This article reviews the current status of hormone receptor evaluation in and out of Japan, and introduces the proposed working protocol of the task force for Adequate immunohistochemical evaluation in routine practice for breast cancer by the Japanese Breast Cancer Society. Understanding the principles and the developmental process of immunohistochemisty helps us to utilize a scoring system adequately. Methodologies of hormone receptor examination and immunohistochemical procedures are briefly introduced. Each scoring system is based on different principles. The proposed working protocol takes into account the reproducibility of results among observers, institutions and staining procedures, which is justified based on the current situation in Japan. Future directions for the standardization of immunohistochemical hormone receptor evaluation are also described.

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HER-2 tests are routinely used for the identification of patients with metastatic breast cancer that is potentially responsive to trastuzumab (herceptin) therapy. Recently, convincing data have been published with regard to the efficacy of trastuzumab as a drug for neoadjuvant therapy or adjuvant therapy for operable primary breast cancer that overexpresses HER-2. It is also noteworthy that a the St. Gallen International Consensus Conference 2005, HER-2 protein overexpression or HER-2 gene amplification has been included as an indicator for higher risk of recurrence for both node-negative and node-positive breast cancers. To measure the HER-2 level, the worldwide consensus appears to be that immunohistochemistry (IHC) should be performed first and, if the results of IHC are uncertain, fluorescence in situ hybridization (FISH) should be performed later, although some investigators argue that FISH should be performed first. These tests should be performed in strict adherence to existing instructions. Quality control is of utmost importance when performing HER-2 tests, both internal and external, for routine diagnosis and in clinical protocol studies.

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Although the histological grading of malignancy in patients with operable breast cancer, typically consisting of three factors: tubular formation, mitotic counts, and nuclear atypia, plays an important role in identifying patients at high risk of recurrence, the most effective combination of factors is still not completely clear. In assessing prognosis, the problems of clinical application of the grade of malignancy are not only related to the assemblage of the factors employed, but also to the heterogeneity within the tumor and interobserver variations. In a review of the correlation between the histological grading system for malignancy in operable breast cancer patients and the recurrence rate, only the grade of nuclear atypia statistically correlated with the rate of recurrence. Furthermore, a grading system consisting of mitotic counts and nuclear atypia was more significantly correlated to the risk of recurrence than was the system based on the three factors described above. Concerning the heterogeneity of histologic features within the primary tumor, a system based on the grade of mitotic counts or nuclear atypia showed a high degree of heterogeneity, but a system based on the grade of tubular formation showed low heterogeneity and bimodal distribution.

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Neoadjuvant therapy consists of systemic drug treatments before surgery for a primary cancer. Currently, several neoadjuvant therapy regimens for breast cancer that use various cytotoxic as well as endocrine-therapeutic and molecular-targeting agents have been performed in clinical practice and/or studies. In neoadjuvant therapy, pre-treatment pathological examination using materials obtained by a core needle biopsy (CNB) is necessary, and pathological diagnosis and evaluation of the biological status, such as hormone receptors and HER-2 over-expression are confirmed. In addition, CNB in the inter-phase of chemotherapy is also thought to be useful for assessment of therapeutic effects before regimens have been completed. After surgery, the therapeutic effects of neoadjuvant therapy have been mainly evaluated on the basis of pathological findings and a pathological complete response (pCR) is considered to be the main target of neoadjuvant therapy. Results of most of clinical studies including NSABP protocol B-18 and B-27 have confirmed the prognostic significance of pCR in neoadjuvant therapy and indicated the significance of pathological evaluation. However, universally accepted pathological response criteria have not been established, but evaluations of the main invasive tumor, intraductal components and regional lymph nodes are thought to be necessary. Additionally, evaluation of the effects below pCR also need examining in a study using a mild anti-cancer drug, such as hormone-therapeutic agent, and the survival outcomes of patients below pCR need to be examined and compared between each grade.

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Seroma, a collection of serous fluid, is the most common problem after breast surgery. The aim of this study was to review the effect of mechanical closure of dead space on seroma formation after breast surgery. There are two mechanical methods for closure of the dead space beneath skin flaps: compression by external pressure, and fixation of the flaps with sutures. There is no evidence to suggest that the routine use of a pressure garment or compression dressing is beneficial. However, it appears that suture flap fixation does reduce seroma formation, simplify postoperative care and dressing, and thus allow early removal of drains and discharge. Drains are helpful for mechanical closure of dead space, but in breast-conserving surgery this technique may preclude the use of a drain. However, previous studies have often been small in scale and poor in quality. Further studies should examine the effect of this technique on quality of life, cosmesis, and medical economics.

