Invasive Colorectal Carcinoma Research Articles

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

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. 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. 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. 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.

Conditions of curability after endoscopic resection for colorectal carcinoma with submucosally massive invasion.

The deepest invasive portion of colorectal carcinoma (CRC) is considered to be the part, which ultimately will invade, spread locally and give metastasis. We have previously reported that histologic differentiation at the deepest invasive portion of CRC closely correlate with metastatic potential and is useful in understanding the curability of endoscopic mucosal resection (EMR). The aim of this study is to clarify the conditions of curative EMR for CRC with submucosally (sm) massive invasion. A total of 521 cases with sm invasive CRC (Group A, 470 surgically resected cases; Group B, 51 followed-up cases after EMR) were studied. The depth of sm invasion was defined as the practically measured distance from muscularis mucosae. Histologic subclassification was performed at the deepest invasive tumor margin as: well-differentiated (W), moderately differentiated (M) and poorly differentiated (Por). By assessing glandular configuration and cellular arrangement, M type was further subdivided into two different groups; moderately-well differentiated (Mw) and moderately-poorly differentiated (Mp). In group A, lymph node (LN) metastasis was detected in 45 (9.6%) of 470 cases. W or Mw lesions showed LN metastasis in 4.9% (19/388). Mp or Por lesions showed LN metastasis in 37.3% (25/67) (W/Mw vs Mp/Por; p<0.01). Of 45 cases with LN metastasis that could be measured the practical distance of sm invasion, W or Mw lesions showed no LN metastasis in cases within 1,500 micrometer invasion. However, Mp or Por lesions showed LN metastasis in cases within 1,500 micrometer invasion (5/15, 33.3%, minimum 400 micrometer invasion; so-called scanty invasion). In group B, none of 51 cases died of LN metastasis and showed no other metastasis, although 17 cases (33.3%) showed an sm invasion more than 1,500 micrometer. These results indicated that CRC even with sm massive invasion can be cured by complete EMR on conditions that the depth of sm invasion is within 1,500 micrometer and histologic grade at the deepest invasive portion is W or Mw, if there are no vessel involvement. However, cases with Mp or Por grade were not curative by EMR, even if they showed an sm scanty invasion.

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.

Immunohistochemical localization of cathepsin D in colorectal tumors.

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. 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. 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. 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.

Expression of pituitary-tumour transforming gene in colorectal tumours

Basic fibroblast growth factor promotes angiogenesis and mitogenesis in colon carcinomas. Pituitary-tumour transforming gene (PTTG1) causes in-vitro and in-vivo transformation, regulates secretion of basic fibroblast growth factor, and inhibits chromatid separation. Most normal tissues show little or no PTTG1 expression but cancer cells express the gene abundantly. We postulated that PTTG1 expression in colorectal tumours is related to tumour invasiveness. PTTG1 gene and protein expression were assessed in 68 colorectal tumours and compared with invasive characteristics, such as lymph-node invasion, evidence of metastases, tumour vessel density, and expression of basic fibroblast growth factor. PTTG1 expression is given in terms of the fold-increase over that in normal-adjacent colorectal tissue. PTTG1 was overexpressed in all of 48 colon carcinomas (median fold-increase 2.2 [IQR 1.8-3.3]) and in 19 of 20 colonic polyps (2.2 [1.6-3.1]) compared with normal colonic tissue. Invasion of surrounding lymph nodes was associated with higher PTTG1 expression than in carcinomas limited to the bowel wall (3.4 [2.1-5.9] vs 1.9 [1.7-2.4], p=0.007), and higher PTTG1 expression was seen in more vascular than in less vascular tumours (2.6 [1.9-5.1] vs 1.9 [1.8-2.5], p=0.04). Increased tumour PTTG1 expression may be a marker of invasive colorectal carcinoma and could represent a new therapeutic target.

Proliferating cell nuclear antigen and p53 protein expression in submucosal invasive colorectal carcinoma.

