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[Nuclear morphometric and DNA content analyses of cancer cells in superficial esophageal cancer with reference to lymph node metastasis].

In 23 cases of surgically resected superficial esophageal cancer which was defined by Japanese Society for Esophageal Diseases, the nuclear area (NA), nuclear shape factor (NSF) and DNA content (DNA) of cancer cells were measured using an image analysis system, and, in 7 out of the 23 cases, biopsy specimens were examined in the same way as well. The results were analyzed and evaluated with respect to lymph node metastasis. The NA was significantly larger (p less than 0.01) and the DNA content value was significantly higher (p less than 0.05) in the tumors with lymph node metastasis than in those with no lymph node metastasis. By means of a linear discriminant analysis using NA and DNA as variables, z = 0.238 X NA + 0.475 X DNA - 11.9, existence of lymph node metastasis could be correctly presumed at 87%. No false discrimination was found on preoperative biopsy specimens in 7 cases in which the accuracy of the discriminant analysis could be confirmed by microscopic examination of the lymph nodes extirpated at operation for esophagectomy. Conclusively NA and DNA correlate significantly with existence of lymph node metastasis in the patients with superficial esophageal cancer, and might be useful for preoperative predicting whether or not lymph node metastasis exists.

Carcinoma, Squamous Cell↗

Expression of sialyl lewis X, sialyl Lewis A, E-cadherin and cathepsin-D in human breast cancer: immunohistochemical analysis in mammary carcinoma in situ, invasive carcinomas and their lymph node metastasis.

OBJECTIVE: Breast cancer cells can invade and generate metastasis via either lymphatic or blood vessels. Sialyl Lewis X (SLeX) and Sialyl Lewis a (SLea) are carbohydrate molecules that mediate the adhesion between tumor cells and the endothelium. These antigens are not expressed on normal breast tissue. Overexpression of SLeX and SLea is combined with poor prognosis and malignant relapse. E-cadherin mediates tumor cell-tumor cell adhesion. Partial or complete loss of E-cadherin expression has also been found to correlate with poor prognosis in breast cancer patients. Another factor involved in metastasis is Cathepsin-D, a lysosomalprotease. Cathepsin-D plays a role in cell proliferation and inhibition of tumor cell adhesion. In this study, we analysed the combined expression of SLeX, SLea, Cathepsin-D and E-cadherin in breast carcinoma in situ, invasive carcinomas without metastasis and invasive carcinomas with lymph node metastasis. MATERIALS AND METHODS: Slides of paraffin-embedded tissue of carcinoma in situ (8 DCIS, 2 CLIS), invasive carcinomas without metastasis (9 ductal, 1 lobular) and carcinomas (7 ductal, 2 lobular, 1 mucinous) with their lymph node metastasis (10 cases) were used. Breast cancer tissue was fixed and incubated with monoclonal antibodies against SLex (IgM) and SLea (IgM), Cathepsin-D (IgG) and E-cadherin (IgG). Staining reaction was performed with the ABC reagent. The intensity of immunohistochemical reaction on digital images of the slides was analyzed using a computer-aided detection system. RESULTS: We found a weak expression of both Sialyl Lewis antigens, a strong expression of E-cadherin and a moderate expression of Cathepsin-D in carcinoma in situ. The expression of both Sialyl Lewis antigens, E-cadherin and Cathepsin-D was moderate in invasive carcinomas without metastases. However, a strong expression of both Sialyl Lewis antigens and a very weak expression of E-cadherin was detected in primary carcinoma with lymph node metastases. The expression of Cathepsin-D was moderate in this tissue. E-cadherin expression was elevated whereas SLeX and Cathepsin-D expression was reduced in lymph node metastases compared to the primary tumor. CONCLUSION: Combined analysis of tumor antigens involved in adhesion of breast cancer cells showed a negative correlation between Sialyl Lewis antigens and E-cadherin as the risk of metastasis progresses. Furthermore, there were significant differences of expression of the Sialyl Lewis antigens, E-cadherin and Cathepsin-D in primary breast cancer cells and their metastases. Evaluation of a panel of markers involved in cell adhesion could be a useful method for defining the metastatic risk in breast cancer patients.

