Histopathologic characteristics of colorectal cancer with liver metastasis

PURPOSE: Although prognostic factors of colorectal cancer have been studied, factors associated with liver metastasis have not been fully investigated. The aim of this study was to clarify the histopathologic characteristics of colorectal cancer with liver metastasis. METHODS: We performed a retrospective histopathologic study on 335 patients who underwent resection of colorectal cancer during 15 years. Histopathologic parameters of tumors with liver metastasis were compared with those without liver metastasis. RESULTS: Forty-one patients (12 percent) had simultaneous liver metastasis. Tumors having liver metastasis, when compared with those not having liver metastasis, were characterized by high frequency of tumor size more than 6 cm (51vs. 28 percent;P<0.01), presence of serosal invasion (98vs. 66 percent;P<0.01), lymphatic invasion (34vs. 15 percent;P<0.01), venous invasion (24vs. 3 percent;P<0.01), and lymph node metastasis (85vs. 39 percent;P<0.01). Multivariate analysis showed that factors independently associated with liver metastasis were serosal invasion, venous invasion, and lymph node metastasis. Accuracy in the diagnosis of liver metastasis was highest for venous invasion (88 percent) and lowest for serosal invasion (41 percent). Among 98 patients with both serosal invasion and lymph node metastasis, tumors with and without liver metastasis were different in frequency of venous invasion (26vs. 6 percent;P<0.01) and extracolic lymph node metastasis (68vs. 47 percent;P<0.05). CONCLUSION: In colorectal cancer important factors associated with liver metastasis were serosal invasion, venous invasion, and lymph node metastasis. Significant determinants for liver metastasis from colorectal cancer were venous invasion and extracolic lymph node metastasis.Presented at the meeting of The Japanese Society for Cancer of the Colon and Rectum, Tokyo, Japan, July 4, 1997.     

Higher frequencies of numerical aberrations of chromosome 17 in primary gastric cancers are associated with lymph node metastasis

We investigated the correlation between the frequency of numerical aberrations of chromosome 17 and clinicopathological features of gastric cancer. The copy number of chromosome 17 was examined with fluorescence in-situ hybridization (FISH) in frozen specimens from 100 primary gastric cancers. Chromosomal numerical aberrations were diagnosed as chromosomal loss (single signal) or gain (triple or more signals), in each cell. The frequency of numerical aberrations of chromosome 17 correlated significantly with the depth of invasion (P < 0.01), lymph node metastasis (P < 0.0001), lymphatic invasion (P < 0.001), and venous invasion (P < 0.01). Numerical aberrations of chromosome 17 were associated with lymph node metastasis in 32 early gastric cancers. Multiple regression analysis identified the depth of invasion and numerical aberrations of chromosome 17 as independent significant determinants of lymph node metastasis. Our findings suggest that alterations in chromosome 17 may be linked with tumor progression in primary gastric cancer. Our results also indicate that numerical aberrations of chromosome 17 detected by FISH provide important information about the malignant potential (in particular, lymph node metastasis) of primary gastric cancer. (Received Feb. 22, 1998; accepted July 24, 1998)     

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     

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.     

Risk of Second Cancers in Patients with Colorectal Carcinoids

INTRODUCTION: It is often stated that patients with colorectal carcinoid tumors have an increased risk of developing other malignancies. However, this risk has not been conclusively documented. A comprehensive evaluation is needed to more thoroughly assess the risk of second cancers in patients with colorectal carcinoids. METHODS: A search of the National Cancer Institute Surveillance, Epidemiology, and End Result database from 1973 to 1996 revealed 2,086 patients with colorectal carcinoids. This subset of patients was examined for occurrence of second cancers. The observed incidence of cancer for each site was compared with the expected incidence based on the gender-adjusted and age-adjusted cancer rates in the remaining Surveillance, Epidemiology, and End Result file. A Poisson distribution probability was used to determine the significance of these comparisons. RESULTS: Patients with colorectal carcinoids had an increased rate of cancer in the colon and rectum (P < 0.001), small bowel (P < 0.001), esophagus/stomach (P = 0.02), lung/bronchus (P < 0.001), urinary tract (P = 0.005), and prostate (P < 0.001), when compared with a control population. Most of the gastrointestinal tract cancers were synchronous cancers, whereas lesions outside the gastrointestinal tract were most commonly metachronous tumors. CONCLUSIONS: A significantly increased risk of synchronous colorectal, small-bowel, gastric, and esophageal cancers and metachronous lung, prostate, and urinary tract neoplasms is clearly demonstrated. After the diagnosis of colorectal carcinoid tumors, patients should undergo appropriate screening and surveillance for cancer at these sites.     