In some cases of early colorectal carcinoma, radical surgical resection might be required because of vessel invasion, distant metastasis, or inadequate surgical margin. To characterize submucosal invasive colorectal carcinoma, we investigated expression of PCNA and p53 protein. Sixty-seven patients who underwent curative resection of submucosal invasive colorectal carcinoma participated in this study. The PCNA labeling index (PCNA-LI) is determined at the deepest lesion of carcinoma. The expression of PCNA and p53 protein were analyzed according to clinicopathological factors. 1) The PCNA-LI was correlated to histological grade, depth of invasion or vessel invasion in polypoid type. 2) The flat type had significantly higher PCNA-LI (65.1+/-8.2%) and p53 protein expression (69.6%) than the polypoid type. 3) The PCNA-LI was higher in cases with lymph node metastasis than in these without lymph node metastasis. 4) Overexpression of the p53 protein was detected in all cases with liver metastasis. Our results suggest that in order to determine the treatment for the patients with submucosal invasive colorectal carcinoma, the expression of PCNA and p53 protein may be a useful biologic marker.

Larger and more invasive colorectal carcinoma contains larger amounts of plasminogen activator inhibitor type 1 and its relative ratio over urokinase receptor correlates well with tumor size

Considering recent findings that both urokinase plasminogen activator receptor (uPAR) and plasminogen activator inhibitors (PAIs) are involved in tumor growth through an urokinase-type plasminogen activator (uPA) activity-independent mechanism, the relation between the presence of these factors in tumor tissue and the clinicopathologic variables in colorectal carcinoma was reevaluated. In 100 colorectal carcinoma patients, antigen levels of u-PA, uPAR, and PAI-1 and PAI-2 were assayed in both tumor tissues and their normal counterparts. Plasma levels of soluble uPAR also were determined. All uPAR, uPA, PAI-1, and PAI-2 antigen levels in tumor tissue were significantly higher than those in normal tissue. Levels of both uPAR and PAI-1 were significantly higher (3.09 +/- 1.37 and 6.63 +/- 7.49, respectively) in large tumors (>/=50 mm in greatest dimension) than those in smaller tumors (< 50 mm) (2.50 +/- 1.07 and 2.72 +/- 2.70, respectively) (P < 0.05). Significant positive correlation coefficients (r) were obtained between tumor size and the calculated ratios of PAI-1/uPAR (r = 0.490; P < 0.0001) and PAI-1/uPA (r = 0. 469; P < 0.0001). In addition to liver metastases (P = 0.004) and lymph node involvement (P = 0.04), high levels of uPAR (P = 0.05) also were found to be of independent prognostic value by multivariate analysis. Higher expression of uPAR was related to poor prognosis of patients with colorectal carcinoma and excess amounts of PAI-1 over uPAR or uPAR-bound uPA appeared to play an important role in tumor progression.

Rationale for bladder-sparing surgery in patients with locally advanced colorectal carcinoma

Total pelvic exenteration (TPE) with urinary diversion is a standard surgical approach for patients with locally advanced rectal carcinoma. Because only approximately 50% of patients undergoing TPE have tumor involving the bladder, the authors evaluated the feasibility of bladder salvage in this setting. The current study presents the results of a retrospective study of patients with advanced colorectal carcinoma (classification of >/= T3) to formulate criteria for selecting patients for bladder-sparing procedures. The charts of 81 patients with rectal carcinoma classified as >/= T3 were reviewed for age, gender, computed tomography (CT) findings, results of intraoperative examination under anesthesia, final pathologic evaluation, urologic complications, local recurrence, and patient survival. Among the 46 patients who underwent TPE, final pathologic evaluation demonstrated tumor involvement of the bladder in 58% of patients. Preoperative identification of a bladder mucosal abnormality accurately predicted bladder involvement in only 57% of the 30 patients who underwent cystoscopy. CT and intraoperative palpation of the bladder individually predicted the final pathologic findings in 69% and 70% of patients, respectively; of the 21 patients in whom both were positive, 90% had bladder involvement. Of the 35 patients (26 females and 9 males) who underwent bladder-sparing procedures, 22 had complete sparing of the bladder, 9 underwent partial cystectomy (5 with ureteroneocystostomy), 4 underwent ureteroneocystostomy alone, and 2 underwent prostatectomy alone. Ninety-four percent of these 35 patients had negative histologic margins. There was no difference in the incidence rate of urinary complications between patients who underwent TPE and those who underwent a bladder-sparing surgery (17% each). The incidence rates of local recurrence (14% vs. 17%) and the 3-year survival rates (49% vs. 39%) did not differ significantly between the 2 groups. Bladder-sparing surgery to treat patients with locally invasive colorectal carcinoma provides good local control without sacrificing survival. Women, whose reproductive organs act as a natural barrier, and selected men in whom CT and intraoperative evaluation identify only localized involvement of the prostate or bladder appear to be reasonable candidates for bladder-sparing procedures.

