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.     

Loss of standard type of CD44 expression in invaded area as a good indicator of lymph-node metastasis in colorectal carcinoma

PURPOSE: Recent advances have made possible the treatment of small invasive colorectal cancer by means of polypectomy or endoscopic mucosal resection. CD44 expression in cancer cells was identified as an indicator of lymph-node metastasis, which could be evaluated in specimens removed by colonoscopy. METHODS: The correlation between lymph-node metastasis and the expression of standard-type CD44 in cancer cells was examined immunohistologically using the invaded cancer cells of 61 tissue samples of superficially invasive colorectal cancer. We defined the above as invasive cancer restricted within the colorectal wall. Of the 61 samples, 31 had submucosal invasion and 30 had muscular invasion. RESULTS: Standard-type CD44 expression in the area of invasion in cases with lymph-node metastasis was remarkably down-regulated. In 43 cases with no lymph-node metastasis, 36 (83.7 percent) of patients had CD44 expression in invaded cells, whereas only two of 18 cases (11.1 percent) with lymph-node metastasis had expression of standard-type CD44 in the same area (P < 0.0001). A total of 69.6 percent (16/23) of patients with loss of standard-type CD44 expression in invaded sites were found to have positive metastasis in the lymph nodes. These results suggest that standard-type CD44 in invasive colon cancer cells could suppress metastasis to the regional lymph nodes. CONCLUSION: In cases of invasive colorectal cancer, the loss of standard-type CD44 expression in the invaded area is a sensitive marker for metastasis to the lymph nodes. Further investigation with larger patient groups is required to clarify the reliability of loss of standard-type CD44 expression as an indicator for additional surgery after endoscopic resection of submucosal invasive colorectal carcinoma.     

大肠癌组织中生长抑素和血管内皮生长因子-C的表达及其临床意义

目的探讨大肠癌组织中生长抑素（SS）和血管内皮生长因子-C（VEGF-C）的表达及其临床意义。方法采用免疫组化法检测60例大肠癌组织及20例正常大肠黏膜组织中SS蛋白和VEGF-C蛋白的表达，采用VEGF-C受体FLT-4阳性脉管标记淋巴管计数，分析SS与大肠癌淋巴管生成、转移的关系。结果SS蛋白表达阳性率在大肠癌组及正常大肠黏膜组分别为37．7％和65％，VEGF-C在癌及正常组阳性表达率分别为60％和30％，差别均有显著性；SS表达与肿瘤分化程度、淋巴结转移、淋巴管侵犯及远处转移密切相关，与浆面膜受累无关；VEGF-C表达与肿瘤淋巴结转移，淋巴管侵犯及远处转移密切相关，而与肿瘤分化和浆面膜受累无关；大肠癌组织中SS和VEGF-C蛋白表达呈显著负相关。结论SS可能通过对VEGF-C／FLT-4信号通路的阻滞而抑制大肠癌淋巴管生成及转移。     

Clinical significance of serum levels of CD44 variant exons 8–10 protein in colorectal cancer

We examined serum levels of a CD44 splice variant that contained variant exons 8–10 (CD44v8–10) as a tumor marker in colorectal cancer patients. We performed enzyme-linked immunosorbent assays in 81 sera obtained from 71 colorectal cancer patients and 10 healthy controls. Serum CD44v8–10 levels were significantly higher in the colorectal cancer patients than in the healthy controls (0.209 ± 0.098 versus 0.114 ± 0.019 OD; P < 0.01). There was a close correlation between immunohistochemical expression and serum CD44v8–10 levels. Surgical resection of the tumors resulted in a reduction of serum CD44v8–10 levels. There was no significant correlation between serum CD44v8–10 level and serosal invasion or histologic type. However, a significant correlation was observed between serum CD44v8–10 level and lymphatic or venous invasion. In addition, serum CD44v8–10 levels were significantly higher in carcinomas associated with lymph node or liver metastasis than in those without metastasis. These findings suggest the usefulness of serum CD44v8–10 level in the prediction of colorectal cancer metastasis. (Received July 25, 1997; accepted Nov. 28, 1997)     

Prognosis and risk factors of metastasis in colorectal carcinoids: results of a nationwide registry over 15 years

