Predictive Histopathologic Factors for Lymph Node Metastasis in Patients With Nonpedunculated Submucosal Invasive Colorectal Carcinoma

PURPOSE Risk factors for lymph node metastasis in patients with nonpedunculated submucosal invasive colorectal carcinoma remain to be characterized. This study examines the relationship between lymph node metastasis and clinicopathologic factors in nonpedunculated submucosal invasive colorectal carcinoma.METHODS The study cohort comprised 155 patients who had undergone surgical treatment for nonpedunculated submucosal invasive colorectal carcinoma. The clinicopathologic factors investigated included gender, age, tumor location, macroscopic type, tumor size, histologic type and grade, intramucosal growth pattern, lymphatic invasion, venous invasion, degree of focal dedifferentiation at the submucosal invasive front, status of the remaining muscularis mucosa, and the depth and width of submucosal invasion.RESULTS Lymph node metastases were found in 19 patients (12.3 percent). Univariate analysis showed that lymphatic invasion, focal dedifferentiation at the submucosal invasive front, status of the remaining muscularis mucosa, and depth of submucosal invasion all had a significant influence on lymph node metastasis. Multivariate analysis showed lymphatic invasion (P = 0.014) and high-grade focal dedifferentiation at the submucosal invasive front (P = 0.049) to be independent factors predicting lymph node metastasis. No lymph node metastasis was found in tumors with a depth of submucosal invasion of <1.3 mm.CONCLUSIONS Lymphatic invasion and high-grade focal dedifferentiation at the submucosal invasive front are important predictors of lymph node metastasis in patients with nonpedunculated submucosal invasive colorectal carcinoma. Depth of submucosal invasion can be used as an identifying marker for patients who do not require subsequent surgery after endoscopic resection.Supported in part by a grant-in-aid for cancer research from the Ministry of Health and Welfare of Japan.     

MIXED INTESTINAL‐ AND DIFFUSE‐TYPE HISTOLOGY IS A RISK FACTOR FOR LYMPH NODE METASTASIS OF SUBMUCOSAL INVASIVE GASTRIC CANCER

Background: Endoscopic submucosal dissection is expected to increase the number of node‐negative submucosal invasive gastric cancers, particularly differentiated‐type adenocarcinomas that can be treated conservatively. Methods: Two hundred and seven consecutive surgically treated cases of differentiated‐type early gastric cancer with submucosal invasion were analyzed clinicopathologically. Comparison was made between patients with node‐positive (n = 33) and node‐negative cancer (n = 174). Whole sections of surgical specimens were reviewed and reclassified as pure intestinal type or mixed type. The intramucosal and submucosal components were also described histologically, and the depth of invasion from the muscularis mucosae as well as the width of submucosal invasion was measured. Results: Twenty‐four of 33 (73%) node‐positive cases were of the mixed type, whereas 71 of 174 (41%) node‐negative cases were of the mixed type (P < 0.01). As for the intramucosal histology, the ratio of mixed‐type was also higher in the node‐positive group (58% vs 34%; P < 0.05). Other factors associated with lymph node metastasis were larger tumor size (P = 0.003), deeper submucosal invasion (P < 0.001) and wider submucosal extension (P = 0.004), and lymphatic permeation (P < 0.001). Multivariate analysis demonstrated that lymphatic permeation (P = 0.001, OR 4.76), and mixed‐type histology (OR 2.56) were independent risk factors. Conclusions: Histological heterogeneity is a risk factor for metastasis of submucosal invasive gastric cancer to lymph nodes. Heterogeneity of mucosal components is also a significant risk factor and thus a good predictor of lymph node metastasis, potentially useful in distinguishing patients ineligible for conservative therapy.     