Indication for Endoscopic Resection of Submucosal Colorectal Carcinoma: Special Reference to Lymph Node Metastasis

We investigated the relationship between histological factors and lymph node metastasis in 77 lesions with submucosally invasive colorectal carcinomas to establish useful criteria for lesions in which endoscopic treatment alone results in cure of malignancy. There were positive correlations between histological factors, including the level of invasion, the histologic grade, presence or absence of lymphatic invasion, presence or absence of budding, and lymph node metastasis (p < 0.05, p < 0.05, p < 0.005, p < 0.01). The presence or absence of venous invasion did not influence lymph node metastasis. Laparoscopic surgery involving lymph node dissection should be indicated for sm1 carcinoma lesions with unfavorable histological factors. In lesions diagnosed as sm2 or sm3 prior to resection, intestinal resection involving lymph node dissection by laparoscopic surgery should be directly performed without endoscopic resection. In treating submucosally invasive colorectal carcinomas, the level of invasion can be clinically diagnosed, consequently endoscopic resection should be initially performed when lesions are evaluated as sm1 prior to resection. When histological investigation reveals sm1 carcinoma with histologic grade I (well-differentiated) or II (moderately-differentiated), and the absence of lymphatic invasion and budding, endoscopic treatment alone is sufficient.

Telomere shortening and the clinicopathologic characteristics of human colorectal carcinomas

It has been reported that shortening of telomeres and strong activation of telomerase occur frequently in colorectal carcinomas. In the current study, the authors examined the correlations between the telomere length of colorectal carcinomas and their clinicopathologic characteristics as well as the activity of telomerase to clarify whether telomere length might represent the biologic behavior of tumors and the mode of tumor development. Telomere length was examined by Southern blot analysis in 61 invasive colorectal carcinomas and corresponding normal mucosas. Telomerase activity was assayed by the telomeric repeat amplification protocol with minor modifications. Shortening of the telomere was detected in 38 (62.3%) and elongation in 3 (4. 9%) of the 61 carcinomas. The telomere shortening occurred more frequently in nonulcerating polypoid carcinomas than in ulcerating carcinomas (P = 0.0373) and also occurred more frequently in ascending colon carcinomas than in sigmoid colon or rectal carcinomas (P = 0.0259 and P = 0.0407, respectively). However, no significant correlation was found between the activity of telomerase and the length of telomere. The results of this study indicate that telomere length may represent the biologic behavior of individual tumors and possibly the mode of development of colorectal carcinomas.

Telomere shortening and the clinicopathologic characteristics of human colorectal carcinomas

BACKGROUND It has been reported that shortening of telomeres and strong activation of telomerase occur frequently in colorectal carcinomas. In the current study, the authors examined the correlations between the telomere length of colorectal carcinomas and their clinicopathologic characteristics as well as the activity of telomerase to clarify whether telomere length might represent the biologic behavior of tumors and the mode of tumor development. METHODS Telomere length was examined by Southern blot analysis in 61 invasive colorectal carcinomas and corresponding normal mucosas. Telomerase activity was assayed by the telomeric repeat amplification protocol with minor modifications. RESULTS Shortening of the telomere was detected in 38 (62.3%) and elongation in 3 (4.9%) of the 61 carcinomas. The telomere shortening occurred more frequently in nonulcerating polypoid carcinomas than in ulcerating carcinomas (P = 0.0373) and also occurred more frequently in ascending colon carcinomas than in sigmoid colon or rectal carcinomas (P = 0.0259 and P = 0.0407, respectively). However, no significant correlation was found between the activity of telomerase and the length of telomere. CONCLUSIONS The results of this study indicate that telomere length may represent the biologic behavior of individual tumors and possibly the mode of development of colorectal carcinomas. Cancer 1999;86:1431–6. © 1999 American Cancer Society.

