Yoshiki Kajiwara

New criteria for histologic grading of colorectal cancer.

Conventional tumor grading systems based on the degree of tumor differentiation may not always be optimal because of difficulty in objective assessment and insufficient prognostic value for decision making in colorectal cancer (CRC) treatment. This study aimed to determine the importance of assessing the number of poorly differentiated clusters as the primary criterion for histologic grading of CRC. Five hundred consecutive patients with curatively resected stage II and III CRCs (2000 to 2005) were pathologically reviewed. Cancer clusters of ≥5 cancer cells and lacking a gland-like structure were counted under a ×20 objective lens in a field containing the highest number of clusters. Tumors with <5, 5 to 9, and ≥10 clusters were classified as grade (G)1, G2, and G3, respectively (n=156, 198, and 146 tumors, respectively). Five-year disease-free survival rates were 96%, 85%, and 59% for G1, G2, and G3, respectively (P<0.0001). Poorly differentiated clusters affected survival outcome independent of T and N stages and could help in more effective stratification of patients by survival outcome compared with tumor staging (Akaike information criterion, 1086.7 vs. 1117.0; Harrell concordance index, 0.73 vs. 0.67). The poorly differentiated cluster-based grading system showed a higher weighted &kgr; coefficient for interobserver variability (5 observers) compared with conventional grading systems (mean, 0.66 vs. 0.52; range, 0.55 to 0.73 vs. 0.39 to 0.68). Our novel histologic grading system is expected to be less subjective and more informative for prognostic prediction compared with conventional tumor grading systems and TNM staging. It could be valuable in determining individualized postoperative CRC treatment.

Potential Prognostic Benefit of Lateral Pelvic Node Dissection for Rectal Cancer Located Below the Peritoneal Reflection

Objective:To identify the parameters related to the effective selection of patients who could receive prognostic benefit from lateral pelvic node dissection. Background:Accurate preoperative diagnosis of lateral nodal involvement (LNI) remains difficult, and the indications for lateral lymph node dissection have been controversial. Patients and Methods:A total of 244 consecutive patients who underwent potentially curative surgery with lateral dissection for advanced lower rectal cancer (1985–2000) were reviewed. Patients were stratified into groups based on various parameters, and the therapeutic value index for survival benefit was compared among groups. The therapeutic index of lateral dissection was calculated by multiplying the frequency of metastasis to the lateral area and the cancer-related 5-year survival rate of patients with metastasis to the lateral area, irrespective of metastasis to other areas (mesorectal, superior rectal artery [SRA], and inferior mesenteric artery [IMA] areas). Results:LNI was observed in 41 patients (17%); and 88% of them had nodal involvement in the region along the internal iliac/pudendal artery or in the obturator region (“vulnerable field”). The cancer-related 5-year survival rate among the patients with LNI was 42%; the therapeutic index for lateral dissection was calculated as 7.0 patients, which was much higher than that of lymphadenectomy of the SRA area (1.6 patients) and the IMA area (0.4 patients), and almost comparable to that of lymphadenectomy of the upward mesorectal area (6.9 patients). Although it was possible to select groups at high and low risk for LNI based on several parameters related to tumor aggressiveness, such as tumor differentiation in biopsy specimens, the therapeutic value index was not significantly different between these groups. Unlike these parameters, the diameter of the largest lymph node in the “vulnerable field,” which was positively correlated with the rate of LNI but irrelevant to the prognosis, was able to successfully stratify patients by therapeutic index. Conclusions:Advanced lower rectal cancer patients having LNI in the lateral pelvic area are likely to receive prognostic benefit from lymphadenectomy. The most efficient means of determining the effectiveness of lateral dissection preoperatively is to estimate the nodal diameter in the “vulnerable” lateral regions by diagnostic imaging.

Prognostic significance of the number of lymph nodes examined in colon cancer surgery: clinical application beyond simple measurement.