Breast Neoplasms↗

The expression of the CD44 variant exon 6 is associated with lymph node metastasis in non-small cell lung cancer.

Recently, it was suggested that splice variants of the surface glycoprotein CD44 (CD44v) were associated with tumor metastasis in some cancers. We examined the expression of variant forms of CD44 in 31 non-small cell lung carcinomas (NSCLCs) and in 8 normal lung tissue samples by reverse transcription-PCR (RT-PCR). CD44v3, CD44v5, CD44v6, and CD44v7 were not expressed or were weakly expressed in normal lung tissue (0 of 8). In contrast, CD44v3, CD44v5, CD44v6, or CD44v7 was expressed in 28 of 31 (90.3%) NSCLCs. Additionally, we examined the expression of CD44v6, which has been shown to be related to metastasis, in 5 normal lungs and 30 NSCLCs by RT-PCR and immunohistochemical analysis to clarify which cells express CD44v6 in NSCLC specimens. Thirty-six of 61 (59%) NSCLCs variably expressed CD44v6 by RT-PCR, and cancer cells were selectively immunostained by anti-CD44v6 antibodies in 23 of 30 (76.7%) NSCLCs. The results of immunohistochemical analysis almost correlated with those of RT-PCR. NSCLCs with lymph node metastasis expressed significantly more v6 exon than did those without lymph node metastasis [23 of 29 (79.3%) versus 13 of 32 (40.6%); P < 0.01]. There was a significant association between the intensity of v6 expression by RT-PCR and the frequency of cases showing lymph node metastasis (Cochran-Armitage's test, P < 0.002). In conclusion, this study demonstrated that in NSCLC, a number of variant forms of CD44 are frequently expressed, although these variants are infrequently expressed in normal lung tissue, and that the expression of CD44v6 is particularly associated with lymph node metastasis in NSCLC.

Adult↗

[Relationship among expression of the VEGF gene and MVD with cervical lymph nodes metastasis in laryngeal squamous cell carcinoma].

OBJECTIVE: To study the relation among the expression of the vascular endothelial growth factor (VEGF) gene and microvessel Density (MVD) with cervical lymph nodes metastasis in laryngeal squamous cell carcinoma (LSCC). METHOD: Appling semi-RT-PCR technique and immunohistochemistry detected the expression of VEGFmRNA and protein and MVD count in 60 cases with LSCC. RESULT: The expression of VEGF and MVD was both higher either at molecular level or at the protein level in the group with cervical lymph nodes metastasis than the those with cervical lymph nodes-negative metastasis. The overexpression of VEGF had a positive correlation with the higher MVD count and were both related to cervical lymph nodes metastasis in the 60 cases with LSCC. CONCLUSION: There was a significant correlation between the expression of VEGF and MVD, which suggested that the overexpression of VEGF was essential to microangiogenesis of LSCC, and the both were related to cervical lymph nodes metastasis and would become a biologic indexes to prognosis of LSCC. Antiangiogenic therapy with specific antibodies to VEGF leads to inhibit angiogenesis and prevent tumor from growth and metastasis, which might have a bright future in clinical application.

Adult↗

Outcome of prophylactic radical lymphadenectomy with gastrectomy in patients with early gastric carcinoma without lymph node metastasis.

