Eriko Iwamoto

Long-term prognostic study of carcinoembryonic antigen (CEA) and carbohydrate antigen 15-3 (CA 15-3) in breast cancer

BackgroundTumor markers are frequently used for screening and monitoring in oncology. We investigated the use of preoperative tumor marker (carcinoembryonic antigen [CEA] and carbohydrate antigen [CA] 15-3) levels in estimating the prognosis of breast cancer patients.MethodsWe conducted a retrospective study in patients who underwent breast cancer surgery at National Cancer Center Hospital between 1975 and 1994 and whose serum CEA (n = 1663) and CA 15-3 (n = 1500) levels were measured prior to operation. When we excluded patients with stage IV disease from the study, the CEA level was within the normal range in 1470 patients, while 150 patients had an elevated CEA level. For CA 15-3, 1395 patients were within the normal range, while 70 patients exhibited an elevated level.ResultsThe 5-year and 10-year survival rates for patients with normal CEA levels were 87% and 76%, respectively. However, the 5-year and 10-year survival rates for patients with elevated CEA levels were 76% and 65%, respectively. At both time points, patients with normal CEA levels had higher survival rates (P < 0.05). The 5-year and 10-year survival rates for the patients with normal CA 15-3 levels were 86% and 76%, respectively, while only 71% and 52% patients with elevated CA 15-3 levels survived at 5 and 10 years, respectively. These differences were also significant (P < 0.05). However, there were no significant differences in disease-free survival (DFS) according to CEA or CA 15-3 levels.ConclusionThere was a positive correlation between CEA levels and CA 15-3 levels and patient prognosis. Thus, the levels of these tumor markers may help to determine prognosis in breast cancer patients.

The Use of Contrast-Enhanced Computed Tomography Before Neoadjuvant Chemotherapy to Identify Patients Likely to Be Treated Safely With Breast-Conserving Surgery

Objective:To select suitable candidates for breast-conserving treatment (BCT) after neoadjuvant chemotherapy (NAC), based on the classification of tumors into localized or diffuse types using contrast-enhanced computed tomography (CE-CT). Summary Background Data:A relatively high rate of loco-regional failure after BCT has been reported with breast cancer downstaged by NAC. Accurate assessment of the suitability of BCT and the response to NAC, before the initiation of NAC, will allow the optimal selection of an appropriate therapeutic course. Methods:We evaluated 110 consecutive patients with operable breast carcinomas measuring 3-cm or more in diameter by CE-CT after NAC treatment with doxorubicin and docetaxel at National Cancer Center Hospital, Tokyo, from May 1998 to November 2001. Lesions were classified as either localized or diffuse types by mammography (MMG), ultrasonography (US), and CE-CT. Results:Tumors designated as localized type by MMG, US, and CE-CT were reduced to tumors less than 3.0 cm (P < 0.0001) in a concentric circle (P < 0.0001). Localized tumors by CE-CT were treated safely with BCT maintaining a negative margin status (P = 0.01). In contrast, diffuse type tumors shrunk into a mosaic pattern consisting of tumors larger than 3.1 cm. Tumors classified as localized by CE-CT responded better pathologically than diffuse tumors (P = 0.0365). Multivariate analysis demonstrated that morphologic type by CE-CT and histologic type were significant predictors of candidates for safe BCT. Conclusions:The classification of tumors into either localized or diffuse types, using CE-CT before NAC administration, accurately predicts which tumors will be suitable candidates for BCT after NAC.