Objective:To identify an optimal cutoff value for the number of lymph node examined (NLNE) to distinguish the prognoses in patients following a curative resection for advanced colon cancer, to clarify the mechanism of the difference, and to suggest the integration of NLNE to colon cancer staging. Patients and Methods:A total of 859 patients who had undergone surgical treatment for localized colon cancer from 1980 to 2000 were reviewed. This was a cohort from a single institution with mean NLNE of 20.7 and more than 12 NLNE in 77% of the patients. The optimal breakpoint for NLNE was calculated by a receiver operating characteristic curve (ROC) analysis. The patients were stratified into groups based on various parameters and underwent univariate and multivariate analyses with respect to survival. Results:The ROC analysis identified NLNE as a significant prognostic factor with cutoff value of 18 for node-negative and 20 for node-positive patients. A multivariate analysis with these cutoff values identified NLNE as a significant prognostic factor independent of tumor depth and the number of lymph nodes involved. The 5-year cause-specific survival of stage IIB patients was 96.5% with 18 or more NLNE and 67.5% with NLNE less than 18 (P[r] = 0.0067). Similarly, a cutoff value of 20 NLNE for node-positive patients separated the 5-year cause-specific survival of stage IIIB patients into 79.3% with 20 or more NLNE and 63.3% with less than 20 NLNE (P = 0.0052). Conclusions:The clinical significance of NLNE is not limited to being a benchmark for quality care, but has a definite benefit as a prognostic indicator across the stages. Patients could be stratified more efficiently by the integration of NLNE to TNM staging.

Objective criteria for the grading of venous invasion in colorectal cancer.

PurposeTo establish an objective histologic grading system of venous invasion. MethodsA total of 229 patients with pT3 and pT4 colorectal cancer who underwent curative surgery with lymph node dissection were retrospectively analyzed. Potential prognosis-related characteristics of venous invasion, including the number of venous invasion, morphologic type of venous invasion, maximum size of veins invaded, and location of venous vessel involved were evaluated on elastica van Gieson stained sections. ResultsThe relapse-free survival curves between the venous-invasion-positive group and the negative group were significantly different (5 y survival rates were 73.4% and 92.2%, respectively, P=0.001). When patients were divided into 3 groups according to the average number of venous invasions observed in a glass slide [G0 (none), G1 (positive but <4), and G2 (4 or more)], there was a significant difference in the survival rate among the 3 groups [5 y survival rates were 92.2%, 77.8%, and 56.4%, respectively, P=0.008 (G0 vs. G1), P=0.017 (G1 vs. G2)]. The postoperative recurrence rate was 10.8% in the G0 patients, whereas it was 32.5% in the G1 and 51.7% in the G2 patients [P=0.0007 (G0 vs. G1), P=0.047 (G1 vs. G2)]. Multivariate analysis showed the number of venous invasions [hazard ratio (HR) 2.72, P=0.027], depth of invasion (HR 2.26, P=0.014), and lymph node metastasis (HR 2.43, P=0.008) were independent prognostic factors. ConclusionsThree ranked tumor grading system based on the number of venous invasion in a glass slide with elastica van Gieson staining could be an objective and important treatment index for colorectal cancer patients.

Histological grading of colorectal cancer: a simple and objective method.