Expression of cathepsin B and cystatin C in human colorectal cancer

Cathepsin B is a matrix protease that may be associated with colorectal carcinoma invasion and progression. In this study, we investigated the localization of cathepsin B in cancerous and noncancerous tissues of 80 patients with colorectal cancer including 25 cases with liver metastasis. In addition, the expression of cystatin C, one of several cathepsin B inhibitors, was compared with that of cathepsin B in the same samples to reveal one of the regulation mechanisms of cathepsin B. The cancer cells in the advancing edge of the tumors often exhibited the strongest immunostaining of cathepsin B, and stromal cells and normal epithelial cells adjacent to the tumors were also positive for cathepsin B. The percentage of cathepsin B-positive cases was significantly larger in the group with liver metastases than in the group without liver metastases. In the group without liver metastases, the cancer cells and stromal cells more frequently exhibited cathepsin B immunoreactivity in Dukes' A cases than in Dukes' B and C cases. In situ hybridization and reverse transcription-polymerase chain reaction (RT-PCR) confirmed cathepsin B synthesis in the cancer and proximal epithelial cells. There was an average 3.7-fold increase in cathepsin B mRNA levels in the cancerous tissues compared with that of noncancerous tissues, and Dukes' A tumors exhibited the highest expression level. Conversely, cystatin C mRNA levels were similar in all samples, and tended to show an inverse correlation with the cathepsin B levels. In conclusion, cathepsin B expression by human colorectal cancers and surrounding noncancerous cell components may contribute to both local invasion at the early stage and remote metastasis without influence of cystatin C.

Distribution of carcinoembryonic antigen and biologic behavior in colorectal carcinoma.

Carcinoembryonic antigen is assumed from the results of several experiments to be associated with invasion of colorectal carcinoma by adhesion or contact inhibition. The patterns and the intensity of carcinoembryonic antigen distribution in colorectal carcinoma were assessed to verify whether they were correlated with malignant potential from those biologic characteristics. Carcinoembryonic antigen distribution was tested in the archival samples of 149 colorectal carcinomas by immunohistochemistry, using three characterized anti-carcinoembryonic antigen monoclonal antibodies: T84.66, PR1A3, and PR3B10. The distribution patterns in neoplastic tissue were categorized into unstained, apicoluminal, and diffuse cytoplasmic patterns. Tumor, invasive tumor margin, and tissue surrounding the tumor were examined. Although all three antibodies revealed a positive correlation, T84.66 showed better discrimination than the others. Although none of the negative staining of the tumor or invasive tumor margin showed recurrence, the apicoluminal pattern showed recurrence, and the diffuse pattern showed the most frequent recurrence (P < 0.01). Recurrence was also associated with staining intensity in the apicoluminal pattern in both the tumor and invasive tumor margin (P < 0.05). Infiltrative tumor growth and lymph node metastasis were more frequent in cases of positive staining in tissue surrounding the tumor. Patients with the apicoluminal pattern achieved longer survival than patients with the diffuse-cytoplasmic pattern in the invasive tumor margin (P = 0.024) by a multivariate analysis including tumor stage and histologic differentiation. The distribution of carcinoembryonic antigen in tumors and surrounding tissue seems to be closely correlated with invasiveness and metastatic behavior in colorectal carcinoma. Carcinoembryonic antigen immune staining can be considered as an efficient tool to determine groups with risk of recurrence.

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

This study was undertaken to clarify the clinical significance of MUC-1 expression in the endoscopic treatment of colorectal carcinoma with submucosal invasion. One hundred eighty-four colorectal carcinomas with submucosal invasion were examined. The depth of submucosal invasion was classified as scanty or massive. The histologic subclassification 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. 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. 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.