Predictive factors for lymph node metastasis in t1 stage colorectal Carcinomas

Purpose Selective endoscopie resection may cure early colorectal cancer (Tl), but the management is controversial. There is concern about the small risk of lymph node metastasis, which will not be treated by endoscopie resection alone. The authors sought predictive markers of lymph node metastasis to assist patient management. METHODS: The authors retrospectively analyzed consecutive cases of Tl stage colorectal cancer resected using endoscopie resection or bowel surgery over the period 1979 to 2000. The risk of lymph node metastasis was analyzed using logistic regression model for the markers selected by univariate analysis: the type of initial treatment, depth of submucosal invasion, lymphatic channel invasion, differentiation of histology, and invasive front histology. RESULTS: Two hundred seventy-eight patients were available for study. Twenty-one had lymph node metastasis. Depth of submucosal invasion (2 2,000 yum) and lymphatic channel invasion significantly predicted risk of lymph node metastasis in multivariate analysis. When these two factors were adopted for the prediction of lymph node metastasis, sensitivity, specificity, positive predictive value, and negative predictive value were 100, 55.6, 15.6, and 100 percent, respectively. CONCLUSIONS: Depth of submucosal invasion and lymphatic channel invasion were accurate predictive factors for lymph node metastasis. These two factors could be used in selecting appropriate cases for surgery after endoscopie resection. Poster presentation at meeting of the American Society of Colon and Rectal Surgeons, San Diego, California, June 2 to 7, 2001.     

Budding as a useful determinant of the optimal treatment for T1 rectal carcinomas

BACKGROUND/AIMS: If a locally excised specimen has poorly differentiated or undifferentiated histology, positive vascular invasion, or massive invasion to the cut end or a positive margin, additional surgery is recommended for the treatment of T1 rectal carcinoma. However, positive predictive values of these histological criteria are low. This study was undertaken to clarify more reliable risk factor(s) for lymph node metastasis in T1 rectal carcinomas. METHODOLOGY: In 58 patients with T1 rectal carcinoma undergoing local excision or radical surgery, the associations between lymph node metastasis or intrapelvic recurrence and clinicopathological features were studied using multiple regression analysis with special reference to tumor budding at the invasive front. RESULTS: Lymph node metastasis was observed in 1 of 9 patients undergoing additional bowel resection after local excision, and in 2 of 24 patients undergoing radical surgery alone. Intrapelvic extrarectal recurrence was observed in 3 of 25 patients undergoing local excision alone. Logistic regression analysis revealed that budding at the invasive front alone was significantly associated with lymph node metastasis or intrapelvic recurrence (p = 0.0484). CONCLUSIONS: Additional bowel resection with lymph node dissection should be recommended for locally excised T1 rectal carcinoma with budding at the invasive front.     

Endoscopically removed malignant colorectal polyps: Clinicopathologic correlations

Treatment options for patients with endoscopically removed malignant colorectal polyps are polypectomy alone vs. polypectomy followed by surgery. The aim of this study was to define histopathologic parameters that can be used for clinically relevant treatment decisions. Five pathologists evaluated 140 polyps for the presence or absence of unfavorable histology. Unfavorable histology was tumor at or near (≤1.0 mm) the margin and/or grade III and/or lymphatic and/or venous invasion. Adverse outcome was recurrent and/or local cancer and/or lymph node metastasis. Adverse outcome was 19.7% (14 of 71), 8.6% (2 of 23), and 0% (0 of 46) when unfavorable histology was present, indefinite (lack of agreement), and absent, respectively (P < 0.0005, present vs. absent). Four patients with cancer >1.0 mm from the margin had an adverse outcome (2 with lymphatic invasion and 2 indefinite for lymphatic invasion). Four patients with negative resections later developed distant metastases. Eight patients (6.3%) died of disease, and 2 of 69 without unfavorable histology (both indefinite for lymphatic invasion) had an adverse outcome. Interobserver strength of agreement was substantial to almost perfect for margin, grade, and venous invasion and fair to substantial for lymphatic invasion. This system is usable clinically. Patients with unfavorable histology are probably best managed by resection postpolypectomy, whereas in the absence of unfavorable histology, they probably can be treated by polypectomy only.     

Lymphatic Vessel Density at the Site of Deepest Penetration as a Predictor of Lymph Node Metastasis in Submucosal Colorectal Cancer

Purpose Lymph node metastasis is an important factor that influences curability after endoscopic treatment of submucosal colorectal cancer. This study was designed to determine the usefulness of identification of lymphatic vessels by immunohistochemistry in predicting lymph node metastasis of submucosal colorectal cancer. Methods Lymphatic involvement was assessed by hematoxylin and eosin staining and podoplanin immunostaining on samples resected from 268 patients with submucosal colorectal cancer. Lymphatic vessel density was estimated by two investigators by average count of three fields (×200) in the area of greatest number of podoplanin-positive capillaries at the site of deepest submucosal penetration. Relations with other clinicopathologic parameters also were investigated. Results Lesions with high lymphatic vessel density (≥9 vessels per field) showed a significantly greater incidence of lymph node metastasis than did those with low lymphatic vessel density (<9 vessels per field; 23.3 vs. 8.4 percent). By multivariate analysis, lymphatic vessel density was determined to be an independent risk factor for lymph node metastasis of submucosal colorectal cancer (P = 0.0044). Lymphatic vessel density also correlated with tumor budding and the degree of inflammation at the invasive front. Conclusions Identification of lymphatic vessels by podoplanin immunostaining provides objective and accurate evaluation of lymphatic involvement. Lymphatic vessel density at the site of deepest penetration is a useful predictor of lymph node metastasis of submucosal colorectal cancer. Supported by a grant from the Japanese Society of Gastroenterological Endoscopy, Chugoku Branch. Presented at the meeting of The Japanese Society of Gastroenterology, Kokura, Fukuoka, Japan, April 20 to 22, 2006. Reprints are not available.     