Objective:Tumor grade employed for colorectal cancer has long been based on the degree of differentiation, which is difficult to judge objectively. The aim of this study was to determine whether the extent of the poorly differentiated component (POR) could be a valuable criterion for a grading system. Patients and Methods:A total of 1075 patients with advanced colorectal cancer were pathologically reviewed. POR was newly defined as a region in which a cancer has no glandular formation, irrespective of a mucin-producing or invasive pattern, and we quantitatively classified the POR into 6 degrees using the microscopic field of an objective lens as a standard. Results:Survival analyses of the extent of POR demonstrated that a 3-category grading system provides the most efficient survival stratification. Grade III was applied to tumors (n = 339) for which the POR fully occupied the microscopic field of a 40× objective lens. For tumors having a smaller POR, cancer clusters without a gland structure composed of ≥5 cancer cells (“clusters”) were counted in the microscopic field of a 4× objective lens, where “clusters” were observed most intensively. Tumors with <10 “clusters” were classified as grade I (n = 161), and those with ≥10 “clusters” as grade II (n = 575). Patients classified as grade I demonstrated a very favorable prognosis, with a 99.3% cancer-related 5-year survival rate, whereas the survival was 86.0% for grade II and 68.9% for grade III (P < 0.0001 in each group). Multivariate analysis demonstrated that the grades of POR function as an independent prognosticator, as do T-stage and N-stage. Conclusions:The grading system utilizing POR is distinctive in terms of the simplicity of judgment based on its quantification and the ability to determine which patients will likely be cured by surgery alone. It will aid in selecting postoperative treatment strategies.

Risk factors of nodal involvement in T2 colorectal cancer.

PURPOSE: Because of the adverse consequences of radical resection of T2 colorectal cancer, criteria are needed for selection of patients who can safely undergo local excision without requiring additional radical surgery. We therefore conducted a retrospective study of patients with T2 colorectal cancer to identify risk factors for nodal involvement that might be used in selecting patients for local excision. METHODS: We reviewed records from consecutive patients who had undergone curative resection of T2 colorectal cancer at the Department of Surgery, National Defense Medical College, Saitama, Japan, between 1985 and 2005. Data on conventional clinicopathologic variables were retrieved from pathology reports at the time of surgery, and archived slides were evaluated regarding potential risk factors such as extent of poorly differentiated component (grade I-III), myxoid cancer stroma, tumor budding, and growth pattern and invasion depth in the muscularis propria. RESULTS: A total of 244 patients (139 men and 105 women) treated for T2 colorectal cancer were included. Nodal involvement was found in 7 (8.4%) of 83 patients classified as grade I on the poorly differentiated component vs. 47 (29.2%) of 161 patients classified as grade II or III (P < .001). Of 148 patients negative for myxoid cancer stroma, 30 (16.9%) had nodal involvement vs. 24 (36.4%) of 42 patients who were positive for myxoid cancer stroma (P = .0011). According to multiple variable logistic analysis, significant independent risk factors for nodal involvement included poorly differentiated component (P = .002), myxoid cancer stroma (P = .032), and lymphovascular invasion (P = .022). CONCLUSIONS: Poorly differentiated component, myxoid cancer stroma, and lymphovascular invasion are significant independent risk factors for nodal involvement in T2 colorectal cancer. We need further study to validate these results on another data set, especially in patients with rectal cancer, and to confirm whether local resection of T2 rectal cancer is able to predict the nodal involvement before laparotomy.

Impact of race/ethnicity on prognosis in patients who underwent surgery for colon cancer: analysis for white, African, and East Asian Americans.

PurposeWe retrospectively investigated the impact of race/ethnicity on prognosis in patients who underwent surgery for colon cancer.MethodsSurveillance, Epidemiology, and End Results population-based data on 39,210 colon cancer patients without distant metastasis who underwent radical surgery were analyzed. Prognostic impact of race/ethnicity for non-Hispanic white, Hispanic white, African American, and East Asian (Japanese, Chinese, Korean) American patients, and confounding factors of age, sex, registry region, year of diagnosis, tumor, node, metastasis system stage, tumor grade, tumor site, and the number of lymph nodes examined were analyzed by the Cox proportional hazard model. The lymph node count was analyzed and adjusted means were calculated by a generalized multiple regression model with respect to race and other factors.ResultsSignificant differences due to race/ethnicity were observed in crude hazard ratios with respect to overall and colon cancer-specific mortality, which persisted even after adjusting for confounding factors. Adjusted hazard ratios of colon cancer-specific mortality for non-Hispanic white, Hispanic white, African American, and East Asian American patients were 1 (reference), 1.01 (95% confidence interval 0.91–1.12), 1.40 (95% confidence interval 1.31–1.50), and 0.83 (95% confidence interval 0.74–0.94), respectively. There were significant differences in crude number of lymph nodes examined among races, which were no longer significant after adjusting for covariates.ConclusionsEast Asian American patients had significantly better prognosis, while African American patients had worse prognosis than non-Hispanic white patients, despite the identical adjusted number of lymph nodes examined after surgery for colon cancer. This disparity in prognosis among races/ethnicities should be taken into consideration when deciding adjuvant chemotherapy for nonwhite patients.

