, angiogenesis, growth pattern, and lymphatic vessel permeation. The haematoxylin and eosin-stained slides of all axillary LNs were revised and two additional levels were cut from each paraffin block for cytokeratin immunohistochemistry. In 24 patients (23%), occult metastases were found. These consisted of single cells or small clusters (SCs) in the marginal sinus in 17 patients (16%) and of larger colonies of cells in seven patients (7%). All detected metastases were smaller than 2 mm in diameter (micrometastases). There was no significant correlation between the presence of occult LN metastases (SCs or colonies) and the prognostically important features of the primary tumour. Early metastatic disease was significantly correlated with larger tumour size (p=0.02), higher histological grade (p=0.0008), mitotic activity (p<0.0001), presence of necrosis (p=0.0004), presence of fibrotic foci (p=0.0005), angiogenesis (p=0.0009), and lymphatic vessel permeation (p=0.018). Multiple logistic regression analysis showed that histological grade and the presence of a fibrotic focus were the only independent prognostic factors and that the presence of occult LN metastases was inversely correlated with early distant relapse. Prospective prognostic studies of occult LN metastases should consider the features of the primary tumour in a multivariate analysis.     

血管内皮生长因子C和趋化因子受体CCR7的表达与膀胱癌淋巴结转移之间的关系

目的观察血管内皮生长因子(VEGF)-C和趋化因子受体CCR7在膀胱移行细胞癌组织内的表达情况,分析VEGF-C和CCR7表达与癌淋巴结转移之间的关系。方法取膀胱癌病例60例,其中,淋巴结转移组36例,无淋巴结转移组24例。应用免疫组化法和Western blot技术观察VEGF-C和CCR7在膀胱癌组织内的表达。结果 VEGF-C和CCR7主要表达于膀胱癌细胞胞浆或/和胞膜内,二者在淋巴结转移组的表达率明显高于无淋巴结转移组。VEGF-C和CCR7蛋白同时表达在淋巴结转移组和非淋巴结转移组中的表达率分别为61.1%和33.3%,VEGF-C和CCR7的表达具有显著的相关性,联合检测VEGF-C和CCR7诊断膀胱癌淋巴结转移具有较高的准确度,ROC曲线下面积达0.708。结论 VEGF-C和CCR7在促进膀胱癌淋巴结转移中可能具有一定的协同作用,二者联合检测有助于膀胱癌淋巴结转移的早期诊断     

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.     

Comparison of molecular determinants of angiogenesis and lymphangiogenesis in lymph node metastases and in primary tumours of patients with breast cancer

Angiogenesis and lymphangiogenesis are complex processes, driven by multiple factors. In primary breast tumours (PTs), VEGFA, -C and -D are the most important (lymph)angiogenic factors. The induction of lymphangiogenesis in axillary lymph node (LN) metastases of patients with breast cancer was described recently. To compare the molecular determinants of (lymph)angiogenesis in LN metastases and PTs of breast cancer patients, RNA was isolated from formalin-fixed, paraffin-embedded tissue sections of a metastatically involved and uninvolved LN and the PT from 26 lymph node-positive patients. The expression of 12 (lymph)angiogenic markers was measured by qRT-PCR. Expression was correlated with tumour cell proliferation, angiogenesis and lymphangiogenesis, quantified by tumour cell proliferation fraction (TCP%) and (lymphatic) endothelial cell proliferation fraction [(L)ECP%]. TCP%, ECP% and LECP% were assessed on immunohistochemical double stains for CD34/Ki-67 and D2-40/Ki-67, respectively. In involved LNs, the relative gene expression levels of PROX1 (p < 0.001) and FGF2 (p = 0.008) were decreased and the expression levels of VEGFA (p = 0.01) and PDGFB (p = 0.002) were increased compared to uninvolved LNs. The expression of most markers was increased in PTs compared to involved LNs. In metastatically involved LNs, the expression of VEGFA correlated with ECP% (r = 0.54, p = 0.009) and LECP% (r = 0.76, p < 0.001). In PTs, VEGFA correlated only with ECP% (r = 0.74, p < 0.001). VEGFD correlated with peritumoural LECP% (r = 0.61, p = 0.001) and with VEGFC (r = 0.78, p < 0.001). Linear regression analysis confirmed the expression of VEGFA as an independent predictor of ECP% in both PTs and LN metastases and of LECP% in LN metastases. The expression of VEGFD, but not of VEGFA, independently predicted peritumoural LECP% in PTs. Our results confirm existing data that, in PTs, angiogenesis and lymphangiogenesis are respectively driven by VEGFA and VEGFD. In contrast, in LN metastases, both processes seem to be driven by VEGFA. Lymphangiogenesis in PTs and in LN metastases might thus be driven by different factors.     