High frequency of altered HLA class I phenotypes in invasive colorectal carcinomas.

We analyzed the expression of HLA class I antigens in 78 tumor tissue samples obtained from patients diagnosed as having colorectal carcinomas. A broad panel of mAbs defining HLA monomorphic, locus-specific and allele-specific determinants was used. In addition, an antibody defining HLA-C locus-specific determinant (L31) was also tested. Previous reports on these tumors indicated HLA class I losses of 30 to 40%. At least 73% of the patients in the present study had a detectable HLA class I alteration. These altered HLA phenotypes were classified as total HLA loss (18%) (phenotype I); HLA-A locus-specific loss (9%) (phenotype IIIa); HLA-B locus-specific loss (8%) (phenotype IIIb); HLA-A and B locus losses (2%) and HLA allelic losses (36%) (phenotype IV). We found no HLA-C locus losses. Autologous peripheral blood lymphocyte HLA class I typing was always necessary to define phenotype IV. We also studied the CD3 zeta chain in tumor tissues to correlate possible changes in the CD3 signal transduction pathway with HLA alterations. The CD3 ratio was frequently altered, but this alteration could not be correlated with tumor HLA phenotypes. The high frequency of HLA class I losses in colorectal carcinomas suggests that this finding is a widespread phenomenon and may be required to escape T-cell recognition. It remains to be determined whether HLA expression is "normal" in the rest of the 27% of our patients.

Colorectal carcinoma invasion inhibition by CO17-1A/GA733 antigen and its murine homologue.

The gastrointestinal carcinoma antigen GA733 is a potential target for passive and active immunotherapy for patients with colorectal carcinoma. This antigen has been characterized previously as a homophilic adhesion (i.e., adhesion to self) protein, but the functional consequences of homophilic adhesion for tumor growth and invasion are unknown. The availability of a murine homologue of GA733, i.e., murine epithelial glycoprotein (mEGP), allows for functional analysis of cell adhesion as it relates to tumor growth and invasion, both in vitro and in vivo. CT-26 murine colorectal carcinoma cells were transfected with complementary DNAs encoding either the human or the murine antigen. GA733- or mEGP-producing cells were evaluated for homophilic adhesion, growth on plastic surfaces, colony formation in soft agar, and invasion through a reconstructed basement membrane (Matrigel). mEGP-producing cells were also examined for their capacity to metastasize in mice. Reported P values are two-sided. Compared with control cells, mEGP-producing cells showed significantly lower growth rates, colony formation, and invasion through Matrigel in vitro (all P values <.05). Compared with vector-only transfected cells and parental cells, mEGP-producing cells showed a reduction in metastatic potential in syngeneic immunodeficient and immunocompetent mice (all P values <.05). In contrast to mEGP-transfected cells, GA733-transfected cells did not exhibit significantly reduced growth or colony formation in vitro (all P values >.05). However, GA733-transfected cells did show reduced invasion through Matrigel compared with vector-only transfected cells or parental cells (all P values <.05). The adhesion proteins GA733 and mEGP inhibit invasion of tumor cells.

転移再発した大腸ｓｍ癌の４例

1976年から1993年までに腸切除あるいは経肛門的切除が行われた大腸sm癌症例51例のうち4例 (7.8%) に転移再発が認められた. 4例の肉眼的形態はいずれもIspで平均腫瘍径は20mm, 占居部位はS状結腸2例, Rs 1例, Rb 1例であった. Rbの1例に局所切除, その他の3例に腸切除が行われ, うち2例がリンパ節転移陽性であった. 再発形式は肝転移1例, 肺転移1例, 大動脈周囲リンパ節転移1例, 肝, 肺, リンパ節転移が同時にみられたものが1例で, 転移再発までの期間は9か月から4年 (平均2年7か月) であった.大腸sm癌の転移再発はまれでなく, 組織学的所見からその予測は困難であることから大腸sm癌であっても的確な経過観察が重要であると考えられた.