BACKGROUND: Prophylactic extended lymphadenectomy with gastrectomy may prolong survival in patients with early gastric carcinoma without lymph node metastasis. However, the therapeutic value of extensive lymphadenectomy in patients with early gastric carcinoma remains controversial. METHODS: The authors retrospectively analyzed 423 patients with early gastric carcinoma without lymph node metastasis who underwent gastrectomy and did not die of other diseases to evaluate the effect of prophylactic extended lymphadenectomy on postoperative survival. The postoperative survival rate of patients who underwent prophylactic extended lymphadenectomy was compared with that of patients who underwent prophylactic limited lymphadenectomy. RESULTS: Although extended lymphadenectomy did not appear to improve the postoperative survival rate of patients with mucosal tumors, it did improve the postoperative survival rate of patients with submucosal tumors. Whether prophylactic extended lymphadenectomy was performed significantly affected outcome in patients with early gastric carcinoma who had submucosal tumors without regional lymph node metastasis. CONCLUSIONS: Extensive lymphadenectomy with gastrectomy should be performed to prolong the survival of the patients with submucosal tumors.

Aged↗

[The relations of cellular DNA content to lymph node metastasis in gastric carcinoma].

The objectives of this study were to evaluate the relations of cellular DNA content, S-phase fraction (SPF) and G2/M-phase(G2/MPF) to lymph node metastasis in gastric carcinoma by using flow cytometry. The results showed that the incidence of lymph node metastasis and SPF were significantly higher in aneuploid carcinoma than in diploid carcinoma(P < 0.05). But the G2/MPF values did not correlate with lymph node metastasis. These findings suggest that correlations between cellular DNA content, SPF and the extent of lymph node metastasis are present.

Adenocarcinoma↗

Incidence and prognostic significance of lateral lymph node metastasis in patients with advanced low rectal cancer.

BACKGROUND: Lateral lymph node metastases occur in some patients with low rectal cancer and may cause local recurrence after total mesorectal excision. The aims of this study were to identify risk factors for lateral node metastases in patients with pathological tumour (pT) stage 3 or pT4 low rectal adenocarcinoma, and to evaluate the prognostic significance of lateral node metastases. METHODS: A retrospective analysis was performed of the outcome of 237 patients with pT3 or pT4 low rectal adenocarcinoma who underwent R0 resection with systematic lateral node dissection. RESULTS: Lateral lymph node metastases were found in 41 patients (17.3 per cent). Increased risk of lateral lymph node metastases was associated with a distal tumour margin close to the anal margin, histological type other than well or moderately differentiated adenocarcinoma, and the presence of mesenteric lymph node metastases. Patients with lateral node metastases had a significantly shorter postoperative survival (5-year survival rate 42 versus 71.6 per cent; P < 0.001) and an increased risk of local recurrence (44 versus 11.7 per cent; P < 0.001) compared with those without lateral node metastases. CONCLUSION: Tumour site, histological type and the presence of mesenteric lymph node metastasis are factors predicting the risk of lateral node metastasis. The poor prognosis of patients with lateral lymph node metastases after systematic lateral dissection suggests the need for adjuvant therapy.

Adenocarcinoma↗

[Risk factors for retroperitoneal lymph node metastasis in ovarian cancer].

The incidence and significant risk factors for retroperitoneal lymph node metastasis were investigated in 48 patients with primary epithelial ovarian cancer. Twenty-four (50.0%) of the 48 patients had para-aortic and/or pelvic lymph node metastases. In retroperitoneal lymphadenectomy at primary cytoreductive surgery, all patients with lymph node metastases were found to have both para-aortic and pelvic lymph node metastases. It is possible that the lymphatic extension, from the pelvic lymph node to the para-aortic lymph node, is one of the routes of retroperitoneal lymph node metastases in primary epithelial ovarian cancer. The incidence of lymph node metastases significantly increased with the spread of the abdominal tumor, peritoneal cytology, peritoneal metastasis, omental metastasis, involvement of both ovaries and poor histological grade. In the multiple analysis, the spread of the abdominal tumor, positive peritoneal cytology and poor histological grade were found to be the most important risk factors for retroperitoneal lymph node metastasis in ovarian cancer.

Cystadenocarcinoma, Serous↗

The utility of EUS and EUS-guided fine needle aspiration in detecting celiac lymph node metastasis in patients with esophageal cancer: a single-center experience.