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 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.     

Comparison between `in vivo' and `in vitro' methods for evaluating tumor angiogenesis using cervical carcinoma as a model

The role of angiogenesis in tumorigenesis is widely accepted. Therefore, it is mandatory to develop a clinically useful method for assessing tumor angiogenesis. This study was designed to compare the `in vivo' and `in vitro' methods for assessing angiogenesis and to evaluate their clinical application using cervical carcinoma as a model. Ninety women with stages IB-IIA cervical carcinoma exhibiting visible cervical tumors by transvaginal ultrasound were enrolled in this study. All patients underwent radical abdominal hysterectomy and pelvic lymph node dissection. Vascularity index (VI) was assessed by power Doppler ultrasound and a quantitative image processing system. The microvessel density (MVD) of the excised tumors was immunohistochemically assessed. Both the enzyme immunoassay and immunohistochemistry methods were performed for assessing the protein levels of vascular endothelial growth factor (VEGF) in tumor tissues. Significantly higher VI, MVD and cytosol VEGF concentrations were detected in tumors with deep stromal invasion (≥1/2 thickness) (11.43 ± 7.25 vs. 5.87 ± 6.81, P < 0.001; 53.0 vs. 37.0, P = 0.006, 550.0 vs. 86.0 pg/mg, P < 0.001), lymphatic invasion (12.21 ± 7.89 vs. 6.86 ± 6.29, P < 0.001; 53.0 vs. 40.0, P = 0.038; 930.0 vs. 110.0 pg/mg, P = 0.002), and pelvic lymph node metastasis (17.15 ± 8.58 vs. 7.83 ± 6.41, P < 0.001; 54.0 vs. 39.0, P = 0.02; 964.0 vs. 131.0 pg/mg, P = 0.002). VEGF-rich tumors detected by immunohistochemistry also revealed higher VI (12.26 ± 7.96 vs. 8.05 ± 7.62, P = 0.012), MVD (53.0 vs. 37.5, P = 0.01) and cytosol VEGF levels (745.0 vs. 98.0 pg/mg, P = 0.002). The relationships between VI values, MVD values and cytosol VEGF concentrations were linear (VI vs. MVD, r = 0.38, P < 0.001; VI vs. VEGF, r = 0.78, P < 0.001; MVD vs. VEGF, r = 0.29, P = 0.006). As revealed by the receiver operating characteristic (ROC) curve analysis, VI is better than MVD and VEGF in predicting lymph node metastasis. In conclusion, there is histological, molecular and clinical evidence supporting VI as a useful `in vivo' indicator of tumor angiogenesis, particularly for predicting lymph node metastases in cervical carcinomas. This revised version was published online in June 2006 with corrections to the Cover Date.     

Direct Tumor Invasion in Colon Cancer: Correlation with Tumor Spread and Survival

Purpose  This study examined the correlation between depth of local invasion in colon cancer and tumor spread and patient survival. Methods  A cohort of 796 patients with a complete set of TNM staging information following an elective resection for colon cancer was selected. The rates of lymph node and distant metastasis, tumor differentiation, and extramural venous invasion for different tumor (T) categories were compared. The effects of initial tumor (T) category on overall patient survival were studied. Results  The depth of local tumor invasion correlated strongly with nodal involvement (P = 0.0001), rates of extramural venous invasion (P = 0.0002), poor differentiation (P = 0.0001), and distant metastasis (P = 0.0001). Fifty-seven percent of the patients remained lymph node-negative and distant metastasis-negative irrespective of their depth of tumor invasion had no impact on overall survival (P = 0.49). For patients with lymph node or distant metastasis (43 percent), depth of tumor invasion had significant impact on overall survival (P = 0.001). Thirteen percent of T3N1, 33 percent of T3N2, 40 percent of T4N1, and 68.percent of T4N2 cases had distant metastasis at presentation. Conclusion  Two types of colon cancer were observed: locally active and tendency to metastasize. For the latter, overall mortality and the risk of metastasis increased with depth of tumor invasion. Reprints are not available.     