Predictive factors for lymph node metastasis of differentiated submucosally invasive gastric cancer

BACKGROUND: For early gastric cancer, submucosal invasion may be unrecognized until histopathologic examination of the specimen obtained by EMR. Gastrectomy with lymphadenectomy is the standard treatment for such submucosal cancers. However, approximately 80% of submucosal cancers do not have lymph node metastasis. Unnecessary surgery could be avoided if a subgroup of patients with submucosal cancer with negligible risk of lymph node metastasis can be defined. This study was conducted to define such a subgroup. METHODS: Data from 104 patients surgically treated for differentiated submucosal cancers were retrospectively collected. A multivariate analysis of clinicopathologic factors was performed to identify predictive factors for lymph node metastasis. RESULTS: Three independent risk factors, namely, female gender (p=0.0174), deep invasion (> or =500 microm) into the submucosal layer (p=0.001), and presence of lymphatic involvement (p < 0.0001) were associated with lymph node metastasis. Lymph node metastasis was not observed in any patient who had limited submucosal invasion and absence of lymphatic involvement. The rate of lymph node metastasis was calculated to be 80% in patients who had both deep submucosal invasion and lymphatic involvement. CONCLUSIONS: If endoscopic resection specimens exhibit no deep penetration (<500 microm) into the submucosal layer and lymphatic involvement is absent, EMR may be sufficient treatment for submucosal well-differentiated early gastric cancers. A long-term follow-up study of patients with such lesions treated by EMR alone is required.     

Endoscopic treatment of submucosal invasive colorectal carcinoma with special reference to risk factors for lymph node metastasis

A clinicopathological analysis of the risk factors for lymph node metastasis was performed in 177 patients with submucosal invasive colorectal carcinoma (CRC). The submucosal deepest invasive portion was histologically subclassified as well (W), moderately (M), or poorly (Por) differentiated. M type was further subdivided into moderately-well (Mw) and moderatelypoorly (Mp) differentiated. The pattern of tumor growth was classified as polypoid growth (PG) and non-polypoid growth (NPG). Lymph node metastasis was detected in 21 (12%) of the 177 patients. Macroscopically, type IIc and IIa+IIc lesions showed a significantly higher incidence of lymph node metastasis (44% and 30%) than type IIa and I (4% and 8%). Regarding the histologic subclassification, Por and Mp lesions showed a significantly higher incidence of lymph node metastasis (67% and 37%) than W and Mw lesions (4% and 14%). NPG tumors showed a significantly higher incidence of lymph node metastasis (29%) than PG tumors (7%). The depth of submucosal invastion and lymphatic invasion (ly) were also significantly correlated with incidence of lymph node metastasis (submucosal scanty (sm-s) invasion 4%, massive invasion 20%; ly(+) 23%, ly(?) 5%). None of the lesions with both sm-s invasion and of W or Mw type showed lymph node metastasis. These results indicate that submucosal invasive CRC with both sm-s invasion and of W or Mw type, which shows no ly, is the appropriate indication for endoscopic curative treatment.     