Frequent overexpression of epidermal growth factor receptor (EGFR) in mammary high grade ductal carcinomas with myoepithelial differentiation

Aims: To evaluate the expression of common biological markers and the epidermal growth factor receptor (EGFR) in mammary high grade ductal carcinomas with myoepithelial differentiation (DCMDs). Materials/methods: Thirty DCMDs were clinicopathologically and immunohistochemically analysed and compared with 36 control cases of high grade conventional invasive ductal carcinoma (IDC). Results: EGFR, HER2/neu, oestrogen receptor, progesterone receptor, and p53 expression was seen in 21, one, three, four, and 20 of the 30 DCMDs, compared with eight, nine, 18, 17, and five of the 36 conventional IDCs (p < 0.05), respectively. In 16 of the 30 DCMDs, metastases were found in the brain, lung, bone, and liver, within a maximum of 47 months (mean, 13.9) after initial surgery, whereas only four of the 36 conventional IDCs metastasised to the lung and bone within a maximum of 27 months (mean, 18.0) after initial surgery (p  =  0.0001). There was a significant difference in disease free survival between DCMD and conventional IDC (p  =  0.001). EGFR was frequently overexpressed in DCMD compared with conventional IDC, whereas the expression of HER2/neu and hormone receptors was lower in DCMD. Fluorescent in situ hybridisation revealed that the mean EGFR to chromosome 7 centromere (CEP7) ratio of the 24 DCMD cases available for evaluation was 1.03, and EGFR gene amplification was not detected in the 21 DCMD cases with EGFR overexpression. Conclusion: Immunohistochemistry for myoepithelial markers and EGFR is useful for the accurate diagnosis and molecular target treatment of high grade DCMD.

Evaluation of axillary status in patients with breast cancer using thin-section CT

BackgroundIn recent years, the surgical management of patients with breast cancer has shifted to a locoregional approach, and evaluating the patient’s axillary lymph node status is of the greatest importance in determining the appropriate treatment strategy. We evaluated on the efficacy of preoperative axillary staging using contrast-enhanced computed tomography (CE-CT).MethodsBetween 2000 and 2003, 235 patients with operable breast cancer who underwent CE-CT before surgery and 137 patients who received neoadjuvant chemotherapy (NAC) and underwent CE-CT before NAC and surgery were enrolled in this study. The axillary status was evaluated based on three criteria (short-axis diameter, shape, and enhancement type), and the diagnosis was correlated with the histopathological results.ResultsIn patients who did not receive NAC, the size criterion of a short-axis diameter of more than 5 mm provided a sensitivity of 78%, a specificity of 75%, and an accuracy of 76% in predicting node-positive status. According to the size criterion of a short-axis diameter of more than 5 mm and the shape criterion of the absence of intranodal fat density, the specificity and accuracy were 90% and 81%, respectively, and according to the enhancement type criterion of early enhancement, the corresponding values were 89% and 78%. Evaluation was more difficult in patients who received NAC and the sensitivity of the size-based criterion in the patients who received NAC was lower than in those who did not.ConclusionThese findings suggest that CE-CT based on size criteria is useful for evaluating the preoperative axillary status of breast cancer patients, but that evaluation is more difficult and the sensitivity is reduced in patients who have received NAC.

Diagnosis of Complete Response to Neoadjuvant Chemotherapy Using Diagnostic Imaging in Primary Breast Cancer Patients

Abstract:   Advances in the therapeutic agents used for neoadjuvant chemotherapy (NAC) have recently achieved higher response rates and induced a greater number of pathologic complete responses (pCR) than ever before. The aim of this study is the diagnosis of pCR after NAC by diagnostic imaging of clinical complete response (cCR) patients. This study included 35 breast cancer patients who demonstrated cCR after receiving NAC with a combination of anthracycline and taxane from May 1998 to August 2003. Surgical treatment included breast‐conserving therapy followed by radiotherapy or mastectomy. The identity of post‐NAC lesions as either a complete response (CR) or partial response (PR) were made by mammography, ultrasonography, and contrast‐enhanced computed tomography (CT). Among the 35 patients, 11 achieved pCR, including the disappearance of both invasive and intraductal components. Of the patients achieving pCR, eight were defined as CR and three were determined to be PR by CT. There was a significant relationship between the pCR and the determination of CR by CT. The determination of CR by ultrasonography was indicative of the disappearance of pathologic invasive components. While mammography appeared to reflect the observed histologic results, we did not observe any statistical differences. A subset of cases exhibited discrepancies between the imaging and pathologic results, likely due to the replacement of destroyed tumor cells by fibrosis and granulomatous tissue. The evaluation of CR by CT was significantly indicative of pCR. The positive predictive value, however, was not large enough to avoid surgical treatment. Further studies will be needed to establish a diagnosis of pCR. 