BACKGROUND: Colorectal carcinoids are often described as low-grade malignant. However, no study has compared the survival between patients with colorectal carcinoids and those with carcinomas, in a large series. In addition, no global consensus has been established on the crucial determinants of metastasis in colorectal carcinoids. AIM: To determine the predictive factors for metastasis in colorectal carcinoids and clarify their prognosis compared with adenocarcinomas. METHODS: Data of all patients diagnosed as having colorectal carcinoids were extracted from a large nationwide database of colorectal tumours, the Multi-Institutional Registry of Large-Bowel Cancer in Japan, for the period from 1984 to 1998. Risk factors for lymph node (LN) metastases and distant metastases were analysed among those who were undergoing surgery, by univariate and multivariate analysis. Cancer-specific survival was also compared between patients with colorectal carcinoids and those with adenocarcinomas registered in the same period. RESULTS: Among the 90 057 cases of colorectal tumours that were diagnosed, a total of 345 cases of carcinoids were identified, including 247 colorectal carcinoids of those undergoing surgery. Risk factors for LN metastasis were tumour size >/=11 mm and lymphatic invasion, whereas those for distant metastasis were tumour size >/=21 mm and venous invasion. Colorectal carcinoids without these risk factors exhibited no LN metastasis or distant metastasis. Cancer-specific survival of patients with colorectal carcinoids without metastasis was better than that of those with adenocarcinomas. However, the survival was similar between carcinoids and adenocarcinomas if the tumours had LN metastasis or distant metastasis. CONCLUSIONS: The presence of metastasis in colorectal carcinoids could lead to survival that is as poor as in adenocarcinomas. Tumours 相似文献   

The expression of matrix metalloproteinases (MMPs), tissue inhibitor of metalloproteinases (TIMPs) and angiogenesis in relation to the depth of tumor invasion and lymph node metastasis in submucosally invasive colorectal carcinoma]

BACKGROUND/AIMS: Lymph node (LN) metastasis occurs in approximately 10% of patients with submucosally invasive colorectal carcinoma. This study was performed to determine the role of matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs) production and microvessel formation on the LN metastasis in submucosally invasive colorectal carcinoma. METHODS: A total of forty-one subjects with surgically resected submucosally invasive colorectal carcinoma were included in this study. Immunohistochemical staining of MMP-2, MMP-9, TIMP-1, TIMP-2, and urokinase-type plasminogen activator were performed. Angiogenesis was evaluated by counting the number of microvessels in each pathologic specimen as identified by CD34 immunohistochemical staining. RESULTS: The depth of submucosal invasion was not significantly correlated with the expression of MMP-2, MMP-9, TIMP-1, TIMP-2, or urokinase-type plasminogen activator, but the microvessel count was significantly correlated with the absolute depth of invasion (r=0.312, p<0.05). Upregulation of TIMP-2 was positively correlated with adjacent lymphatic invasion (p<0.05) and increased TIMP-2 expression was correlated with LN metastasis in submucosally invasive colorectal carcinoma (p=0.088). CONCLUSIONS: These results suggest that the expression of TIMP-2 and the microvessel count may be useful parameters for considering additional surgery after endoscopic treatment of submucosally invasive colorectal carcinoma.     

Significance of lymphatic invasion and cancer invasion-related proteins on lymph node metastasis in gastric cancer

Background and Aims:  Cancer invasion and metastasis are critical events for patient prognosis; however, the most important step in the whole process of lymph node (LN) metastasis in gastric cancer remains obscure. In this study, the significance of cancer cell behaviors, such as cell detachment, stromal invasion and lymphatic invasion on regional LN metastasis in gastric cancer was investigated by comprehensive immunohistochemistry.
Methods:  A total of 210 cases with gastric cancer were selected. These consisted of 105 cases with regional LN metastasis (LN[+] group) and 105 cases without LN metastasis (LN[–] group). Both groups exhibited the same depth of invasion. Cancer tissues were subjected to immunohistochemistry with antibodies against claudin-3, claudin-4, β-catenin, matrix metalloproteinase (MMP)-1, and MMP-2, as well as endothelial markers of lymphatic vessel endothelial hyaluronan receptor-1 and von Willebrand factor for the objective discrimination between lymphatics and blood vessels. The expression of each protein as well as the histopathological parameters were compared between LN(+) and LN(−) groups.
Results:  Along with lymphatic invasion by cancer cells and gross tumor size, MMP-1 expression in cancer cells at the invasive front of the primary tumor was a significant, independent predictor of LN metastasis. The expression of claudins and β-catenin was associated with the histopathological type of cancer, but not with LN status.
Conclusion:  Among the cancer invasion-related proteins examined, MMP-1 plays a vital role in LN metastasis of gastric cancer. Tumor size, lymphatic invasion and MMP-1 expression level at the invasive front were the predictive factors of LN metastasis of gastric cancer.     

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.     