Lymph node metastasis in early gastric cancer with submucosal invasion： Feasibility of minimally invasive surgery

AIM:To explore the feasibility of performing minimally invasive surgery(MIS) on subsets of submucosal gastric cancers that are unlikely to have regional lymph node metastasis.METHOPS:A total of 105 patients underwent radical gastrectomy with lymph node dissection for submucosal gastric cancer at our hospital from January 1995 to December 1995,Besides investigating many clinicopathological features such as tumor size,gross appearance,and differentiation,we measured the depth of invasion into submucosa minutely and analyzed the clinicopathologic features of these patients regarding lymph node metastasis.RESULTS:the rate of lymph node metastasis in cases where the depth of invasion was&lt;500μm,500-200μm,or&gt;2000μm was 9% (2/23),19%(7/36),and 33%(15/46),respectively(P&lt;0.05).In univariate analysis,no significant correlation was found between lymph node metastasis and clinicopathological characteristics such as age,sex,tumor location,gross appearance,tumor differentiation,Lauren‘s classification,and lymphatic invasion,In multivariate analysis,tumor size(&gt;4cm vs≤2cm,odds ratio=4。80,P=0.04)and depth of invasion(&gt;2000μm vs ≤500μm,odds ratio=6.81,P=0.02)were significantly correlated with lymph node metastasis,Combining the depth and size in cases where the depth of invasion was less than 500μm,we found that lymph node metastasis occurred where the tumor size was greater than 4 cm.In cases where the tumor size was less than 2 cm,lymph node metastasis was found only where the depth of tumor invasion was more than 2000μm.CONCLUSION:MIS can be applied to submucosal gastric cancer that is less than 2 cm in size and 500μm in depth.     

Lymphatic Microvessel Density is an Independent Prognostic Factor in Colorectal Cancer

Purpose Although lymph node metastasis via lymphatic vessels often is related with an adverse outcome, it is not well known whether lymphatic spread to lymph node needs the development of the new lymphatic formation. In addition, the correlation between lymphangiogenesis and prognosis has not been well documented. This study was designed to assess the prognostic value of lymphangiogenesis and lymphatic vessel invasion in colorectal cancer. Methods We examined 106 colorectal cancer specimens by immunostaining for podoplanin, lymphatic endothelial specific marker. We evaluated lymphangiogenesis, as measured by lymphatic microvessel density, and lymphatic vessel invasion. We next investigated the association of these two parameters with the clinicopathologic findings and prognosis. Results A significant correlation was observed between high lymphatic microvessel density and positive lymphatic vessel invasion (P = 0.0003). Positive lymphatic vessel invasion was significantly associated with the presence of lymph node metastasis (P = 0.0071). The survival curves demonstrated that both high lymphatic microvessel density and positive lymphatic vessel invasion were correlated with an adverse outcome (P = 0.0004 and P = 0.009, respectively). In a univariate analysis, high lymphatic microvessel density and positive lymphatic vessel invasion were negatively associated with the overall survival (P = 0.0011 and P = 0.0118, respectively). Furthermore, high lymphatic microvessel density, but not lymphatic vessel invasion, correlated with a poor outcome in a multivariate analysis (P = 0.0114). Conclusions Our data suggested that lymphatic vessel invasion was related with lymph node metastasis and that both lymphatic microvessel density and lymphatic vessel invasion were related with an adverse outcome in colorectal cancer. Furthermore, lymphatic microvessel density may be a useful prognostic factor in colorectal cancer. *Deceased. The Poster presentation at the meeting of the Japanese Society of Gastroenterology, Sapporo, Japan, October 11 to 14, 2006. Reprints are not available.     

Risk factors for lymph node metastasis of submucosal invasive differentiated type gastric carcinoma: clinical significance of histological heterogeneity

Background. The use of endoscopic resection for submucosal invasive gastric carcinoma (Sm-ca) with histologically differentiated type has been expected. However, the treatment criteria remain controversial. The purpose of this study was to clarify the relationship between lymph node metastasis and the histologic features of differentiated Sm-ca. Methods. The clinicopathologic features of 35 patients with node-positive differentiated Sm-ca were compared with those of 221 patients with node-negative differentiated Sm-ca by multivariate analysis with logistic regression. To clarify the metastatic behavior of differentiated Sm-ca, we examined mucin-histochemical expression and immunohistochemical staining, using Ki-67, p53, and c-erbB2. Results. The rate of lymph node metastasis was significantly higher in differentiated Sm-ca with histologi-cal heterogeneity (combined differentiated type, with poorly differentiated component) than in that without histological heterogeneity (27% vs 7%; P < 0.001). Multivariate analysis revealed that lymphatic vessel invasion was the most significant determinant (odds ratio, 8.68) for lymph node metastasis. Histological heterogeneity (odds ratio, 3.88) was next, followed by papillary adenocarcinoma (odds ratio, 3.28), and submucosal invasion level (odds ratio, 2.34). The mean value of the Ki-67 labeling index for node-positive differentiated Sm-ca was higher than that of node-negative differentiated Sm-ca (47% vs 39%; P < 0.05). Conclusions. When the extension of endoscopic surgery to differentiated Sm-ca is considered, this therapeutic technique should be limited to the differentiated type of Sm-ca without histological heterogeneity. The Ki-67 labeling index provides useful information for identifying those patients with a high risk of lymph node metastasis. Received: January 9, 2001 / Accepted: April 13, 2001     