Prognosis of breast cancer patients with familial history classified according to their menopausal status.

Abstract:  Breast cancer patients were classified in the family history positive (FHP) group when they had at least one second‐degree relative who was a breast cancer patient. The results of a comparative study with patients classified in the family history negative (FHN) group showed the prognosis of the FHP group was significantly better than that of the FHN group. However, when those patients were classified according to their menopausal status at onset, there were no significant differences in survival rates between the FHP and FHN groups with onset before menopause, whereas the survival rate of the FHP group was significantly higher than that of the FHN group with onset after menopause. The same results were found when the FHP group was subgrouped into the FHP group with first‐degree relatives and the FHP group with second‐degree relatives. Further investigations on background factors revealed that the patients with onset before menopause showed no significant differences between the FHP and FHN groups in age at surgery, diameter of the tumor, histologic grade, the number of metastatic lymph nodes, body weight, estrogen receptor (ER) status, and the values of CEA and CA15‐3 before surgery. On the other hand, the FHP patients with onset after menopause showed significantly lower numbers of metastatic lymph nodes and trends showing higher ER values and lower CA15‐3‐values. Therefore the favorable prognosis in the FHP group seems to be attributable to the higher survival rate of the FHP patients with onset after menopause.

Histopathological effect of radiofrequency ablation therapy for primary breast cancer, with special reference to changes in cancer cells and stromal structure and a comparison with enzyme histochemistry

Radiofrequency ablation (RFA) therapy is expected to be applicable to small breast cancers, but no criteria for its histopathological effect have yet been established. Using samples obtained from 15 patients who had undergone RFA and subsequent mastectomy, we compared the histopathological changes in the ablated area with the results of histochemical staining based on the reduction of nitroblue tetrazolium chloride (NBT) by nicotinamide adenine dinucleotide (NADH) diaphorase in frozen tissue sections, and looked for histological changes indicative of the effect of RFA on breast cancer. Grossly, the ablated area in most of the tumors was rough, gritty, less moist, and surrounded by a red congestive limbic zone. The ablated area showed no staining by the NADH diaphorase reaction, and cancer cells in the area showed marked destruction characterized by an unclear intercellular boundary, elongated eosinophilic cytoplasm, pyknotic “streaming” nuclei, and a poorly defined nuclear and cytoplasmic texture. At the same time, fibrous connective tissue also showed degenerative changes, becoming densely homogeneous with loss of its delicate wavy structure. The area in which RFA appeared to have been histopathologically effective was mostly concordant with the area in which the NADH diaphorase reaction was negative. In the periphery of the ablated area, however, cellular changes caused by RFA were less marked, although the NADH diaphorase reaction was visualized with NBT. A larger number of cases should be examined in order to establish criteria for the histopathological effect of RFA on breast cancer.

Usefulness of preoperative multidetector-row computed tomography in evaluating the extent of invasive lobular carcinoma in patients with or without neoadjuvant chemotherapy