BACKGROUND: The aims of this study were to determine the utility of EUS and EUS-guided fine needle aspiration (EUS-FNA) in the detection and confirmation of celiac lymph node metastasis in patients with esophageal cancer and to define EUS features predictive of celiac lymph node metastasis in these patients. METHODS: The records of 211 patients with esophageal cancer who underwent EUS staging were reviewed. The operating characteristics of EUS were determined in patients where either surgery, EUS-FNA of a celiac lymph node, or both were performed (n = 102). The association between selected variables and the presence of celiac lymph node metastasis was evaluated by univariate and multivariable analyses. RESULTS: EUS in 48 patients provided a true-positive diagnosis of celiac lymph node involvement, a false-positive and false-negative result, respectively, in 6 and 14 patients, and a true-negative diagnosis in 34 patients. The sensitivity of EUS in detecting celiac lymph node was 77% (95% CI [67, 88]), specificity 85% (95% CI [74, 96]), negative predictive value 71% (95% CI [58, 84]), and the positive predictive value 89% (95% CI [81, 97]). EUS-FNA was performed in 94% (51/54) of patients with celiac lymph nodes. The accuracy of EUS-FNA in detecting malignant celiac lymph nodes was 98% (95% CI [90, 100]). Advanced T-stage, the need for dilation, detection of peritumoral lymph nodes, and black race were associated with celiac lymph node involvement. In multivariable analysis, advanced T-stage was the strongest predictor of celiac lymph node involvement. CONCLUSION: EUS and EUS-FNA are highly accurate in detecting and confirming celiac lymph nodes metastasis. Depth of tumor invasion as assessed by EUS is a strong predictor of celiac lymph node metastasis in patients with esophageal cancer.

Adenocarcinoma↗

Involvement of microsatellite instability in lymph node metastasis of endometrial carcinoma.

We evaluated microsatellite instability (MSI) in primary lesions and lymph node metastatic lesions in 66 patients with endometrial carcinoma (FIGO stage IIIC) accompanied by lymph node metastasis. DNA was extracted from paraffin-embedded tissue of both the primary and lymph node metastatic lesions of endometrial carcinoma, and MSI was evaluated using microsatellite markers at five loci. Microsatellite instability was positive in the primary lesion in 27 patients (41%). All patients with MSI-positive primary lesions also showed MSI-positive in lymph node metastatic lesions. Of the other 39 patients with MSI-negative primary lesions, 4 showed MSI-positive in lymph node metastatic lesions. As the result of individual identification by polymerase chain reaction (PCR) using short tandem repeat loci in these 4 patients, PCR profiles of primary and metastatic lesions matched with those of normal controls in all 4 patients. Therefore, it was confirmed that both primary and metastatic lesions developed from the same individual. These results suggest that MSI is also involved in lymph node metastasis in the development and/or progression of endometrial carcinoma in some patients.

Adult↗

Clinical value of multidetector row computed tomography in detecting lymph node metastasis of early gastric cancer.

AIMS: To evaluate the clinical value of multidetector row computed tomography (MDCT) as a pre-operative staging tool for lymph node metastasis in patients with early gastric cancer (EGC). METHODS: In 278 consecutive patients with EGC, lymph node metastasis was evaluated pre-operatively with MDCT at a slice thickness of 2.5mm (n=57), 5.0mm (n=188), or 7.5mm (n=33). RESULTS: Overall accuracy of nodal category from N0 to N3 was 86% for MDCT and 95% for operative assessment. Regarding accuracy in detecting at least one metastatic lymph node, area under curves (AUC) of receiver operating characteristics for 2.5, 5.0, and 7.5-mm slices and assessment during surgery were 0.87, 0.67 and 0.47, and 0.70, which were significantly different (P<0.0001). MDCT image with 2.5-mm could discriminate the presence of lymph node metastasis with diagnostic accuracy: sensitivity 80%; specificity 92%; positive predictive value (PPV) 50%; negative predictive value (NPV) 98%, whereas assessment during surgery was as follows: sensitivity 65%; specificity 98%; PPV 72%; and NPV 97%. CONCLUSIONS: These results suggest that pre-operative assessment with MDCT using thinner slices may detect at least one lymph node metastasis as accurately as assessment during surgery for patients with EGC.