Immunohistochemical molecular markers as predictors of curability of endoscopically resected submucosal colorectal cancer

AIM： To clarify the usefulness of immunohistochemical molecular markers in predicting lymph node metastasis of submucosal colorectal cancer.
METHODS： We examined microvessel density, lymphatic vessel density, the Ki-67 labeling index, expression of MUC1 and Matrix metalloproteinase-7 （MMP-7） in tumor cells, and expression of cathepsin D in stromal cells at the invasive front by immunostaining of samples resected from 214 patients with submucosal colorectal cancer. Pathologic features were assessed on hematoxylin-eosinstained samples. We evaluated the relations between clinicopathologic/immunohistochemical features and lymph node metastasis.
RESULTS： Lesions of the superficial type, with an unfavorable histologic grade, budding, lymphatic involvement, high microvessel density （≥ 40）, high lymphatic vessel density （≥9）, high Ki-67 labeling index （≥ 42）, and positivity of MUC1, cathepsin D, and MMP-7 showed a significantly high incidence of lymph node metastasis. Multivariate analysis revealed that high microvessel density, unfavorable histologic grade, cathepsin D positivity, high lymphatic vessel density, superficial type, budding, and MUC1 positivity were independent risk factors for lymph node metastasis.A combined examination with four independent immunohistochemical markers （microvessel density, cathepsin D, lymphatic vessel density, and MUC1） revealed that all lesions that were negative for all markers or positive for only one marker were negative for lymph node metastasis.
CONCLUSION： Analysis of a combination of immuno- histochemical molecular markers in endoscopically resected specimens of submucosal colorectal cancer allows prediction of curability regardless of the pathologic features visible of hematoxylin-eosin-stained sections.     

Clinical utility of grading criteria for submucosal invasion in the prognosis of T1 colorectal carcinomas

Background: The clinical utility of relative and absolute grading criteria for submucosal invasion in T1 colorectal carcinomas has been controversial. Methods: In 51 T1 colorectal carcinomas, depth of submucosal invasion was graded either according to a modified Haggitt's classification (a relative criterion) or by direct measurement using a micrometer (an absolute criterion), and immunostaining for E-cadherin, α-catenin, β-catenin, matrilysin, and CD44 variant 6 was performed on formalin-fixed, paraffin-embedded sections. The associations between lymph node metastasis or local recurrence (locoregional failure) and tumor budding, and clinicopathologic parameters and immunoreactivity were examined statistically. Results: By univariate analysis, tumor budding, histology, and the co-expression pattern of nuclear β-catenin and CD44 variant 6 were significantly associated with locoregional failure. The relative and absolute grading of submucosal invasion were not significantly associated with locoregional failure. Multivariate analysis showed that tumor budding alone was significantly associated with locoregional failure, and the association between the co-expression pattern of nuclear β-catenin and CD44 variant 6, and locoregional failure was marginally significant (P = 0.0502). Lymphatic invasion and absolute grading of depth and width of submucosal invasion were significantly associated with tumor budding, and the associations between tumor budding, and histologic differentiation and membranous α-catenin expression were marginally significant (P = 0.06; P = 0.08), whereas, a relative grading of submucosal invasion was not significant (P = 0.58). Analysis of variance showed that histologic differentiation and lymphatic invasion were independently and significantly associated with tumor budding (P = 0.005; P < 0.001). Conclusions: These results suggest that the grading of submucosal invasion, either relative or absolute, may not be a useful risk factor for lymph node metastasis or local recurrence in T1 colorectal carcinomas. Received: January 16, 2002 / Accepted: May 17, 2002 Acknowledgements. We thank Drs. Y. Shimada, K. Nunomura, and S. Uchiyama for providing tissue blocks. For expert technical assistance we thank Ms. N. Shiota and Ms. K. Ooshima. Reprint requests to: T. Masaki     

Evaluation of Tumor Cell Dissociation as a Predictive Marker of Lymph Node Metastasis in Submucosal Invasive Colorectal Carcinoma