Invasive front of colorectal cancer： Dynamic interface of pro-/anti-tumor factors

Tumor-host interaction at the invasive front of colorectal cancer represents a critical interface encompassing a dynamic process of de-differentiation of colorectal carcinoma cells known as epithelial mesenchymal transition (EMT). EMT can be identified histologically by the presence of "tumor budding", a feature which can be highly specific for tumors showing an infiltrating tumor growth pattern. Importantly, tumor budding and tumor border configuration have generated considerable interest as additional prognostic factors and are also recognized as such by the International Union Against Cancer. Evidence seems to suggest that the presence of tumor budding or an infiltrating growth pattern is inversely correlated with the presence of immune and inflammatory responses at the invasive tumor front. In fact, several tumor-associated antigens such as CD3, CD4, CD8,CD20, Granzyme B, FOXP3 and other immunological or inflammatory cell types have been identified as potentially prognostic in patients with this disease. Evidence seems to suggest that the balance between pro-tumor(including budding and infiltrating growth pattern) and anti-tumor (immune response or certain inflammatory cell types) factors at the invasive front of colorectal cancer may be decisive in determining tumor progression and the clinical outcome of patients with colorectal cancer. On one hand, the infiltrating tumor border con-figuration and tumor budding promote progression and dissemination of tumor cells by penetrating the vascular and lymphatic vessels. On the other, the host attempts to fend off this attack by mounting an immune response to protect vascular and lymphatic channels from invasion by tumor buds. Whereas standard pathology reporting of breast and prostate cancer involves additional prognostic features, such as the BRE and Gleason scores, the ratio of pro- and anti-tumor factors could be a promising approach for the future development of a prognostic score for patients with colorectal cancer which could complement tumor node metastasis staging to improve the clinical management of patients with this disease.     

Clinicopathologic and immunohistochemical study of early colorectal cancer with liver metastases

Seven (3.3%) of 213 patients who underwent surgery for early colorectal cancer (invasion limited to no deeper than the submucosa) at the National Cancer Center Hospital, Tokyo, between 1986 and 1995 had synchronous (2 patients) or metachronous (5 patients) liver metastases. The average period from surgical resection of the primary colorectal cancer to the diagnosis of liver metastases was 25 months (range, 0–52 months). The clinicopathologic and immunohistochemical features of the primary lesions in these patients were compared with these features in the lesions in consecutive patients with early colorectal cancer who had no evidence of liver metastases within at least 5 years after colorectal resection. Venous invasion was more frequent in the primary lesions with liver metastases than in those without liver metastases (57% vs 0%; P = 0.0035). Expression of p53 and CD44v9 was more frequent in the primary lesions with liver metastases (71% and 100%) than in those without metastases (56% and 72%). In contrast, MUC2 expression was more frequent in the primary lesions without liver metastases (72%) than in those with metastases (43%). Venous invasion is considered to be closely related to liver metastasis, and the immunohistochemical expression of p53 and CD44v9 provides useful information for identifying those patients with early colorectal cancer who have a high risk of developing liver metastases. Received: June 16, 1998/Accepted: October 23, 1998     

Immunohistochemical localization of cathepsin D in colorectal tumors

PURPOSE: Although it has been suggested that cathepsin D, a lysosomal protease, is involved in tumor invasion and metastasis in human colorectal cancers, conflicting studies have also been reported recently. In addition, this issue has been only rarely studied in human colorectal tumors by use of immunohistochemical methods. The aim of the study presented here was to clarify not only the correlation between cathepsin D expression and tumor invasion or metastasis but also the correlation between the intracellular immunostaining pattern of cathepsin D and tumor invasion and metastasis in human colorectal tumors. METHODS: Thirty-four primary colorectal adenocarcinomas and 24 adenomas were immunostained by use of an anticathepsin D antibody. Both the incidence and the immunostaining patterns of cathepsin D were investigated in all tissue samples. RESULTS: Three different immunostaining patterns,i.e., supranuclear, basal, and diffuse, were observed in samples containing cathepsin D. Although the incidence of cathepsin D-positive carcinomas was not correlated with tumor progression, invasion, or metastasis, the immunostaining pattern was significantly correlated with lymphatic invasion. CONCLUSIONS: The results of this study suggest that abnormal cathepsin D immunostaining patterns (basal or diffuse) can be used to predict a potential for lymphatic invasion in colorectal carcinoma.Supported in part by a Grant-in-Aid for Cancer Research (9–24) from the Ministry of Health and Welfare, Japan.     