Prognostic factors in lymph node metastases of prostatic cancer patients: the size of the metastases but not extranodal extension independently predicts survival

Aims: To analyse tumour characteristics and the prognostic significance of prostatic cancers with extranodal extension of lymph node metastases (ENE) in 102 node‐positive, hormone treatment‐naive patients undergoing radical prostatectomy and extended lymphadenectomy. Methods and results: The median number of nodes examined per patient was 21 (range 9–68), and the median follow‐up time was 92 months (range 12–191). ENE was observed in 71 patients (70%). They had significantly more, larger and less differentiated nodal metastases, paralleled by significantly larger primary tumours at more advanced stages and with higher Gleason scores than patients without ENE. ENE defined a subgroup with significantly decreased biochemical recurrence‐free (P = 0.038) and overall survival (P = 0.037). In multivariate analyses the diameter of the largest metastasis and Gleason score of the primary tumour were independent predictors of survival. Conclusions: ENE in prostatic cancer is an indicator lesion for advanced/aggressive tumours with poor outcome. However, the strong correlation with larger metastases suggests that ENE may result from their size, which was the only independent risk factor in the metastasizing component. Consequently, histopathological reports should specify the true indicator of poor survival in the lymphadenectomy specimens, which is the size of the largest metastasis in each patient.     

L-CAM expression in lymph node and liver metastases of colorectal carcinomas

L-CAM, also known as E-cadherin, is a cell adhesion molecule expressed on the plasma membranes of epithelial cells at the intercellular interface. From in vitro gene transfection experiments the idea has been conceived that loss of L-CAM expression might be related to the invasive capacity as well as metastatic potential of tumour cells. In several tumours a relation between the grade of differentiation and L-CAM expression has been noticed: loss of differentiation appears to be associated with loss of L-CAM immunoreactivity. Also, in lymph node metastases of poorly differentiated carcinomas loss of L-CAM expression was demonstrated. In this study we describe L-CAM expression in lymphogenous and haematogenous metastases of large bowel adenocarcinomas, using an indirect immunoperoxidase method with the monoclonal anti-L-CAM antibody 6F9. All the metastases studied—lymphogenous as well as haematogenous—demonstrated L-CAM immunoreactivity in a pattern comparable to that of primary tumours. Intratumour heterogeneity in expression was noted, with normal intercellular, apical (non-functional), and focally negative areas in the same tumour. The data indicate that primary tumours and their metastases do not differ strikingly in their pattern of L-CAM expression. This would be consistent with transient rather than constitutive down-regulation of L-CAM in invasive and metastatic cancer cells.     

乳腺癌非前哨淋巴结转移的预测

目的 :预测非前哨淋巴结 (non SLN)转移 ,以筛选出转移局限于前哨淋巴结 (SLN)的乳腺癌患者。方法 :采用99mTc SC作为示踪剂 ,对 95例乳腺癌患者行前哨淋巴结活检 ,对乳腺癌非前哨淋巴结转移进行单因素和多因素分析。结果 :95例患者中成功发现 91例患者有SLN (95 8% ) ,其中 85例患者SLN能准确反映腋窝淋巴结的病理状况 (93 4% )。临床肿块大小(P =0 0 2 8)、肿瘤分级 (P =0 0 40 )和原发灶cyclinD1蛋白 (P =0 0 17)的表达与non SLN转移显著相关。而Logistic多因素分析证实 ,临床肿块大小、肿瘤分级为独立的预测非前哨淋巴结转移的因子。结论 :可根据临床病理学特征 ,筛选出乳腺癌转移只局限于前哨淋巴结的患者 ,也存在免除腋窝淋巴结清扫的可能性     

