Eiji Shinto

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.

Preoperative Parameters Expanding the Indication of Sphincter Preserving Surgery in Patients With Advanced Low Rectal Cancer

Objective:To clarify the preoperative parameters of the required distal margin that can be applied to the criteria of sphincter-preserving surgery in rectal cancer. Summary Background Data:Although aggressive sphincter-preserving surgery, including intersphincteric resection, is beginning to be applied to low rectal tumors, unexpected distal cancer spread might undermine local control in patients undergoing such a procedure. The ‘two-centimeter rule’ of distal clearance is predominant at present, whereas preoperative criteria to determine the individual required distal margin have not yet been established. Methods:First, by reviewing 556 rectal cancers, promising risk parameters of intramural distal spread (IM) were selected and, subsequently, such parameters were examined in regard to whether they could be evaluated preoperatively. Furthermore, 80 patients with lower rectal cancers located above the anal canal who were undergoing abdominoperineal resection were reviewed as to whether IM risk factors could be used as criteria to identify the low rectal cancer with or without anal canal involvement. Results:IM was observed in 10.6% (IM ≥ 10 mm: 2.3%) of the patients examined, and the incidence was higher in tumors with certain unfavorable histologic characteristics, including tumor “budding,” in their submucosal region at the distal edge (24.4%) than in those with no such histology (5.3%). Regarding such unfavorable histology as IM risk factor, together with 3/4 or more annularity and type 3 gross appearance, IM rates were 3.3% (IM ≥ 10 mm: 0.5%) in the no-risk group, 9.1% (IM ≥ 10 mm: 1.7%) in the one-risk group, and 29.1% (IM ≥ 10mm: 7.8%) in the multiple-risks group. These results were reproduced well even if such risk factors were evaluated endoscopically or histologically on preoperative biopsy specimens. Furthermore, no anal canal involvement was observed in 32 tumors without IM risk; however, microscopic cancer spread down to the anal canal, including that into outside of the internal sphincter muscle, was observed in 9.1% of tumors with one IM risk and in 26.7% of multiple-risk tumors. Conclusions:The preoperative evaluation of particular parameters related to IM enabled the accurate selection of rectal cancer to which the one-centimeter rule of distal clearance can be applied. This could allow us to expand the indication of sphincter preservation for very low rectal cancer patients.

Correlation of KIT and EGFR overexpression with invasive ductal breast carcinoma of the solid‐tubular subtype, nuclear grade 3, and mesenchymal or myoepithelial differentiation

Although KIT and EGFR overexpressions are reported to occur in breast cancer, their pathological significance is still unclear. We examined KIT, EGFR, and c‐erbB‐2 overexpressions immunohistochemically in 150 cases of surgically resected breast cancer and their correlation with the histological type and grade and mesenchymal and/or myoepithelial immunophenotype of primary tumors. To facilitate the analysis, we constructed a tissue microarray comprising 2‐mm diameter tissues cored from the representative tissue block of each tumor. KIT, EGFR, and c‐erbB‐2 overexpressions were detected in 15 (10%), 12 (8%), and 23 (15%), respectively. The KIT was more frequent in the group comprising comedo‐type ductal carcinoma in situ and invasive ductal carcinomas (IDCs) of the solid‐tubular subtype than in the group of other histological types (P = 0.027), and the EGFR was more frequent in IDCs of solid‐tubular type than in other histological types (P < 0.05). KIT and EGFR overexpressions were correlated with nuclear grade 3 (P = 0.0095 and 0.0005) and tended to be concurrent (P = 0.005). KIT overexpression was correlated with vimentin and S‐100 expression (P = 0.003 and P = 0.005), and EGFR overexpression was correlated with S100 expression (P = 0.0001). These correlations with grade and mesenchymal/myoepithelial markers were not observed for c‐erbB‐2 overexpression. KIT and EGFR appeared to be indicators of high‐grade breast carcinoma groups that often contain the carcinomas with mesenchymal and/or myoepithelial differentiation, which are distinct from the group with c‐erbB‐2 overexpression. (Cancer Sci 2005; 96: 48 –53)

Optimal margins and lymphadenectomy in colonic cancer surgery

A standard management policy has not yet been established with respect to the extent of lymphadenectomy for colonic cancer.