Microscopic venous invasion in patients with pancreatic neuroendocrine tumor as a potential predictor of postoperative recurrence

BackgroundMicroscopic venous and lymphatic invasion is a known prognostic factor for various cancers, but its prognostic relevance for pancreatic neuroendocrine tumors (PNETs) is unclear.MethodsThirty-two consecutive patients with PNET who had complete resection were included in this study. Venous and lymphatic invasion was identified on elastic tissue or immunohistochemical staining, and correlated with other clinicopathological factors, including recurrence-free survival.ResultsVenous and lymphatic invasion was identified in nine (28%) and three (9%) patients, respectively. Tumors with venous invasion were of significantly larger size, higher Ki-67 index, and higher mitotic counts. Patients with venous invasion showed significantly worse prognosis than those without venous invasion (P = 0.001). Five of nine patients (56%) with venous invasion had tumor recurrence, while a relapse was found in one case in patients without venous invasion (n = 23). Lymphatic invasion was not correlated with any other clinicopathological parameters including lymph node metastasis and recurrence-free survival. Predictive factors for recurrence in univariate analysis included microscopic venous invasion, tumor size ≥ 20 mm, non-functionality, and WHO grades. In multivariate analysis where WHO grades and microscopic venous invasion were applied, venous invasion remained a significant predictor of poor recurrence-free survival (P = 0.021).ConclusionsMicroscopic venous invasion may serve as a predictive factor for tumor recurrence in patients with resectable PNET. The combination of WHO grades and microscopic venous invasion may assist in the stratification of the patients for risk of tumor recurrence.     

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.     

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.     

Breast Cancer Subtype is Associated With Axillary Lymph Node Metastasis: A Retrospective Cohort Study

The purpose of this study was to assess whether breast cancer subtype (BCS) as determined by estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 can predict the axillary lymph node metastasis in breast cancer.Patients who received breast conserving surgery or mastectomy and axillary lymph node dissection were identified from 2 cancer centers. The associations between clinicopathological variables and axillary lymph node involvement were evaluated in univariate and multivariate regression analyses.A total of 3471 patients met the inclusion criteria, and 53.0% had axillary lymph node metastases at diagnosis. Patients with hormone receptor (HR)−/human epidermal growth factor receptor 2 (HER2)− subtype had a higher grade disease and the lowest rate of lymphovascular invasion. Univariate and multivariable logistic regression analyses showed that BCS was significantly associated with lymph node involvement. Patients with the HR−/HER2− subtype had the lowest odds of having nodal positivity than those with other BCSs. HR+/HER2− (odds ratio [OR] 1.651, 95% confidence interval [CI]: 1.349–2.021, P < 0.001), HR+/HER2+ (OR 1.958, 95%CI 1.542–2.486, P < 0.001), and HR−/HER2+ (OR 1.525, 95%CI 1.181–1.970, P < 0.001) tumors had higher risk of nodal positivity than the HR−/HER2− subtype. The other independent predictors of nodal metastases included tumor size, tumor grade, and lymphovascular invasion.Breast cancer subtype can predict the presence of axillary lymph node metastasis in breast cancer. HR−/HER2− is associated with a reduced risk of axillary lymph node metastasis compared to other BCSs. Our findings may play an important role in guiding axillary treatment considerations if further confirmed in larger sample size studies.     

