Hideyuki Shimazaki

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.

Primary small cell (oat cell) carcinoma of the breast: Report of a case and review of the literature

A case of primary small cell (oat cell) carcinoma of the breast in a 41‐year‐old woman is presented. The patient was alive and well without disease 16 months after modified radical mastectomy and subsequent chemotherapy. The tumor cells revealed morphologic similarity to oat cell carcinoma of the lung and immunohistochemical expression of neuroendocrine markers. In ultrastructural examination, the tumor cells had neurosecretory granules. Review of nine previously reported cases and this case of primary small cell carcinoma of the breast has revealed that this type of tumor shows prominent vascular invasion, frequent lymph node metastasis, infrequent expression of estrogen receptor, and also very poor prognosis. Immunohistochemical study for the c‐kit proto‐oncogene product, which has been reported to be a specific marker for pulmonary small cell carcinoma, demonstrated positive reactivity in approximately 80% of the tumor cells of this case, which is the first report according to our knowledge. The expression of c‐kit might be some aid to the diagnosis of primary small cell carcinoma of the breast.

Optimal Colorectal Cancer Staging Criteria in TNM Classification

PURPOSE Histologic components of the TNM classification system have been repeatedly revised since the fifth edition (TNM5). TNM classification revisions provide different criteria for categorizing tumor nodules without residual lymph node structure (ND). However, there are few systematic evaluations regarding the effectiveness of these revisions. PATIENTS AND METHODS A multicenter pathologic review for ND in colorectal cancer (CRC) was performed. Tumor staging defined by TNM5, sixth edition (TNM6), and seventh edition (TNM7) were compared on the basis of Akaike information criterion (AIC) and Harrells concordance index (c-index). Moreover, TNM7s prognostic value was compared between the original ND and modified criteria, which considered all regional NDs as lymph node metastasis (LNM) irrespective of the original structure. RESULTS In 1,716 treated patients with CRC (1994 to 1998), tumor stages (I/II/III) exhibited better prognoses in TNM7 (AIC, 3055.1; c-index, 0.7215) than in TNM6 (AIC, 3063.7; c-index, 0.7149), but not better than in TNM5 (AIC, 3051.6; c-index, 0.7240). Comparing the original TNM7 and modified criteria, 4.2% of patients were classified in different N stages (N0/N1/N2a/N2b); both AIC and the c-index were superior in the modified criteria (AIC, 3029.40; c-index, 0.7271) compared with the original criteria (AIC, 3040.58; c-index, 0.7230). Modified criteria were also associated with improved prognostic power of tumor stages (I/IIA/IIB/IIC/IIIA/IIIB/IIIC). These results were similar in another cohort of 2,242 treated patients with CRC (1999 to 2003). CONCLUSION The prognostic value of TNM7 is better than that of TNM6; however, improvement over TNM5 is insignificant. By considering all regional NDs as LNM irrespective of their morphology, TNM classification can be simplified and its prognostic value improved.

Increased xCT expression correlates with tumor invasion and outcome in patients with glioblastomas.

BACKGROUND xCT is a light chain of the cystine/glutamate antiporter system xc. Glutamate that is released by system xc plays an important role in the infiltration of glioblastoma (GBM) cells. Furthermore, increased glutathione synthesis by system xc may protect tumor cells against oxidative stress induced by radiotherapy and chemotherapy. OBJECTIVE To investigate whether the levels of xCT expression correlated with infiltrative imaging phenotypes on magnetic resonance imaging and outcomes in patients with GBMs. METHODS Forty patients with histologically confirmed primary GBMs were included in the study. Patient charts were retrospectively reviewed for age, sex, Karnofsky Performance Status Scale score, Mini-Mental State Examination score, magnetic resonance imaging features, xCT expression, isocitrate dehydrogenase 1 R132H expression, O-methylguanine-DNA methyltransferase promoter methylation status, type of surgery, progression-free survival, and overall survival. RESULTS In invasive margins, xCT expression was weak in 20 patients and strong in 20 patients. A Cox regression model revealed that a Karnofsky Performance Status Scale score less than 60 (hazard ratio [HR]: 4.525; P = .01), partial removal (HR: 2.839; P = .03), and strong xCT expression (HR: 4.134; P < .001) were significantly associated with shorter progression-free survival and that partial removal (HR: 2.865; P = .03), weak isocitrate dehydrogenase 1 R132H expression (HR: 15.729; P = .01), and strong xCT expression (HR: 2.863; P = .04) were significantly associated with shorter overall survival. CONCLUSION These findings suggest that xCT is an independent predictive factor in GBMs.

Solitary peripheral ciliated glandular papillomas of the lung: a report of 3 cases.

We report 3 cases of solitary papillomas located in peripheral regions of the lung that are extremely rare in the literature. The patients were 75-year-old and 72-year-old men and a 53-year-old woman. One patient complained of recurrent hemoptysis. The other 2 had no symptoms, but abnormal nodular shadows were revealed by chest radiographs during a health check. The maximum diameters of the tumors were 1.0, 1.4, and 1.1 cm, respectively. The 3 tumors gave almost the same histologic findings. Papillomatous fronds lined by a stratified columnar epithelium were seen in the lumens of peripheral bronchi, bronchioles, or alveoli. The stratified columnar epithelium consisted of ciliated, mucous, and basal cells. The neoplastic epithelium extended to the alveolar region and showed a similar appearance to bronchioloalveolar or papillary type adenocarcinomas. For differential diagnosis, it is noteworthy that endobronchiolar papillomatous fronds constantly exist and spreading along alveolar walls is limited in adjacent alveoli in peripheral papillomas. The presence of ciliated cells and basal cells is considered an important finding to suggest benign character of the lesion.

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.

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.

Characterization of perineural invasion as a component of colorectal cancer staging.

Perineural invasion (PN) in colorectal cancer (CRC) is a site-specific prognostic marker, as mentioned by the AJCC Cancer Staging Manual, but it remains to be clearly defined. We aimed to identify an optimal characterization of PN as a component of cancer staging. On the basis of the anatomic features of the nervous system of the large bowel, site-specific pathologic criteria were assigned to PN according to the location of PN. Multi-institutional pathologic review based on these criteria was performed for 962 patients with stage I to III CRC at 2 institutions (1999 to 2004, cohort 1) and 1883 patients from 8 other institutions (2000 to 2004, cohort 2). In cohort 1, intramural and extramural PN were observed in 152 and 101 patients, respectively, which had a different impact on disease-free survival (hazard ratio, 2.6 [1.9 to 3.5] vs. 4.7 [3.4 to 6.5], respectively). A 3-tiered grading system (Pn0; Pn1a, intramural PN; Pn1b, extramural PN) distinguished 5-year disease-free survival as 88%, 70%, and 48%, respectively; and multivariate analysis identified PN grade as a significant prognostic marker independent of T or N stage. These results were similar in cohort 2. Interinstitutional difference of the prognostic impact of PN grade was acceptably small among all institutions. Interobserver study among 6 gastrointestinal pathologists showed superior judgment reproducibility for PN compared with vascular invasion. The results of our study indicate that PN is an important prognostic marker in CRC. The value of cancer staging could be enhanced by PN assessment using site-specific criteria and a simple grading system based on PN location within the bowel.