Effect of Gleason scores of lymph node metastases on prognosis of patients with prostate cancer

The long-term mortality risk from prostate cancer increases in lymph node (LN) positive patients. This study was done to assess the effect of lymph node Gleason score (LNGS) on prognosis in patients with LN-positive prostate cancer. Among the 1,415 patients who received pelvic lymph node dissection (PLND), 117 (8.4%) patients had a positive LN. The PGS of the prostate specimens and the LNGS of the positive LNs were assessed by uropathologists. The median age of patients at surgery was 67 years (interquartile range [IQR], 62-71 years) and the median follow-up duration was 44.3 months (IQR, 27.0-78.5 months). Pathologic Gleason scores (PGS) of 6-9 included one (0.9%), 53 (49.5%), 22 (20.6%), and 31 (29.0%) patients. The median total number of retrieved LNs was 9.0 (IQR, 5.3-12.8). The median number of positive LNs was one (IQR, 1-2). Cancer architecture with a Gleason pattern and score were observed in LNs as in ordinary prostate specimens. LNGS 6-9 included nine (8.1%), 57 (51.4%), 31 (27.9%), and 14 (12.6%) patients. The speaman’s analysis showed the meaningful correlation between PGS and LNGS (P = 0.249, P = 0.011). The univariate analysis showed that the number of positive LNs and LNGS were significantly associated with prostate cancer-specific survival (P = 0.028; P = 0.005). The same architecture that is seen in the prostate was seen in positive LNs, and LNGS may be a significant prognostic factor in patients with LN-positive prostate cancer.     

胸中上段食管癌三野淋巴结清扫及二野淋巴结清扫预后比较分析

目的探讨并分析胸中上段食管癌三野淋巴结清扫及二野淋巴结清扫对患者的不同预后情况。方法选择2010年10月至2011年10月我院收治的120例食管癌患者,按淋巴结清扫方式分为三野清扫组跟二野清扫组,每组各60例。二野清扫组采用二野淋巴结清扫治疗,三野清扫组采用三野淋巴结清扫治疗。比较2组经治疗后淋巴结的转移率、手术生存率,以及并发症的发生情况。结果经手术治疗后,三野清扫组淋巴结的转移率分别为18.33%和20.00%,并发症的总发生率为30.00%,均低于二野清扫组;手术生存率为83.33%,明显高于二野清扫组的58.33%,P0.05,差异具有统计学意义。结论食管癌三野淋巴结清扫,能有效地改善患者的预后,提高临床疗效,具有一定的临床意义。     

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.     

A very rare case of synchronous primary lung cancer lymph node metastasis

A 76 year old patient presented with two synchronous primary lung tumours. One was identified as an adenocarcinoma and the second as an atypical carcinoid tumour. When reviewing the lymph node slides it was seen that one lymph node contained metastatic deposits from both primary tumours. Synchronous lung tumours are fairly rare occurrences, but even rarer is the finding of synchronous metastases to the same lymph node. The atypical carcinoid deposit was very subtle in appearance and could easily have been overlooked. This case demonstrates a useful learning point to not miss these rare and subtle findings as the resulting tumour staging was affected and may have implications for further patient management.     

Accuracy of axillary staging using sentinel node biopsy or diagnostic axillary lymph node dissection--a case-control study

We aimed to compare the accuracy of axillary staging in breast cancer between sentinel node biopsy (SNB) and axillary lymph node dissection (ALND). The prevalence of axillary metastases was studied in 166 breast cancer patients with SNB and pair-matched control patients with ALND. The matching factors included age of the patient and grade, histological type and histological size of the tumour. There were 37% of patients with axillary metastases in the SNB group and 31% in the ALND group. Altogether, 57 pairs were discordant in relation to axillary metastases. In 34 discordant pairs the SNB patient and in 23 the ALND patient had axillary metastases, p=ns. Among the 36 discordant pairs with invasive ductal carcinoma (IDC), axillary metastases were detected as often in the SNB and the ALND patients. In the 21 discordant pairs with other histological types, the SNB patient had axillary metastases in 16 pairs and the ALND patient in 5 pairs, p<0.03. SNB seems to be as accurate a method for axillary staging as ALND. However, SNB generated no upstaging effect in IDC, only in other histological tumour types.     

