Motoki Iwasaki

Histopathological criteria for additional treatment after endoscopic mucosal resection for esophageal cancer: analysis of 464 surgically resected cases

No previous reports on lymph-node metastasis (LNM) from superficial squamous cell carcinoma of the esophagus have proposed definite criteria for additional treatment after endoscopic mucosal resection (EMR). We investigated the association between histopathological factors and LNM in 464 consecutive patients with superficial squamous cell carcinoma of the esophagus who had undergone a radical esophagectomy with lymph-node dissection (14 ‘M1’ lesions: intraepithelial tumors, 36 ‘M2’ lesions: tumors invading the lamina propria, 50 ‘M3’ lesions: tumors in contact with or invading the muscularis mucosa, 32 ‘SM1’ lesions: tumors invading the most superficial 1/3 of the submucosa and 332 ‘SM2/3’ lesions: tumors invading deeper than SM1 level). Histopathological factors including invasion depth, size, lymphatic invasion (LY), venous invasion, tumor differentiation, growth pattern, degree of nuclear atypia and histological grade were assessed for their association with LNM in 82 M3 or SM1 lesions to determine which patients need additional treatment after EMR. LNM was found in 0.0, 5.6, 18.0, 53.1 and 53.9% of the M1, M2, M3, SM1 and SM2/3 lesions, respectively. A univariate analysis showed that each of the following histopathological factors had a significant influence on LNM: invasion depth (M3 vs SM1), LY, venous invasion and histological grade. Invasion depth and LY were significantly associated with LNM in a multivariate analysis. Four out of 38 patients (10.3%) with M3 lesions without LY had LNM, whereas five out of 12 patients (41.7%) with M3 lesions and LY had LNM. Only patients with M1/2 lesions are good candidates for EMR. Invading the muscularis mucosa (M3) is a high-risk condition for LNM the same as submucosal invasion, but M3 lesions without LY can be followed up after EMR without any additional treatment.

Metaplastic carcinoma of the breast

The purposes of this study were to investigate whether the biological characteristics or outcomes of patients with metaplastic carcinoma, invasive ductal carcinoma, or invasive lobular carcinoma of the breast differ; to determine whether the metaplastic carcinoma subtypes have similar malignant potentials; and to identify accurate predictors of outcome in patients with metaplastic carcinoma. The subject comprised 6137 invasive ductal carcinoma patients, 301 invasive lobular carcinoma patients, and 46 metaplastic carcinoma patients of the breast. The metaplastic carcinomas were classified according to the World Health Organization classification. Multivariate analyses clearly demonstrated that the metaplastic carcinoma patients had a significantly poorer outcome than the invasive ductal carcinoma patients or the invasive lobular carcinoma patients independent of the nodal status or age not exceeding 39 years, whereas patients with triple-negative metaplastic carcinomas or triple-negative invasive lobular carcinomas had a poorer outcome than those with triple-negative invasive ductal carcinomas. Although no significant differences in clinical outcome were observed among the metaplastic carcinoma subtypes in multivariate analyses, an age not exceeding 39 years, the presence of skin invasion, and the presence of a squamous cell carcinoma component in nodal tumors were significant outcome predictors for metaplastic carcinoma patients. In conclusion, the results of this study clearly demonstrated that metaplastic carcinoma is more aggressive than invasive ductal carcinoma or invasive lobular carcinoma. Although the metaplastic carcinoma subtypes had no prognostic significance, an age not exceeding 39 years, the presence of skin invasion, and the presence of a squamous cell carcinoma component in nodal tumors were significant predictors of outcome among metaplastic carcinoma patients.

p53 expression in tumor-stromal fibroblasts is closely associated with the nodal metastasis and outcome of patients with invasive ductal carcinoma who received neoadjuvant therapy

The purpose of this study was to determine whether p53 immunoreactivity in tumor-stromal fibroblasts assessed by the Allred scoring system in biopsy specimens obtained before neoadjuvant therapy and assessed in surgical specimens obtained after neoadjuvant therapy is significantly associated with nodal metastasis by invasive ductal carcinoma and with the outcome of 318 patients with invasive ductal carcinoma who received neoadjuvant therapy, according to UICC pathologic TNM stage, in multivariate analyses with well-known clinicopathologic factors. The Allred scores for p53 in tumor-stromal fibroblasts in the surgical specimens were significantly associated with the presence of nodal metastasis. The Allred scores for p53 in the tumor-stromal fibroblasts of biopsy and surgical specimens were a very important outcome predictive factor for patients who received neoadjuvant therapy, independent of UICC pathologic TNM status, but the outcome predictive power of the Allred scores for p53 in tumor-stromal fibroblasts assessed in the surgical specimens was superior to that of the Allred scores for p53 in tumor-stromal fibroblasts in the biopsy specimens. The results indicated a close association between p53 protein expression in tumor-stromal fibroblasts, especially in surgical specimens, and both the presence of nodal metastasis and the outcome of invasive ductal carcinoma patients who received neoadjuvant therapy.