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Background: Although breast cancer in women remains relatively rare in Korea, its incidence and mortality figures are increasing, consistent with the increasing risk observed in successive generations of Korean women. The aim of the current study was to examine time trends of breast-cancer mortality during the period 1984-2003 in Korea, assessing the importance of the effects of age, period and birth cohort as risk factors.
Methods: Data on the annual number of deaths due to female breast cancer and on female population statistics from 1984 to 2003 were obtained from the Korean National Statistical Office. A log-linear Poisson age-period-cohort model was used to estimate age, period and cohort effects.
Results: The trend of breast cancer mortality was explained by an age-cohort model based on goodness of fit, even though the significance of the cohort effect was marginal (p=0.08) after adjusting for age. The risk of breast cancer death was found to increase with age after adjusting for the cohort effect, and it was different from the cross-sectional age curve. Also, breast cancer mortality increased along with the birth cohort.
Conclusions: Even though the cohort effect was found to have a marginally significant effect on breast cancer mortality, it is expected to be more significant in the future given the recent on-going changes in diet and reproductive behavior shown by Korean women.

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Background: Fine-needle aspiration (FNA) biopsy of breast tumors is a reliable diagnostic method for identifying breast carcinoma. However, it is sometimes difficult to definitely distinguish malignant from benign lesions. To improve the cytological diagnosis of breast tumors, we investigated the expression of active matrix metalloproteinase-2 (MMP-2), as detected by film in situ zymography (FIZ).
Methods: We evaluated 34 fresh breast tumors, 25 paraffin-embedded breast tissue specimens, and a human cancer cell line (HT1080). MMP-2 expression was determined by immunocytochemistry or immunohistochemistry. Frozen sections and aspiration cytology samples of breast cancer were incubated on gelatin-coated films for the detection of active MMP-2.
Results: Immunohistochemistry showed that MMP-2 was expressed in cancer cells and stromal cells, but not in most benign breast lesions. Active MMP-2, but not pro-MMP-2, in the conditioned medium of HT1080 cells showed gelatinolytic activity on FIZ analysis, while the expression of both forms of MMP-2 was detected by immunocytochemistry. Gelatinolytic activity was also detected by FIZ analysis of aspiration cytology samples and frozen sections from the breast cancers, and there was a significant correlation between this gelatinolytic activity and the detection of MMP-2 expression by immunocytochemistry.
Conclusions: The present study demonstrated that measurement of gelatinolytic activity by FIZ analysis of aspiration cytology samples may be useful for improving the cytological diagnosis of breast tumors.

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Background: Few reports have addressed the feasibility and safety of classic Cyclophosphamide, Methotrexate, and Fluorouracil (CMF) therapy in Japanese female breast cancer patients.
Methods: Twenty-four Japanese patients who received classic CMF, identical to the originally described treatment regimen were studied in terms of treatment dose, treatment delay, and toxicity.
Results: Classic CMF was not discontinued in any of the cases. The median delay in treatment was 14 days, and the mean administered dose of cyclophsphamide was 98.2% of the planned dose. None of the patients suffered severe side-effects such as febrile neutropenia; however, in 22 patients in whom the effect of CMF on hair loss could be assessed, 7 (31.8%) had to wear hats or wigs.
Conclusions: Classic CMF is a feasible and safe regimen in Japanese breast cancer patients. In Japan, this regimen is still available for some specific groups of early breast cancer patients.

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Background: Anastrozole and tamoxifen have mild toxicity. However, we noticed that more patients treated with anastrozole complained of joint symptoms than expected. In particular, digital stiffness as is seen with rheumatoid arthritis is a problem. Some clinical trials of anastrozole in Europe and the United States reported musculoskeletal disorders as adverse events, however, joint symptoms were not described in detail.
Patients and Methods: At our clinic from August 2001 to March 2005, 53 postmenopausal women with estrogen receptor-positive breast cancer were treated with anastrozole. We calculated the incidence and classified the grade of joint symptoms by interviewing patients. We also investigated the patients' characteristics and their relevance to joint symptoms.
Results: Of 53 patients, 14 patients (26%) had joint symptoms (13 patients with digital stiffness and 3 patients with arthralgias of wrist and shoulders). Joint symptoms tended to occur in the patients who had previously undergone chemotherapy; however, there has no relationship between prior hormonal therapy and joint symptoms. Seven patients who discontinued anastrozole treatment showed improved symptoms. Five patients with grade 1 digital stiffness continued anastrozole treatment without additional treatment. Two patients with grade 1 digital stiffness, who took a Chinese herbal medicine showed improved symptoms and continued anastrozole treatment.
Conclusion: Benefits to the patients may possibly be lost by discontinuation of anastrozole or changing to tamoxifen since the clinical superiority of anastrozole to tamoxifen has been reported. We should continue anastrozole in patients with low grade symptoms, while ensuring that patients are aware of the toxicity of anastrozole.