Prognostic implication of laminin-5 gamma 2 chain expression in the invasive front of colorectal cancers, disclosed by area-specific four-point tissue microarrays

The laminin-5 gamma 2 chain (LN-5γ2) is known to be a marker of invasion in several cancer types. Our purpose was to examine the prognostic significance of LN-5γ2 expression in different areas of individual colorectal cancers (CRCs) by using tissue microarrays (TMAs), and to clarify the optimal areas for prognostic assessment. Using formalin-fixed paraffin-embedded tissue blocks of pT3 primary CRCs resected from 120 patients, we constructed TMA blocks of tissue core specimens taken from the submucosal invasive front, subserosal invasive front, central area, and rolled edge of each tumor. Using these four-point TMA sets, cytoplasmic LN-5γ2 expression was immunohistochemically surveyed, and the area-specific prognostic significance of LN-5γ2 expression was evaluated. The data revealed that 35, 30, 15 and 10% of the 120 CRCs showed high-grade LN-5γ2 expression in the submucosal invasive front, subserosal invasive front, central area and rolled edge, respectively. Disease-specific survival curves for the groups with high- and low-grade LN-5γ2 in the submucosal invasive front and subserosal invasive front were different significantly or of marginal difference (respective 5-year survival rates: 54 and 78% for submucosal invasive front (P=0.030) and 58 and 75% for subserosal invasive front (P=0.055)). Multivariate analysis revealed that the grades of LN-5γ2 expression in submucosal invasive front (hazard ratio=2.0, P=0.047) and subserosal invasive front (hazard ratio=2.9, P=0.0033) were independent prognostic factors. In contrast, the grades of LN-5γ2 expression in the central area and rolled edge did not have a significant impact on patient prognosis. Analysis using area-specific four-point TMAs clearly demonstrated that LN-5γ2 expression in the invasive front largely influences the degree of clinical aggressiveness of CRC and its tendency to metastasize.

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.

Site-specific Tumor Grading System in Colorectal Cancer Multicenter Pathologic Review of the Value of Quantifying Poorly Differentiated Clusters

The study aimed to determine the value of a novel site-specific grading system based on quantifying poorly differentiated clusters (PDC; GradePDC) in colorectal cancer (CRC). A multicenter pathologic review involving 12 institutions was performed on 3243 CRC cases (stage I, 583; II, 1331; III, 1329). Cancer clusters of ≥5 cancer cells and lacking a gland-like structure (PDCs) were counted under a ×20 objective lens in a field containing the maximum clusters. Tumors with <5, 5 to 9, and ≥10 PDCs were classified as grades G1, G2, and G3, respectively. According to GradePDC, 1594, 1005, and 644 tumors were classified as G1, G2, and G3 and had 5-year recurrence-free survival rates of 91.6%, 75.4%, and 59.6%, respectively (P<0.0001). Multivariate analysis showed that GradePDC exerted an influence on prognostic outcome independently of TNM staging; approximately 20% and 46% of stage I and II patients, respectively, were selected by GradePDC as a population whose survival estimate was comparable to or even worse than that of stage III patients. GradePDC surpassed TNM staging in the ability to stratify patients by recurrence-free survival (Akaike information criterion, 2915.6 vs. 2994.0) and had a higher prognostic value than American Joint Committee on Cancer (AJCC) grading (GradeAJCC) at all stages. Regarding judgment reproducibility of grading tumors, weighted &kgr; among the 12 institutions was 0.40 for GradeAJCC and 0.52 for GradePDC. GradePDC has a robust prognostic power and promises to be of sufficient clinical value to merit implementation as a site-specific grading system in CRC.

T Lymphocyte Numbers in Human Gut Associated Lymphoid Tissue Are Reduced Without Enteral Nutrition

BACKGROUND Clinically, in the absence of enteral nutrition, the morbidity of infectious complication is high. Although experiments using mice have shown alterations in gut-associated lymphoid tissue (GALT) to be an important mechanism underlying impaired host defense, there are no clinical studies on the effects of nutritional routes on GALT. METHODS A total of 27 colon cancer cases who underwent right colectomy or hemicolectomy were reviewed. Six patients did not receive enteral nutrition for 4 to 28 days before surgery because of bowel obstruction (parenteral nutrition [PNI group). Twenty-one patients were enterally fed before surgery (enteral nutrition [EN] group). The terminal ileum from resected specimens was examined microscopically. T-cell numbers in intraepithelial spaces (IE) and the lamina propria (LP) were determined immunohistochemically in blinded fashion. RESULTS There were no significant differences in baseline characteristics between the 2 groups. T-cell number in the LP was significantly lower in the PN group than in the EN group, with no difference in IE cell numbers. CONCLUSIONS Lack of enteral delivery of nutrients reduces GALT cell number in patients with colon cancer, as is the case in mice.

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.