Adenocarcinoma↗

High incidence of lymph node metastasis in major salivary gland cancer.

OBJECTIVE: To analyze the incidence and risk factors for clinically apparent and occult lymph node metastases in patients with major salivary gland cancers. DESIGN: Cohort of patients with a median follow-up of 46 months (range, 1-174 months). SETTING: University-based referral center. PATIENTS: A total of 160 consecutive patients with complete clinical and pathologic data. INTERVENTION: Neck dissection was performed in all cases. Patients were treated with surgery alone (55%); surgery and radiation therapy (43%); or a combination of surgery, radiation, and chemotherapy (2%). MAIN OUTCOME MEASURE: Incidence of apparent and occult lymph node metastases. Univariate and multivariate analyses were used to evaluate the significance of clinical and pathologic data. RESULTS: Histologically confirmed positive neck was found in 53% of all cases. Histologic diagnosis was significantly related to the incidence of lymph node metastasis: 89% (16/18) for undifferentiated carcinomas. However, so-called low-risk tumors had incidence rates of 22% to 47%. Twenty-one patients (13%) presented with clinically apparent cervical lymph node metastasis. Of the 139 patients with clinical N0 neck, 45% had occult neck metastasis. Neck metastasis was found in 29% (10/34) of T1, 54% (38/70) of T2, 65% (20/31) of T3, and 54% (16/25) of T4 tumors. Assessment of survival according to nodal status revealed significant correlations for overall (P<.001) and disease-free survival (P<.001). CONCLUSIONS: We found a high incidence of lymph node metastasis from major salivary gland cancers. Neck dissections should be considered as an integral part of the surgical approach in patients with major salivary gland cancer, especially if no postoperative radiation therapy is planned.

Adenocarcinoma↗

Effect of radiotherapy on pelvic lymph node metastasis in cervical cancer stages IB2-IVA: a retrospective analysis of two comparative series.

Efficiency of radiotherapy in controlling lymph node metastasis is a controversial issue. A continuous series of 87 patients affected by cervical cancer stages IB2-IVA and treated using pelvic radiotherapy is presented. A retrospective comparison is made between two populations. In the two populations, a staging lymphadenectomy was carried out before the onset of the therapeutic program. In the first population (53 patients), the pelvic nodes only were dissected and in the second one (34 patients), the pelvic lymph nodes were left in place and the paraaortic nodes only were dissected. In both series, a completion surgery was performed after finalization of the radiotherapy. It was carried out at open abdomen in both series. It included a systematic pelvic dissection for the patients whose pelvic nodes had been intentionally left in place at the time of the initial staging lymphadenectomy. Both series were identical as far as classic risk factors were concerned (FIGO stage, maximal tumor diameter, lymphovascular space involvement). The radiotherapy administered to the pelvis was the same in both populations. The number of patients with pelvic lymph node metastasis was 21 (39.6%) in the first population versus 6 (17.6%) in the second one (P = 0.03). The percentage of positive lymph nodes among the retrieved lymph nodes was 18.94 in the first population versus 2.8 in the second one (P = 0.0001). Pelvic radiotherapy is likely to control most of the pelvic lymph node metastasis, but not all of them. Practical deductions and further developments are discussed.

Adult↗

Cyclophosphamide-dependent lymph node modification in lymph node metastasis of MM48 tumor cells in syngeneic mice.

We investigated the role of immunosuppressive activity induced in the regional lymph nodes (RLN, popliteal lymph nodes) in the establishment of lymph node metastasis by cyclophosphamide (CY) administration. The CY treatment led to the elimination of suppressive activity with the appearance of positive immune responses, and the inhibition of lymph node metastasis of MM48 tumor cells. In CY-treated mice, the removal of RLN together with the primary tumor lowered the survival rate compared with the mice in which the RLN remained intact. During 4 days after primary tumor resection, the proliferation of tumor cells in the RLN was significantly decreased in CY-treated mice. These results suggested that the induction of suppressive activity in the lymph node is closely associated with the establishment of lymph node metastasis.