Predictive value of histology at the invasive margin in the prognosis of early invasive colorectal carcinoma

To accurately select patients with malignant colorectal polyps who are at high risk of adverse outcome, we examined the predictive value of clinicopathological factors, with special attention paid to the histology at the invasive margin. We examined 75 submucosal carcinomas from 75 patients, initially resected by polypectomy, including endoscopic, trans-anal, trans-sacral, and trans-sphincteric local excision. The associations between clinicopathological features such as sex and age; tumor size, location, shape, depth of submucosal invasion, vascular invasion, histology at the central part, and histology at the invasive margin; and the presence or absence of a residual adenomatous component and adverse outcome were examined by univariate and multivariate logistic regression analyses. Lymph node metastases were found in 2 patients, local recurrence in 4, and distant metastases in 2. Univariate logistic regression analysis showed that unfavorable histology at the invasive margin was significantly associated with lymph node metastasis or local recurrence (P = 0.0373), whereas the association of lymphatic invasion and vascular (lymphatic or venous) invasion with lymph node metastasis or local recurrence had marginal significance (P = 0.0785; P = 0.0990). Multivariate logistic regression analysis, with unfavorable histology at the invasive margin and lymphatic invasion as independent variables, showed that unfavorable histology alone had significance (P = 0.0373) in predicting adverse outcome. Widely accepted criteria such as massive submucosal invasion, positive vascular invasion, and poorly differentiated histology, were less useful in predicting adverse outcome. These results suggest that unfavorable histology at the invasive margin is a useful risk factor for predicting lymph node metastasis or local recurrence in patients with malignant colorectal polyps. Received: March 23, 1999 / Accepted: August 27, 1999     

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.     

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.     

Location of Early Colorectal Cancers at Fold-Top May Reduce the Risk of Lymph Node Metastasis

Purpose This study was designed to look for significant correlations between location of early colorectal cancer, distance from muscularis mucosae to muscularis propria, and the frequency of lymph node metastasis. Methods A total of 166 early colorectal cancers, including 67 surgically resected lesions, were evaluated. The cancers were divided into two groups: metastatic and nonmetastatic. Cancer lesions were further subtyped at the fold-top or fold-bottom. Macroscopic classifications and histology were performed. Absolute invasive depth and distance from muscularis mucosae to muscularis propria was measured. Multivariate analysis was used to assess relationships among the variables. Results The percentage of polypoid cancer lesions at fold-bottom was higher than at fold-top (74.5 vs. 51.8 percent), whereas flat-type cancer lesions at fold-bottom occurred less often than at fold-top (8.2 vs. 30.4 percent). Logistic regression showed that deep absolute invasive depth, lymphatic and vessel invasion, and cancer location (at fold-bottom) were the significant risk factors for early colorectal cancers leading to lymph-node metastasis. The distance from muscularis mucosae to muscularis propria with lymph-node metastasis (1,396.7 ± 728.4 μm) was shorter than without lymph-node metastasis (3,533.9 ± 2,507.8 μm; P < 0.01). Multivariate analysis showed that distance from muscularis mucosae to muscularis propria was a statistically significant factor for early colorectal cancers leading to lymph node metastasis (P = 0.0054). Conclusions We conclude that early colorectal cancers at the fold-top or with a long distance from muscularis mucosae to muscularis propria have less tendency to metastasize to lymph nodes. Clinically, these results provide evidence of a new indicator of endoscopic mucosal resection for early colorectal cancers at the fold-top.     

Small spot sign of rectal carcinoma by endorectal ultrasonography

PURPOSE: We observed small spots at the margin of rectal carcinomas on endorectal ultrasonography. Our aim was to study the relationship between ultrasonographic evidence of these spots and histologic characteristics of disease and postoperative recurrence. PATIENTS AND METHODS: The study group comprised 55 patients, 36 men and 19 women, with rectal carcinoma as confirmed by biopsy. The patients were followed up at three-month intervals for six months to three years and six months after the operation. Endorectal ultrasonography was performed in the usual manner. Surgically resected specimens were stained with hematoxylin and eosin and histologically examined. Vessel invasion was graded from 0 (not invasive) to 3 (most invasive). RESULTS: Among the 55 patients studied, 3 had Stage T2,N0,M0 rectal carcinomas and 35 had Stage T3,N0,M0 carcinomas, 5 (14.3 percent) of whom had echographic evidence of small spots. Thirteen patients had Stage T3,N1/2,M0 carcinomas, comprising 12 (92.3 percent) with small spots, and four patients had T3,N1/2,M1 carcinomas, all with small spots. Vessel invasion of Grade 2 or higher was observed around the carcinomas in 20 of 21 patients who had small spots. Ten of 13 patients with many spots at the margin of the carcinoma (a spot grade of ++) histologically had marked venous or lymphatic invasion (an invasion Grade 3). The presence of small spots was closely associated with massive venous or lymphatic invasion (a vessel invasion grade of 2 or more). Four patients had synchronous liver metastases, and small spots were found in all four. Distant metastases and local recurrence were found in 11 of 21 patients with small spots. We found no recurrence in any patient without small spots on endorectal ultrasonography. CONCLUSIONS: Small spots indicate the presence of massive venous or lymphatic invasion and a high risk of postoperative recurrence.Podium presentation at the meeting of The American Society of Colon and Rectal Surgeons, Philadelphia, Pennsylvania, June 22 to 26, 1997.     