Expression of L1 Cell Adhesion Molecule and Morphologic Features at the Invasive Front of Colorectal Cancer

To obtain the correlation between morphologic features in the invasive fronts of colorectal cancer (CRC) and L1 cell adhesion molecule (L1CAM) expression, 275 CRCs were assessed with L1CAM immunostaining and 29 CRCs were examined for L1CAM messenger RNA (mRNA) expression. Based on immunostaining, the positive rate of L1CAM expression increased according to the grade of tumor budding (P = .0002) and solid cancer nests (SCNs; P = .0046). L1CAM mRNA levels at the invasive front of the tumor were higher than those at the center of the tumor (median, 3.7-fold). The gap of L1CAM mRNA level between the invasive front and the central area was 7.3-fold in tumors having SCN lesions, whereas it was 1.9-fold in tumors having non-SCN lesions (P = .0004). L1CAM expression was correlated with nodal involvement in protein and mRNA levels (P = .0007 and P = .036, respectively). Tumor regulation of L1CAM expression is associated with morphologic features at the invasive front in CRC.

Prognostic impact of histological categorisation of epithelial–mesenchymal transition in colorectal cancer

Background:The crosstalk between cancer cells and stroma is involved in the acquired capability for metastasis through the induction of epithelial–mesenchymal transition (EMT). We aimed to clarify the prognostic value of the histological category of EMT in colorectal cancer (CRC).Methods:Tumour EMT was graded into one of three histological categories on the basis of integrated assessment of poorly differentiated clusters and pro-EMT desmoplasia at the leading edge of the primary tumour (HistologyEMT). Stage II and III CRC patients (cohort 1, N=500) and stage IV patients (cohort 2, N=196) were retrospectively analysed.Results:In cohort 1, patients were stratified into three groups with widely different disease-free survival rates (95%, 83% and 39%) on the basis of HistologyEMT (P<0.0001). In cohort 2, HistologyEMT significantly stratified overall survival of patients irrespective of metasectomy. Multivariate analyses indicated that HistologyEMT had a strong prognostic impact independent of staging factors. Statistically, HistologyEMT had a better prognostic stratification power than T and N stages; however, in cohort 2, the power of M substage was superior.Conclusions:A histological model to categorise EMT by integrated assessment of dedifferentiation and desmoplastic environment is a potent prognostic index independent of staging factors.

Peritumoral deposits as an adverse prognostic indicator of colorectal cancer.

BACKGROUND The aim of this study was to determine the prognostic value of peritumoral deposits (PTDs) in colorectal cancer (CRC). METHODS A total of 695 patients with pT3/T4 CRC (1980 to 1999) were reviewed. Tumor deposits located ≥2 mm from the front of the direct spread in the primary tumor were evaluated as PTDs. RESULTS PTDs were observed in 111 patients (16.0%). The incidence of PTDs increased according to increasing N stage: 7% for N0, 22% for N1, and 39% for N2 (P < .0001). Five-year disease-specific survival was 85.0% in patients without PTDs and 59.5% in those with PTDs (P < .0001). Multivariate analysis showed that PTDs affected disease-specific survival independent of T and N stages. A significant prognostic impact of PTDs was similarly observed in another cohort comprising 474 patients with pT3/T4 CRC (2000 to 2005). The κ values among 8 observers were .70 for PTDs and .32 for the conventional growth pattern. CONCLUSIONS PTDs have considerable prognostic relevance and offer improved judgment reproducibility in assessing the invasive margin of CRC.