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Background: Accelerated partial breast irradiation (APBI) is generally limited to patients at extremely low risk of local recurrence. The significance of the risk factors, however, depends on the extent of surgery, radiation, and systemic therapy. In Japan, wide excision is generally supplemented by intraoperative margin-directed re-excision if the frozen section examination yields positive results. This approach combined with conventional radiotherapy achieved an excellent 10-year local control rate of 93%, and young age and ductal carcinoma in situ were not risk factors for local recurrence. To reduce the treatment duration, high-dose-rate interstitial brachytherapy (HDRIB) was employed. The first APBI phase I / II trial in Japan was conducted to determine if wider indications for early breast cancer patients were appropriate.
Methods: The subjects comprised 20 patients including those with extensive intraductal component (n=7), ductal carcinoma in situ (n=2), positive final margins (n=3), and of younger age (≤ 45 years; n=5). Breast-conserving surgery using an intraoperative re-excision approach was followed by intraoperative implantation of applicators. Sole HDRIB of a 36-42 Gy in 6-7 fractions was delivered postoperatively over 3-4 days. Tumors were staged as follows: cT1 (n=12), cT2 (n=8), cN0 (n=20). Systemic therapy was used in 16 patients (80%). The median follow-up period was 52 months (range, 26-86 months).
Results: Te five-year crude local, distant control, and Kaplan-Meier cause-specific survival rates were 95%, 95%, and 89%, respectively. Fat necrosis developed in 1 patient.
Conclusions: Sole HDRIB with intraoperative margin-directed re-excision was feasible under wider indications compared to other contemporary APBI series, and achieved acceptable and similar results to these series in terms of the local control rate and complications.

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Objectves: We analyzed non-genetic risk factors for adverse skin reactions to irradiation at 4 collaborating Japanese institutions, to design future investigation into genetic risk factors for adverse skin reactions to irradiation in a multicenter setting.
Methods: From April 2001, 284 breast cancer patients, who underwent radiotherapy with breast-conserving surgery, were enrolled from 4 collaborating institutions in Japan. We graded skin reactions according to international scoring systems. Clinical factors were tested against adverse effects.
Results: Grade 1+ skin reactions were observed in 261 (92%) of the patients in less than 3 months, 118 (42%) at 3 months, and 29 (10%) at 6 months in the late phase. Univariate analysis of treatment risk factors (such as the use of a multi-leaf colimeter, wedge-filter, or immobilization device) for skin reactions revealed a significant association (p< 0.0001). After a variable selection procedure with logistic regression, the institution, operative procedure, and magnitude of photon energy remained significantly associated with acute skin reactions. Only the institution was an explanatory variable for skin reactions at 3 and 6 months in the final logistic model.
Conclusion: After stratification, substantial remaining variations in the occurrence of skin reactions of a given level suggested that individual genetic factors contribute markedly to individual radiosensitivity. Analysis of genetic factors associated with adverse effects would be possible by stratifying patients according to institution. Selection of eligible institutions, where appropriate treatment modalities could be performed, would also be possible when planning such a study.