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。     

MUC-1 expression as a predictor of the curative endoscopic treatment of submucosally invasive colorectal carcinoma

PURPOSE: This study was undertaken to clarify the clinical significance of MUC-1 expression in the endoscopic treatment of colorectal carcinoma with submucosal invasion. METHODS: One hundred eighty-four colorectal carcinomas with submucosal invasion were examined. The depth of submucosal invasion was classified as scanty or massive. The histologic subclassfication at the deepest invasive portion was defined as well-differentiated, moderately well-differentiated, moderately to poorly differentiated, poorly differentiated, or mucinous adenocarcinoma. MUC-1 expression was examined immunohistochemically at the deepest invasive portion. In addition, the Ki67 labeling index was also examined immunohistochemically. RESULTS: Lymph node metastases were detected in 28 (15.2 percent) of 184 lesions. Lesions with both scanty submucosal invasion and well-differentiated or moderately well-differentiated adenocarcinomas had no lymph node metastases. MUC-1 expression was detected in 88 (47.8 percent) of 184 lesions and correlated significantly with the presence of lymph node metastases. The Ki67 labeling index also correlated significantly with lymph node metastases. Furthermore, lesions with both MUC-1-negative and low Ki67 labeling index showed no lymph node metastases, even in lesions with massive submucosal invasion. Multivariate analysis indicated that MUC-1 expression was one of the most important risk factors for lymph node metastases and histologic grade among the clinicopathologic factors usually examined. CONCLUSION: MUC-1 expression is one of the accurate predictors of the presence of lymph node metastases among the clinicopathologic factors commonly used. Combined analysis of MUC-1 expression and Ki67 labeling index may be a useful indicator of lymph node metastases and may broaden the indications for the curative endoscopic treatment of carcinoma with massive submucosal invasion.     

Evaluation of the usefulness of tumor budding on the prediction of metastasis to the lung and liver after curative excision of colorectal cancer

BACKGROUND/AIMS: We evaluated the usefulness of tumor budding, defined as the morphology of infiltration by small clusters of undifferentiated adenocarcinoma into the invasive front of the lesion, for the prediction of metastasis to the lung and liver after curative excision of colorectal cancer. METHODOLOGY: The subjects were 491 patients with a single colorectal cancer lesion, in whom follow-up observation was performed for more than 5 years, consisting of 278 patients without recurrence, 155 patients with the first metastasis to the liver alone, and 58 patients with the first metastasis to the lung alone. The invasive front was histologically re-examined using sections with the largest diameter of the primary colorectal cancer lesion, and the tumor budding was classified into 3 grades based on the morphology of infiltration. The usefulness of this factor for the prediction of metastasis to the lung and liver was examined by multivariate analysis together with conventional clinicopathological factors such as age, sex, tumor location, tumor size, histological type, tumor depth, invasion of lymph ducts, venous invasion, and metastasis to lymph nodes. RESULTS: Comparisons of the no-recurrence and lung metastasis groups by multivariate analysis indicated that moderate to severe tumor budding (odds ratio=0.1291, P<0.0001) and positive metastasis to lymph nodes (odds ratio=0.1142, P<0.0001) were extracted as the independent prediction factors of metastasis to the lung. Comparisons of the no-recurrence and liver metastasis groups indicated that infiltration over the proper muscular tunics (odds ratio=0.0284, P<0.0001) and positive metastasis to lymph nodes (odds ratio=0.3289, P=0.0002) were extracted as the independent prediction factors of metastasis to the liver. CONCLUSIONS: Tumor budding in the invasive front of the lesion was considered to be a simple and useful pathohistological factor for the prediction of metastasis to the lung in patients with colorectal cancer after curative excision. It was suggested that this factor is important for the prediction of metastasis to the lung after surgery and for the planning of treatment methods.