Animals↗

Possible role of stromal-cell-derived factor-1/CXCR4 signaling on lymph node metastasis of oral squamous cell carcinoma.

We examined the role of chemokine signaling on the lymph node metastasis of oral squamous cell carcinoma (SCC) using lymph node metastatic (HNt and B88) and nonmetastatic oral SCC cells. Of 13 kinds of chemokine receptors examined, only CXCR4 expression was up-regulated in HNt and B88 cells. CXCR4 ligand, stromal-cell-derived factor-1alpha (SDF-1alpha; CXCL12), induced characteristic calcium fluxes and chemotaxis only in CXCR4-expressing cells. CXCR4 expression in metastatic cancer tissue was significantly higher than that in nonmetastatic cancer tissue or normal gingiva. Although SDF-1alpha was undetectable in either oral SCC or normal epithelial cells, submandibular lymph nodes expressed the SDF-1alpha protein, mainly in the stromal cells, but occasionally in metastatic cancer cells. The conditioned medium from lymphatic stromal cells promoted the chemotaxis of B88 cells, which was blocked by the CXCR4 neutralization. SDF-1alpha rapidly activated extracellular signal-regulated kinase (ERK)1/2 and Akt/protein kinase B (PKB), and their synthetic inhibitors attenuated the chemotaxis by SDF-1alpha. SDF-1alpha also activated Src family kinases (SFKs), and its inhibitor PP1 diminished the SDF-1alpha-induced chemotaxis and activation of both ERK1/2 and Akt/PKB. These results indicate that SDF-1/CXCR4 signaling may be involved in the establishment of lymph node metastasis in oral SCC via activation of both ERK1/2 and Akt/PKB induced by SFKs.

Animals↗

The development of a treatment model for lymph node metastasis in nude mice transplanted with rat fibrosarcoma clone A.

We have tried to establish a model for lymph node metastasis in nude mice transplanted with clone A of methylcholanthrene-induced rat fibrosarcoma. Tumor cells transplanted either subcutaneously or intrafootpad metastasized exclusively to the lymph nodes in nude mice treated with antiasialo GM1 antiserum. In the experiments of intrafootpad transplantation, all the mice died of disseminated lymph node metastasis if the leg was not resected, or was resected more than 3 weeks after the transplantation of clone A. Some mice whose legs were amputated 1 or 2 weeks after transplantation could be cured by amputation alone. The maximum effective dose of in vitro active drug could improve the survival in mice, and 3/5, 4/5, and 3/5 mice treated with MMC, ACNU and CDDP respectively were cured even if their legs were amputated 3 weeks after transplantation. This tumor-bearing animal system was considered to provide a valuable experimental model for lymph node metastasis.

Amputation, Surgical↗

p53 overexpression and proliferative activity do not correlate with lymph node metastasis in early gastric cancer.

We investigated p53 overexpression and the proliferative activity of the primary lesion as well as the clinicopathological features of 75 patients with gastric cancer invading the submucosa (sm cancer), of whom 14 (18.7%) had lymph node metastasis. Among the clinicopathologic features studied, only lymphatic invasion by the primary tumor was related to lymph node metastasis. There was no relationship between immunohistochemical staining for p53 protein or Ki-67 and lymph node metastasis. The p53-positive rate was 35.7 and 57.1% in patients with and without metastasis, respectively, while the mean Ki-67 labeling index was 38.9 and 38.1%, respectively. Our results suggest that p53 mutation or the proliferative activity of sm cancer do not influence lymph node metastasis, even though p53 mutation may enhance the proliferative activity and metastatic potential of advanced gastric cancer.

Adenocarcinoma↗