PURPOSE Tumor cell dissociation—the histologic finding of small solid carcinoma cell clusters and groups of dissociated dedifferentiated carcinoma cells at the invasive front–is related to tumor metastasis and patient prognosis. However, few previous reports have examined tumor cell dissociation in submucosal invasive colorectal carcinoma. We investigated the relation between tumor cell dissociation and lymph node metastasis in submucosal invasive colorectal carcinoma. We also examined immunohistochemical expression of E-cadherin and beta-catenin in submucosal invasive colorectal carcinoma.METHODS Submucosal invasive colorectal carcinoma tissue samples from 20 patients with lymph node metastasis and 100 patients without lymph node metastasis were evaluated. Sections stained with hematoxylin and eosin were evaluated for tumor cell dissociation. Immunohistochemistry was used to determine the expression and cellular distribution of E-cadherin and beta-catenin.RESULTS Tumor cell dissociation was more frequently identified in submucosal invasive colorectal carcinoma cases with lymph node metastasis than in those without lymph node metastasis (P = 0.0001). Decreased membranous expression of E-cadherin occurred more frequently in submucosal invasive colorectal carcinoma cases with lymph node metastasis than in those without lymph node metastasis (P = 0.025). Nuclear expression of beta-catenin tended to be present in submucosal invasive colorectal carcinoma cases with lymph node metastasis (P = 0.063). Decreased membranous expression of E-cadherin occurred more frequently in submucosal invasive colorectal carcinoma cases with tumor cell dissociation than in those without tumor cell dissociation (P = 0.0023).CONCLUSIONS Our results suggest that there is a relation between tumor cell dissociation and lymph node metastasis in submucosal invasive colorectal carcinoma. Tumor cell dissociation formation might be related to abnormal expression patterns of E-cadherin and beta-catenin in submucosal invasive colorectal carcinoma. Tumor cell dissociation and decreased membranous expression of E-cadherin would be important predictive markers for lymph node metastasis in submucosal invasive colorectal carcinoma.Presented at the 93rd Japanese Society of Pathology, Sapporo, Japan, June 9 to 11, 2004.     

Clinicopathological features,diagnosis, and treatment of sessile serrated adenoma/polyp with dysplasia/carcinoma

Sessile serrated adenoma/polyps (SSA/Ps) are early precursor lesions in the serrated neoplasia pathway, which results in BRAF‐mutated colorectal carcinomas with not only high levels of microsatellite instability but also microsatellite stable. SSA/Ps with advanced histology, including cytological dysplasia or minimally invasive carcinomas, are important lesions because SSA/Ps are considered major contributors to “interval cancers” and these lesions can rapidly become dysplastic or invasive carcinomas. Clinicopathologically, SSA/Ps with dysplasia or invasive carcinoma were associated with advanced age, female sex, and proximal colon. Although SSA/Ps with submucosal invasive carcinoma were smaller and invaded less deeply into the submucosal layer than conventional tubular adenomas with submucosal invasive carcinoma, SSA/Ps with submucosal invasive carcinoma frequently had a mucinous component and exhibited a higher potential for lymphatic invasion and lymph node metastasis. In an SSA/P series, endoscopic characteristics, including (semi)pedunculated morphology, double elevation, central depression, and reddishness, may help accurately diagnose SSA/Ps with advanced histology. Removal of SSA/Ps with dysplasia or invasive carcinoma was recommended. Endoscopic treatment such as endoscopic mucosal resection or endoscopic submucosal dissection is useful for those lesions. However, surgical resection with lymph node dissection might be indicated when SSA/Ps with invasive carcinoma are endoscopically suspected, because these have the high risk of lymph node metastasis. Greater awareness may promote further research into improving the detection, recognition, and complete resection rates of SSA/Ps with dysplasia or invasive carcinoma and reduce the interval cancer rates.     

Risk Factors for Occult Lymph Node Metastasis of Colorectal Cancer Invading the Submucosa and Indications for Endoscopic Mucosal Resection