Pancreatic invasion is a prognostic indicator after radical resection for carcinoma of the ampulla of Vater

Sixty-three patients who had undergone pancreatoduodenectomy for carcinoma of the ampulla of Vater were analyzed with respect to tumor extent and prognosis. The postoperative mortality rate was 3% and overall survival rates 3 and 5 years after surgery were 55% and 46%, respectively. pTNM stage did not reflect prognosis after resection in patients at stages 2 and 3, while pancreatic invasion and regional lymph node metastasis clearly reflected prognosis after resection. Of the 26 patients who had no pancreatic invasion, regional lymph node metastasis was seen in only 19%, whereas of the 37 patients with pancreatic invasion, 62% exhibited lymph node metastasis. These factors were significantly correlated (P<0.001). Pancreatic invasion appeared to be an indirect indicator of regional lymph node metastasis. We conclude that, to improve prognosis for patients with pancreatic invasion, extended resection including extended lymphadenectomy, is a preferable additional procedure.     

Reduced Survival of Rectal Cancer Patients With Increased Tumor Epidermal Growth Factor Receptor Levels

PURPOSE: The epidermal growth factor receptor and its various ligands (epidermal growth factor, transforming growth factor-alpha, amphiregulin, heparin-binding epidermal growth factor, heregulin, and betacellulin) have been implicated in growth and regeneration of intestinal mucosa and might be related to the development and progression of gastrointestinal tumors. Although some studies have investigated levels of epidermal growth factor receptor by radioligand binding studies, none of them have further analyzed these levels in patients with rectal cancer and investigated their prognostic value. METHODS: We quantitatively determined tumor epidermal growth factor receptor levels in 38 patients with colorectal cancer compared with adjacent normal mucosa by iodine-125–labeled epidermal growth factor binding studies and Scatchard analysis. Patients were followed up for 49.5 ± 32.2 (range, 2–120) months. RESULTS: Epidermal growth factor receptor capacity was increased in invasive colorectal carcinomas according to T classification (P < 0.001), tumors with lymph node infiltration (P = 0.038), and advanced International Union Against Cancer stage (P < 0.001). Survival of colorectal cancer was reduced in patients with advanced International Union Against Cancer stage (P < 0.001), tumors with positive lymph nodes (P < 0.001), and tumors with elevated epidermal growth factor receptor levels (P = 0.024). In rectal cancer patients, poor prognosis was associated with advanced International Union Against Cancer stage (P = 0.029), tumors with lymph node infiltration (P = 0.040), and increased epidermal growth factor receptor levels (P = 0.002). Multivariate Cox regression analysis indicated that elevated levels of epidermal growth factor receptor were an independent predictor of reduced survival in patients with rectal cancer (P = 0.005). CONCLUSION: The epidermal growth factor receptor/ligand system appears to be involved in tumor development and tumor progression of colorectal carcinomas, with prognostic implication especially in patients with invasive rectal carcinomas. These patients might take advantage of therapies that specifically block epidermal growth factor receptor–mediated signal transduction.     

MUC6 down-regulation correlates with gastric carcinoma progression and a poor prognosis: an immunohistochemical study with tissue microarrays

Purpose MUC6 was first discovered by screening a gastric mucosa cDNA library and is expressed in the mucous cells of the neck zone and antral glands of the stomach. The aim of the present study was to clarify whether down-regulation has any clinicopathological or prognostic significance in gastric neoplasia.Methods Expression of MUC6, MUC5AC and MUC2 was examined using tissue microarrays for immunohistochemistry in gastric carcinomas (n = 225), adenomas (n = 40), and normal mucosa (n = 89) and compared with clinicopathological parameters and survival data.Results MUC6 expression was lower in gastric carcinomas than in adenomas or normal mucosa (P < 0.05) and inversely correlated with tumor size, depth of invasion, lymphatic and venous invasion, lymph node metastasis and UICC staging (P < 0.05). Positive links with expression of MUC2 and MUC5AC were noted (P < 0.05). MUC6 expression was lower in diffuse-type than intestinal-type lesions (P < 0.05). Kaplan–Meier analysis indicated that cumulative survival of patients with no MUC6 expression was significantly lower than with weak, moderate or strong expression in all and even advanced gastric carcinoma (P < 0.05). Multivariate analysis showed three independent prognostic factors, depth of invasion, lymphatic and venous invasion, to concordantly affect the relationship between MUC6 expression and prognosis.Conclusions Down-regulation of MUC6 may contribute to malignant transformation of gastric epithelial cells and underlie the molecular bases of growth, invasion, metastasis and differentiation of gastric carcinoma. Altered expression might therefore be employed as an indicator of pathobiological behaviors and prognosis of gastric carcinoma.     