Clinicopathological study of superficial-type invasive carcinoma of the colorectum

We investigated the relationship between histological parameters such as the level of invasion (scanty submucosal invasion, sm-s or massive submucosal invasion, sm-m), histologic grade (presence or absence of grade III carcinoma), lymphatic invasion, venous invasion, budding and lymph node metastasis in 33 lesions of superficial-type invasive colorectal carcinoma. On statistical analysis, there was no definite influence of any histological parameter on lymph node metastasis. None of 6 sm-s lesions showed lymph node metastasis, however, 7 sm-m lesions were found to have lymph node metastasis (25.9%). Whereas only 16.7% (1/6) of the lesions showing sm-s had one or more unfavorable histological parameters, 85.2% (23/27) of the lesions showing sm-m had one or more of unfavorable histological parameters. There was a significant difference between the two types of lesions (p<0.003). Consequently, in the treatment of superficial-type invasive carcinoma, sm-s lesions without unfavorable histological parameters could be radically cured by endoscopic mucosal resection alone.

Proliferating cell nuclear antigen expression and its relationship to malignancy potential in invasive colorectal carcinomas.

Cellular proliferative activity is a useful indicator of biologic aggressiveness in colorectal carcinoma. Immunohistochemical analysis of proliferating cell nuclear antigen (PCNA) has important advantages of maintaining tissue architecture and technical simplicity. The aim of this study was to investigate the correlation between proliferative activity and malignancy potential in colorectal carcinomas to determine whether proliferative index of cancer cells has prognostic significance using immunohistochemical technique. Proliferation index at the invasive tumor margin of 86 paraffin sections of advanced colorectal carcinomas was assessed by immunohistochemical study using a mouse monoclonal antibody to PCNA (PC-10) and was compared with conventional clinicopathologic factors and other possible prognostic parameters, including p53 overexpression, tissue carcinoembryonic antigen immunoreactivity pattern, and flow cytometric DNA ploidy. In addition, recurrence and survival were analyzed in accordance with degree of PCNA expression. PCNA labeling index (PCNA-LI) increased significantly as the Astler-Coller stage advanced (P = 0.0001). Strong correlations were observed between PCNA-LI and various pathologic parameters, including histologic differentiation (P = 0.0027), lymphatic invasion (P = 0.0001), vascular invasion (P = 0.0001), lymph node metastasis (P = 0.0001), and liver metastasis (P = 0.0036). Mean PCNA-LI was also significantly higher in tumors with DNA aneuploidy (P = 0.0006) and negative and cytoplasmic patterns of carcinoembryonic antigen immunoreactivity (P = 0.01). Linear relationships were demonstrated between PCNA-LI and clinical outcomes; recurrence rate was significantly greater in the group with higher than the mean PCNA-LI, who underwent curative resection (P < 0.01), and four-year survival rates for both overall and curative cases with higher than the mean PCNA-LI were significantly poorer than those with lower than mean PCNA-LI (P < 0.005 and P < 0.01, respectively). Evaluation of PCNA-LI at the invasive tumor margin in colorectal carcinomas is suggested to be valuable in predicting those people with a higher potential for metastasis and recurrence after surgery; thus, the evaluation is helpful in planning reasonable adjuvant therapy, even in the earlier stages.

Determination of β-glucuronidase in human colorectal carcinoma cell lines.

To study the relationship between β-glucuronidase and the invasiveness of human colorectal carcinoma cell lines. Six colorectal carcinoma cell lines, including three well-differentiated (CX1, CCL187, and CCL229) and three poorly differentiated ones (CCL227, CCL228, and Clone A), were analyzed by Fischman's method to determine the concentration of β-glucuronidase in the medium. Low levels of β-glucuronidase (activity range: 1.29 to 1.96 μg/106 cells·h) were associated with poor invasiveness. This finding was in contrast to the elevated levels of the enzyme (2.46-3.37 μg/106·h) detected in the medium derived from the more aggressively invasive cells (CCL 227, CCL 228, Clone A, and CCL 229). Highly invasive colorectal carcinoma cells secreted higher levels of β-glucuronidase than the poorly invasive cells. Determination of secreted β-glucuronidase might represent a useful in vitro measurement tool to assess the invasiveness of colorectal carcinoma.