Purpose Although risk factors for histologically overt lymph node metastasis in patients with early-stage colorectal cancer have been clarified, the risk factors for occult lymph node metastasis are not clear. This study was designed to clarify risk factors for lymph node metastasis, including occult metastasis, in patients with colorectal cancer invading the submucosa and to determine the criteria for endoscopic resection of early colorectal cancer. Methods The risk factors for lymph node metastasis, including occult metastasis, were analyzed in 86 cases of surgically resected colorectal cancer invading the submucosa. The lymph nodes were assessed by immunohistochemistry with cytokeratin antibody CAM5.2. Results The frequencies of overt and occult metastasis to the lymph nodes were 13 percent (11/86) and 13 percent (10/75), respectively. Multivariate analysis showed vascular invasion (P = 0.001) and tumor budding (P = 0.003) to be independent risk factors for lymph node metastasis, including occult metastasis. For tumors with submucosal invasion ≤1,000 μm, no lymph node metastasis was found. The frequencies of lymph node metastasis for tumors with submucosal invasion of 1,000 to 2,000 μm and >2,000 μm were 21 and 37 percent, respectively. In considering combinations of risk factors, there was no lymph node metastasis in tumors having neither vascular invasion nor tumor budding and submucosal invasion of ≤3,000 μm. Conclusions Vascular invasion, tumor budding, and the degree of submucosal invasion were significant risk factors for lymph node metastasis, including occult metastasis. These three factors can be used in combination to identify patients requiring additional surgery after endoscopic resection. Supported in part by a Grant-in-Aid for Scientific Research (no. 15390401) from the Japanese Ministry of Education, Science, and Culture. Presented at the Congress of Japan Surgery Society, Tokyo, Japan, March 29 to 31, 2006. Reprints are not available.     

Expression of urokinase-type plasminogen activator receptor and plasminogen activator inhibitor-1 in gastric cancer

In gastric cancer, the urokinase-type plasminogen activator (uPA) system plays important roles in invasion and metastasis, processes which entail proteolysis and adhesion. Both the urokinasetype plasminogen activator receptor (uPAR) and the plasminogen activator inhibitor-1 (PAI-1) are thought to be important factors in this system. To clarify the relationship between these two factors and gastric cancer invasiveness, we evaluated the expression of uPAR and PAI-1 in 91 cases of gastric cancer by immunohistochemistry and in situ hybridization. Urokinase-type plasminogen activator receptor-mRNA, PAI-1-mRNA, uPAR and PAI-1 protein were diffusely distributed in the cytoplasm of the cancer cells and concentrated at invasive foci. Urokinase-type plasminogen activator receptor protein expression correlated with lymphatic, venous invasion (P<.01) and lymph node metastasis (P<0.05); uPAR-mRNA expression correlated with lymphatic, venous invasion and lymph node metastasis (P<0.05). Plasminogen activator inhibitor-1 protein expression correlated with lymphatic, venous invasion, lymph node metastasis and depth of invasion (P<0.01); PAI-1-mRNA expression was linked to lymphatic, venous invasion (P<0.01), lymph node metastasis and depth of invasion (P<0.05). This suggests that the proteolytic activity of uPAR and the cellular motility of PAI-1 in gastric cancer cells may determine penetration of lymphatic and blood vessels, whereby lymph node metastasis may be promoted and that the promotion of cellular motility by PAI-1 may influence the depth of cancer invasion.     

Predictive factors for lymph node metastasis and endoscopic treatment strategies for undifferentiated early gastric cancer

Background and Aim: Although more than 80% of undifferentiated early gastric cancers (EGC) are not associated with lymph node metastasis, endoscopic mucosal resection is not generally accepted as a means of curative treatment because of an abundance of conflicting data concerning clinicopathological characteristics and prognoses. The aim of this study was to define a subgroup of undifferentiated EGC that could be cured by endoscopic treatment without the risk of lymph node metastasis. Method: A total of 591 patients surgically resected for undifferentiated EGC between January 1999 and March 2005 were reviewed. Associations between various clinicopathological factors and the presence of lymph node metastasis were analyzed to identify the risk factors of lymph node metastasis. Results: Lymph node metastasis was found in 79 patients (13.4%). By multivariate logistic regression analysis, a tumor diameter 2.5 cm or larger, invasion into the middle third of the submucosal layer or deeper, and lymphatic involvement were identified as independent risk factors of lymph node metastasis (P < 0.001, respectively). Lymph node metastasis was not found in any patient with undifferentiated EGC smaller than 2.5 cm confined to the mucosa or upper third of the submucosal layer without lymphatic involvement. Conclusions: Undifferentiated intramucosal EGC smaller than 2.5 cm without lymphatic involvement was not associated with lymph node metastasis. Thus, we propose in this circumstance that endoscopic mucosal resection could be considered a definitive treatment without compromising the possibility of cure.     