Clinicopathological and prognostic significance of epidermal growth factor receptor overexpression in patients with esophageal adenocarcinoma: a meta‐analysis

The prognostic significance of epidermal growth factor receptor (EGFR) overexpression in patients with esophageal adenocarcinoma (EAC) remains controversial. Eligible studies that investigated the association between survival in EAC and the expression status of EGFR were identified by an electronic search of PubMed, EMBASE, and ISI Web of Science. A meta‐analysis was performed to clarify the impact of EGFR overexpression on clinicopathological parameters or overall survival (OS) in EAC. A total of seven studies including 1028 patients were subjected to the final analysis. The overall results suggested that overexpression of EGFR was significantly correlated with not only the depth of invasion, lymph node status, and tumors stage of EAC, with a pooled odds ratio of 2.99 (95% confidence interval [CI]: 1.07–8.35; Z = 2.09; P = 0.037), 3.05 (95% CI: 1.77–5.27; Z = 4.00; P < 0.001), and 5.37 (95% CI: 2.49–11.57; Z = 4.29; P < 0.001), respectively, but also the poorer OS with a pooled hazard ratio of 2.20 (95% CI: 1.47–3.31; Z = 3.79; P < 0.001). Overexpression of EGFR correlates with not only the clinicopathological features, but also the worse OS, and it might be useful as a predictive biomarker in clinical practice, yet the clinicopathological and prognostic role of EGFR in EAC still needs further confirmation by well‐designed prospective studies.     

Prognostic value of the histochemical expression of Helix pomatia agglutinin in advanced colorectal cancer

PURPOSE: The expression of helix pomatia agglutinin in advanced colorectal cancer was evaluated in order to determine whether helix pomatia agglutinin could serve as an effective prognostic indicator. METHODS: Using the histochemical procedure, the expression of helix pomatia agglutinin was studied in 117 patients with primary colorectal cancer. Sixty of 117 patients who died of either recurrence or metastasis within two years (Group 1) after resection were compared with the other 57 patients who survived for five years or longer (Group 2). RESULTS: The helix pomatia agglutinin-positive expression was seen in 34 cases of Group 1 and in only 15 cases of Group 2 (P<0.01). Lymph node metastasis, lymphatic invasion, venous invasion, mucin production, and helix pomatia agglutinin expression all had a significant correlation with the prognosis in the univariate analysis; however, only lymph node metastasis, venous invasion, and helix pomatia agglutinin expression were prognostic factors with a significant difference in the multivariate analysis. CONCLUSIONS: Histochemical expression of helix pomatia agglutinin will indeed aid in accurately predicting the prognosis of patients with advanced colorectal cancer.     

DNA index as a significant indicator of lymph node metastasis and local recurrence of rectal cancer

To confirm the prognostic significance of the DNA index (DI) in cases of rectal cancer, the nuclear DNA content of tumor cells was examined in 184 cases of rectal cancer treated with curative surgery, and the incidence of lymph node metastasis and recurrence of the cancer was analyzed. The incidence of lymph node metastasis was 43.9 percent in cases with aneuploidy (DI above 1.5), being statistically different from the 18.0 percent incidence in cases with diploidy (P <0.001). Although the extent of lymph node metastasis was limited to adjacent lymph nodes in cases with diploidy, distant lymph node metastases were frequent in cases with aneuploidy, especially in those with a DI above 1.5. Furthermore, the incidence of recurrence of cancer, and especially of local recurrence, was significantly higher (P <0.001) in cases with aneuploidy (DI above 1.5) than in cases with diploidy and aneuploidy (DI below 1.4). These findings indicate the significant value of the DNA index for the prediction of lymph node metastasis and local recurrence in patients with rectal cancer.     

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