Atypical tumor-stromal fibroblasts in invasive ductal carcinoma of the breast.

Tumor-stromal fibroblasts have recently been reported to play important roles in the tumor progression of cancer in various organs. The purpose of this study was to investigate whether any characteristic histologic features of tumor-stromal fibroblasts could accurately predict the outcome of 1042 patients with invasive ductal carcinoma of the breast. We observed a small number of tumor-stromal fibroblasts with characteristic nuclear features existing inside and outside of fibrotic foci and named them atypical tumor-stromal fibroblasts. We then classified invasive ductal carcinomas into 4 types (1, 2, 3, and 4) according to the absence or presence of fibrotic foci and the absence or presence of atypical tumor-stromal fibroblasts. We then analyzed the outcome predictive powers of these types of invasive ductal carcinomas using multivariate analyses that included well-known clinicopathologic factors. The multivariate analyses showed that type 4 invasive ductal carcinomas with fibrotic foci and atypical tumor-stromal fibroblasts had significantly higher hazard ratios for tumor recurrence and tumor-related death, independent of the nodal status and histologic grade, and the type 2 invasive ductal carcinomas without fibrotic foci but with atypical tumor-stromal fibroblasts had a significant higher hazard ratio for tumor recurrence among patients with invasive ductal carcinoma with nodal metastasis and those with histologic grade 3 disease. The results of this study clearly indicated that the presence of atypical tumor-stromal fibroblasts, especially in fibrotic foci, is significantly associated with tumor recurrence and tumor-related death of patients with invasive ductal carcinoma of the breast.

p53 expression in tumor stromal fibroblasts is associated with the outcome of patients with invasive ductal carcinoma of the breast

The purpose of this study was to determine whether p53 protein expression in tumor stromal fibroblasts assessed immunohistochemically by the Allred score system is significantly associated with nodal metastasis by invasive ductal carcinoma (IDC), and significantly associated with the outcome of 1042 IDC patients according to adjuvant therapy status, UICC pTNM stage, and triple‐negative IDC status, in multivariate analyses with well‐known clinicopathological factors. The Allred scores for p53 expression in tumor stromal fibroblasts were significantly associated with the number of nodal metastases, and Allred scores of 4–8 for p53 in tumor stromal fibroblasts significantly increased the hazard rate for distant organ metastasis or for tumor death in the triple‐negative IDC patients, and the UICC pTNM stage I, II, and III patients. The results indicated that p53 protein expression in tumor stromal fibroblasts is closely associated with the number of nodal metastases and the outcome of IDC patients. (Cancer Sci 2009; 00: 000–000)

Important histologic outcome predictors for patients with invasive ductal carcinoma of the breast.

The pathologic diagnosis is regarded as the final diagnosis of a disease, and pathologic examination based on tumor histology is very important for the accurate assessment of the biological characteristics of tumors. The purpose of this study was to investigate the histologic factors that accurately predict patient outcome among 1042 patients with invasive ductal carcinoma of the breast. Both well-known histologic factors and our proposed histologic factors were examined according to several tumor statuses using multivariate analysis. This study clearly demonstrated that type 4 invasive ductal carcinomas having fibrotic foci and atypical tumor-stromal fibroblasts within the fibrotic foci are significant outcome predictors for lymph node-negative and lymph node-positive, the pathologic UICC-TNM stage II and III, luminal A-subtype, luminal B-subtype, and equivocal HER2 subtype invasive ductal carcinoma patients. Lymph vessel tumor embolus grades 2 and 3 were significant outcome predictors for lymph node-positive, UICC pTNM stages II and III, luminal A-subtype, and triple-negative invasive ductal carcinoma patients (except lymph vessel tumor embolus grade 2 in luminal A-subtype patients). More than 5 mitotic figures in metastatic carcinoma to the lymph nodes was a significant outcome predictor for lymph node-positive, UICC pTNM stage II, and luminal A-subtype invasive ductal carcinoma patients. A fibrotic focus diameter >8 mm was a significant outcome predictor for UICC pTNM stages I and III invasive ductal carcinoma patients. These findings strongly suggest that these histologic factors are very useful for accurately predicting the outcomes of patients with invasive ductal carcinoma of the breast.

Grading system for lymph vessel tumor emboli: significant outcome predictor for invasive ductal carcinoma of the breast

The purpose of this study was to confirm that the grading system for lymph vessel tumor emboli is a significant histologic outcome predictor for patients with invasive ductal carcinoma. The subjects of this study were 1042 invasive ductal carcinoma patients who did not receive neoadjuvant therapy. We classified all invasive ductal carcinomas according to the grading system for lymph vessel tumor emboli we devised, and performed multivariate analyses with well-known prognostic factors. Of 1042 carcinomas, 666, 250, 97, and 29 were classified according to the grading system for lymph vessel tumor emboli as grade 0 (no lymph vessel invasion), grade 1, grade 2, and grade 3, respectively. The univariate analyses showed that the difference in outcome between the group with grade 0 and the group with grade 1 was not significant, but that survival time was significantly shorter in the group of patients with grade 2 carcinomas than in the group with grade 1 carcinomas and significantly shorter in the group of patients with grade 3 carcinomas than in the group with grade 2 carcinomas. Multivariate analyses demonstrated that having a grade 2 or grade 3 carcinoma significantly increased the hazard rates for tumor recurrence and tumor-related death in the patients as a whole as well as in both the group of patients with nodal metastasis and the group without nodal metastasis. The grading system for lymph vessel tumor emboli is an excellent histologic grading system for predicting the outcome of patients with invasive ductal carcinoma of the breast.