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Background: There is lack of information on the present status of adjuvant therapy for breast cancer in Kyushu. Therefore, the Kyushu Breast Cancer Study Group (KBC-SG) started registering newly diagnosed breast cancer patients who were to receive adjuvant therapy.
Methods: During a period from 2001 to 2003, institutions participating in KBC-SG registered new patients who underwent curative surgical treatment for breast cancer to the registration office. One year later, the office sent them inquiries to gather any missing information.
Results: A total of 2284 patients were registered from 49 institutions. The mean age was 55, ranging from 30 to 93 years, and 46% had stage I disease. Estrogen and/or progesterone receptor was positive in 71% by immunoperoxidase staining, and HER2 was expressed in 297 (33%) of 906 patients. Twenty percent of the patients underwent adjuvant radiation therapy with or without antineoplastic agents. Overall, 98% received hormonal and/or cytotoxic agents. Anthracycline-containing regimens were given to 628 of 1285 (49%) patients with chemotherapy, while 360 (28%) received oral 5-fluorouracil derivatives with or without oral cyclophosphamide.
Conclusions: Anthracycline combination chemotherapy was commonly used as adjuvant therapy, but there were over a quarter of patients only given oral 5-FU derivatives, which might not be recommended by worldwide consensus. Adjuvant radiation therapy was also given to only 20% of the patients in Kyushu, which might be fewer than the report by the Japanese Breast Cancer Society. Based on these data, the KBC-SG will continue cooperative studies to improve the quality of adjuvant treatment for early breast cancer.

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We report a patient with metachronous bilateral breast cancer who has twice developed radiation pneumonitis after breast-conserving therapy for each breast. The patient was a 48-year-old woman, who presented with Stage I right breast cancer. After wide excision of the right breast tumor and dissection of level I axillary lymph nodes, systemic therapy with oral 5-FU and tamoxifen was started. Subsequently, tangential irradiation with a total dose of 50 Gy in 25 fractions was given. Seven months after irradiation, she developed respiratory symptoms and radiation pneumonitis was diagnosed. The symptoms resolved with oral prednisolone. Thirty months after the right breast cancer treatment, Stage I left breast cancer was diagnosed. After wide excision of the left breast tumor and partial removal of the level I axillary lymph nodes, the same oral systemic chemo-hormonal therapy was initiated. Thereafter, tangential irradiation with a total dose of 50 Gy in 25 fractions was given. Four months after irradiation, she developed respiratory symptoms. A chest X-ray showed an area of increased density in the left lung consistent with radiation pneumonitis. The symptoms were mild and they improved spontaneously without medication. Although there is insufficient evidence to justify or withhold whole breast radiation therapy from patients with a history of contralateral breast cancer and radiation pneumonitis, it is essential to discuss the adequacy of whole breast irradiation and the possibility of alternative approaches, such as breast-conserving surgery without irradiation or partial breast irradiation for this rare condition.

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We report a rare case of sudden hemorrhage caused by breast cancer. A 70-year-old Japanese woman noted fresh bleeding from her left breast. On physical examination, continuous hemorrhage accompanied by an open cavity was observed in the left breast. Mammography and ultrasonography revealed a well-circumscribed mass, with solid and cystic components, that was highly suggestive of intracystic breast carcinoma with direct skin invasion. Computed tomography and bone scintigraphy showed no distant metastasis. Aspiration biopsy of the lesion showed several clusters of adenocarcinoma cells. Modified radical mastectomy was performed with a presumptive diagnosis of stage III B left breast cancer. Invasive ductal carcinoma without skin invasion was diagnosed histologically. To the best of our knowledge, only 6 other cases of sudden hemorrhage caused by breast cancer without skin invasion have been reported in Japan. We review the literature and discuss the clinical characteristics of this unusual phenomenon.

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Primary breast lymphoma, particularly primary mucosa-associated lymphoid tissue (MALT) lymphoma, is a rare disease. We report here a case of a MALT lymphoma of the breast with high-grade transformation. An 84-year-old woman presented with a Pagetoid mass in her right breast. After a clinical diagnosis of breast cancer, T2N1M0, stage II B, she underwent mastectomy with axillary lymph node dissection. She had no history of autoimmune disease such as Hashimoto thyroiditis or Sjögren disease. Pathologically the tumor tissue was composed of small to large lymphoid cells. The large cells contained a considerable number of centroblasts, forming a sheet-like proliferation centrally. Among the small cells many small cleaved cells were present, which were more predominant in the peripheral areas. Immunohistochemistry revealed that these cells were positive for CD20 and CD79a. The tumor cells infiltrated the ductular epithelial cells, distorting the duct structures, to form lymphoepithelial lesions. Immunohistochemistry for cytokeratin and CD20 was helpful for identification. No germinal centers were formed. MALT lymphoma with high-grade transformation was diagnosed. Rituximab (anti-CD20 antibody) was prescribed as systemic treatment without chemotherapy or irradiation. After 18 months, no tumor recurrence was observed. We emphasize the importance of lymphoepithelial lesions for the diagnosis of MALT lymphoma of the breast.

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