T1期直肠癌淋巴结转移相关临床病理因素分析

目的研究与T1期直肠癌淋巴结转移相关的临床病理因素,为临床医生选择适当的治疗方式及判断预后提供依据。 方法本研究选取T1期直肠癌病例,分析相关临床和组织病理学指标与淋巴结转移、远处转移和生存的关系。 结果共计251例根治性手术切除的连续性T1期直肠癌病例,淋巴结转移率11.2%（28/251）。3年、5年和10年的总生存率分别为98.6%、96.8%和94.9%。有淋巴结转移的病例3年、5年和10年的总生存率分别为100%、95.6%和90.9%;无淋巴结转移的病例3年、5年和10年的总生存率分别为99%、96.9%和95.4%,高于有淋巴结转移组,但差异无统计学意义。单因素分析显示患者的年龄（P=0.05）、腺瘤背景（P<0.01）、组织学分化（P<0.01）、筛状结构（P=0.03）、低分化肿瘤细胞簇（PDC）（P=0.02）、肿瘤出芽（TB）（P=0.01）、淋巴管血管侵犯（LVI）（P<0.01）、黏膜下静脉侵犯（VI）（P<0.01）、浸润深部腺体类型（P=0.04）与淋巴结转移有关。多因素logistic回归分析显示患者年龄（P=0.02）、腺瘤背景（P<0.01）、组织学分化（P=0.04）、黏膜下静脉侵犯（P=0.02）是淋巴结转移的危险因素。单因素分析显示肿瘤浸润最深处的腺体为开放型与淋巴结转移相关（P=0.04）。腺体的开放型还显示与肿瘤大体平坦型（P=0.03）、无腺瘤背景（P=0.03）、黏膜肌完全消失（P=0.05）、高级别肿瘤出芽（P <0.001）和肿瘤内坏死（P<0.001）有关。 结论本项研究验证了多种已知的组织学特征与T1期直肠癌淋巴结转移的相关性,并且提出了筛状结构、腺体为开放型与淋巴结转移相关。     

Expression of vascular endothelial growth factor C and chemokine receptor CCR7 in gastric carcinoma and their values in predicting lymph node metastasis

AIM: To study the expression of vascular endothelial growth factor C (VEGF-C) and chemokine receptor CCR7 in gastric carcinoma and to investigate their associations with lymph node metastasis of gastric carcinoma and their values in predicting lymph node metastasis. METHODS: The expression of VEGF-C and CCR7 in gastric carcinoma tissues obtained from 118 patients who underwent curative gastrectomy was examined by immunohistochemistry. Among these patients, 39 patients underwent multi-slice spiral CT (MSCT) examination. RESULTS: VEGF-C and CCR7 were positively expressed in 52.5 and 53.4% of patients. VEGF-C expression was more frequently found in tumors with lymph node metastasis than those without it (P<0.001). VEGF-C expression was also closely related to lymphatic invasion (P<0.001), vascular invasion (P<0.01), and TNM stage (P<0.001). However, there was no significant correlation between VEGF-C expression and age at surgery, gender, tumor size, tumor location, Lauren classification, and depth of invasion. CCR7 expression was significantly higher in patients with lymph node metastasis compared with those without lymph node metastasis (P<0.001) and was also associated with tumor size (P<0.01), depth of invasion (P<0.001), lymphatic invasion (P<0.001), and TNM stage (P<0.001). However, the presence of CCR7 had no correlation to age at surgery, gender, tumor location, Lauren classification, and vascular invasion. Among the 39 patients who underwent MSCT examination, only CCR7 expression was related to lymph node metastasis determined by MSCT (P<0.05). In the current retrospective study, the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of VEGF-C and CCR7 expression in the diagnosis of lymph node metastasis for patients with gastric carcinoma were 73.8%, 70.2%, 72.6%, 71.4% and 72.0%, and 82.0%, 77.2%, 79.4%, 80.0% and 79.7%, respectively. After subdivision according to the combination of VEGF-C and CCR7 expression, receiver operating characteristic (ROC) analysis showed that the accuracy of the combined examination of VEGF-C and CCR7 expression in predicting lymph node metastasis was relatively high (area under ROC curve [Az]=0.83). CONCLUSION: The expression of VEGF-C and CCR7 is related to lymph node metastasis of gastric carcinoma and both of them may become new targets for the treatment of gastric carcinoma. Furthermore, the combined examination of VEGF-C and CCR7 expression in endoscopic biopsy specimens may be useful in predicting lymph node metastasis of gastric carcinoma and deciding the extent of surgical lymph node resection.