BackgroundThe present study was conducted to assess the clinical usefulness of multidetector-row CT (MDCT) in determining the extent of invasive lobular carcinoma (ILC) and especially the extent of residual tumor after neoadjuvant chemotherapy (NAC).Patients and methodsThe subjects were 24 patients with primary ILC who underwent surgery without NAC and 17 patients with ILC who underwent surgery after NAC at National Cancer Center Hospital (NCCH) between April 1999 and December 2005. The extent of primary ILC was assessed by ultrasound, mammography, and MDCT before surgery, and the results obtained using each modality were compared with the results of pathological examination after surgery. In addition, the characteristic findings of ILC obtained by MDCT were assessed. Similarly, the extent of residual tumor after NAC was evaluated using ultrasound, mammography, and MDCT before surgery in the subjects who underwent NAC, and the results obtained by each modality were compared with the results of pathological examination after surgery.ResultsThe findings of primary ILC obtained by MDCT showed that the carcinoma was the non-localized type rather than the localized type in 63% of the subjects. In addition, with regard to the pattern of time-sequential contrast enhancement, the persistent pattern (in which tumor enhancement is strong in the late phase rather than in the early phase) was observed in 46% of the subjects, and the plateau pattern (in which contrast enhancement is weak in both the early phase and the late phase) was observed in 38% of the subjects. These trends were significant in the subjects who underwent NAC and in whom tumor enhancement could not be clearly observed by MDCT. Assessment of the extent of carcinoma showed that the diagnostic accuracy of MDCT was 79%, as compared with 71% for either ultrasound or mammography. Assessment of the extent of carcinoma after NAC also showed that the diagnostic accuracy of MDCT was 71%, as compared with 48% for ultrasound and 53% for mammography, indicating that MDCT provided the highest accuracy. It should be noted that for all modalities, the extent of ILC was not overestimated as compared with the tumor diameter measured during pathological examination.ConclusionAssessment by MDCT showed that ILC tends to be diffuse, tumor enhancement tends to be very weak, and the rate of enhancement tends to be low. In addition, MDCT was found to be useful for determining the extent of carcinoma, and the diagnostic accuracy of MDCT, especially in determining the extent of carcinoma after NAC, was much higher than that of ultrasound or mammography.

Synchronous unilateral triple breast cancers composed of invasive ductal carcinoma, invasive lobular carcinoma, and Paget’s disease

We report a case of synchronous unilateral triple breast cancers comprising invasive ductal carcinoma (IDC), invasive lobular carcinoma (ILC), and Paget’s disease. A 57-year-old woman with a left breast mass was referred to our hospital. Mammography revealed only an isodense area with foci of microcalcification in the lateral area of the left breast. Ultrasonography revealed 2 hypoechoic masses in the outer lower and inner upper areas, and these 2 lesions were diagnosed by core needle biopsy as ILC and IDC, respectively. Left total mastectomy with sentinel lymph node biopsies was performed. In addition to the ILC and IDC, histological examination also identified Paget’s disease. Breast cancer often manifests as multiple unilateral lesions; however, it is sometimes difficult to determine whether these tumors have developed multicentrically or have multifocally invaded from an intraductal carcinoma. This case was clearly diagnosed to have occurred multicentrically because of the absence of continuity among the 3 tumors, the presence of a non-invasive component in all 3 tumors, and different histopathological findings. The synchronous unilateral development of ILCs is well known. Cases of synchronous unilateral triple or more breast cancers were reviewed, and their histopathological characteristics, including the incidence of Paget’s disease, is discussed.

Histopathological Evaluation of the Therapeutic Effect of RFA for Early Breast Cancer

We performed a pilot study to evaluate the efficacy and safety of radiofrequency ablation (RFA) for primary breast cancer. With tumor specimens resected from the 28 patients, we aimed to establish histopathological criteria for evaluating the therapeutic effect of RFA by comparing histopathological features after staining with hematoxylin and eosin (H&E) and enzyme histochemical features after staining with nicotinamide adenine dinucleotide (NADH) diaphorase. The following are histopathological features characteristic of the RFA effect: (1) elongated eosinophilic cytoplasm with pyknotic “streaming” nuclei, (2) unclear intercellular boundaries and nuclear and cytoplasmic details, and (3) dense homogeneous and highly eosinophilic collagen fibers in the fibrous stroma. The validation of these histopathological criteria is ongoing in a multicenter, prospective study of image-guided RFA for small breast carcinomas.