p53 expression in tumor-stromal fibroblasts forming and not forming fibrotic foci in invasive ductal carcinoma of the breast

The purpose of this study was to determine whether p53 protein expression in tumor-stromal fibroblasts forming fibrotic foci is a significant outcome predictor, similar to p53 protein expression in tumor-stromal fibroblasts not forming fibrotic foci, and whether the combined assessment of p53 expression in tumor-stromal fibroblasts forming and not forming fibrotic foci served as an important outcome predictor among 1039 patients with invasive ductal carcinoma of the breast. We analyzed the outcome predictive power of the Allred score risk classification for p53 in tumor-stromal fibroblasts forming and not forming fibrotic foci using multivariate analyses with well-known clinicopathological factors. The Allred score risk classifications for p53 in tumor-stromal fibroblasts forming and not forming fibrotic foci were superior to the Allred scores for p53 in tumor-stromal fibroblasts not forming fibrotic foci alone for accurately predicting the tumor-related death of patients with invasive ductal carcinoma when examined using multivariate analyses. The Allred score risk classification for p53 in tumor-stromal fibroblasts forming and not forming fibrotic foci significantly increased the hazard rates for tumor recurrence and tumor-related death independent of the UICC pTNM stage in the multivariate analyses. These results indicated that the Allred score risk classification based on the combined assessment of p53 expression in tumor-stromal fibroblasts forming and not forming fibrotic foci is a very useful outcome predictor among patients with invasive ductal carcinoma.

Prognostic significance of mitotic figures in metastatic mammary ductal carcinoma to the lymph nodes.

We previously reported that the number of mitotic figures in metastatic mammary carcinoma to the lymph nodes accurately predicted the outcome of patients with invasive ductal carcinoma with nodal metastasis. To confirm these previous findings, the present study investigated the number of mitotic figures and other histologic characteristics in metastatic mammary carcinoma to the lymph nodes and their associations with patient outcome according to nodal status and the histologic grade of primary invasive ductal carcinomas in a different series of 1039 patients with invasive ductal carcinoma. Multivariate analyses examining well-known clinicopathologic factors, the number of mitotic figures in the primary invasive ductal carcinomas, the grading system for lymph vessel tumor emboli, the p53 Allred score risk classes of tumor-stromal fibroblasts forming and not forming a fibrotic focus, and 9 histologic features of metastatic mammary carcinoma to the lymph nodes were performed. The presence of 6 or more mitotic figures in metastatic mammary carcinoma to the lymph nodes significantly increased the hazard ratios for tumor recurrence and tumor-related death among patients with invasive ductal carcinoma as a whole, those with nodal metastasis, and those with a histologic grade of 2 or 3. The presence of 6 or more mitotic figures in metastatic mammary carcinoma to the lymph nodes also significantly increased the hazard ratio for tumor recurrence among patients with histologic grade 1 invasive ductal carcinoma. In conclusion, this study clearly confirmed the excellent outcome predictive power of the number of mitotic figures in metastatic mammary carcinoma to the lymph nodes.

Atypical tumor-stromal fibroblasts in invasive ductal carcinomas of the breast treated with neoadjuvant therapy

Tumor-stromal fibroblasts have recently been reported to play important roles in the tumor progression of cancer in various organs. The purpose of the present study was to investigate whether any characteristic histologic features of tumor-stromal fibroblasts could accurately predict the outcome of 318 patients with invasive ductal carcinoma of the breast who had received neoadjuvant therapy. We observed a small number of tumor-stromal fibroblasts with characteristic nuclear features existing in the tumor stroma and named these cells atypical tumor-stromal fibroblasts. We then assessed the absence or presence of atypical tumor-stromal fibroblasts in biopsy (taken before neoadjuvant therapy) and surgical (taken after neoadjuvant therapy) materials and analyzed the outcome predictive powers of the presence of atypical tumor-stromal fibroblasts in biopsy and surgical materials using multivariate analyses that included well-known clinicopathological factors. The multivariate analyses demonstrated that the presence of atypical tumor-stromal fibroblasts assessed using biopsy materials had significantly higher hazard ratios for tumor recurrence and tumor-related death in patients with nodal metastasis and also significantly higher hazard ratios for tumor recurrence and tumor-related death independent of the hormone receptor status of the tumors. The results of this study clearly indicated that the presence of atypical tumor-stromal fibroblasts, especially in biopsy materials, is significantly associated with tumor recurrence and the tumor-related death of patients with invasive ductal carcinoma of the breast who have received neoadjuvant therapy.