吲哚菁绿荧光腹腔镜在膀胱癌盆腔淋巴结清扫术中的应用价值

目的:探讨吲哚菁绿(ICG)荧光腹腔镜在膀胱癌盆腔淋巴结清扫术(PLND)中的应用价值。方法:回顾性队列研究。纳入2018年6月—2019年10月蚌埠医学院第一附属医院泌尿外科膀胱癌患者59例,其中男25例、女34例,年龄(59.1±4.3)岁,均采用腹腔镜膀胱癌根治术+PLND术治疗。按腹腔镜类型分组：观察组24例,...     

The expression of aldehyde dehydrogenase 1 in invasive primary breast tumors and axillary lymph node metastases is associated with poor clinical prognosis

The enzyme aldehyde dehydrogenase 1 (ALDH1) has been reported as a biomarker for identifying cancer stem cells. Previous studies have shown that ALDH1 expression in primary breast cancers was associated with poor clinical prognosis. In this study, we aimed to determine whether ALDH1 expression in axillary lymph node metastases (ALNM) of breast cancer patients was also associated with poor prognosis. Expression of ALDH1, ER, PgR, HER2 and KI-67 was examined in primary tumors and ALNM of 161 patients with invasive breast cancer. Survival analysis and multivariate analysis were used to determine the relationship between ALDH1 expression and clinical prognosis. Patients with positive ALDH1 expression in primary tumors and in ALNM had significantly shorter relapse-free survival (RFS) times and overall survival (OS) times compared to those whose tissues were ALDH1 negative. ALDH1-positivity in primary tumors was significant both in univariate and multivariate analyses of RFS and OS. ALDH1 expression in ALNM was significant in a univariate analysis of RFS and OS but not in a multivariate analysis of RFS and OS. We conclude that the expression of ALDH1 in primary breast tumors or ALNM may be one potential risk factor for poor, long-term outcomes.     

MELF invasion in endometrial cancer as a risk factor for lymph node metastasis

Pavlakis K, Messini I, Vrekoussis T, Panoskaltsis T, Chrysanthakis D, Yiannou P & Voulgaris Z
(2011) Histopathology  58 , 966–973
MELF invasion in endometrial cancer as a risk factor for lymph node metastasis Aim: To investigate whether the microcystic, elongated and fragmented (MELF) pattern of myometrial invasion encountered in certain endometrioid endometrial carcinomas can be considered as a risk factor for lymph node metastasis. Methods and results: A total of 351 cases of total abdominal hysterectomy and bilateral salpingo‐oophorectomy with/without lymphadenectomy or lymph node sampling, performed for endometrioid endometrial adenocarcinoma, were included in this study. The existence of MELF invasion, vascular invasion, fibromyxoid stromal reaction and lymph node metastasis were recorded. Immunohistochemistry for endothelial and epithelial markers was performed on selected cases. MELF invasion was identified in 20 (10.81%) and 13 cases (13.13%) treated without and with lymphadenectomy, respectively. All these cases were either well or moderately differentiated carcinomas, stages IA–II (without considering lymph node status). Positive lymph nodes were detected in seven of 13 MELF‐positive (53.84%) and six of 86 MELF‐negative cases (6.97%) This observation was statistically significant. Of the seven MELF‐positive tumours with lymph node metastasis, three cases exhibited intravascular tumour emboli while four showed a fibromyxoid stromal reaction. Conclusion: MELF pattern invasion was found to be related statistically to lymph node metastasis. Nevertheless, further studies are needed in order to evaluate the clinical significance of this observation.