Sentinel lymph node (SLN) biopsy has become a common procedure for breast cancer patients. Many reported feasibility studies have revealed a high identification (95.4% of 2,125 cases) and accuracy rate on histopathological analysis (94% frozen and 97% paraffin). However, about 5 to 8% of cases false-negative are in this examination. Various methods of histopathological examination have been reported by many authors, but the Philadelphia consensus meeting recommended that sections less than 2.0 mm in thickness should be prepared and examined to detect metastasis larger than 2.0 mm. In addition, immunohistochemistry for cytokeratin is considered to be useful to detect isolated tumor cells (ITC) in the representative sections. On the other hand, real-time reverse transcriptase-polymerase chain reaction (RT-PCR) might detect micrometastasis (larger than 0.2 mm) (sensitivity and specificity; 89.5% and 96.7% frozen sections) and expected to be used as a routine method instead of histopathological examination.

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Accurate intraoperative diagnosis of sentinel node metastases enables the selection of patients for axillary lymph node dissection, thus avoiding an unnecessary additional operation in patients with false-negative results. The main reason for false-negative results of imprint cytology was poor quality of the imprint samples because of sampling error. False-positive imprint cytology results that lead to an unnecessary axillary lymph node dissection are very rare. Imprint cytology can be recommended for the intraoperative examination of sentinel nodes in breast cancer patients.

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Sentinel lymph node biopsy (SLNB) is based on the hypothesis that the sentinel lymph node (SLN) reflects the lymph-node status and a negative SLN might allow complete axillary lymph node dissection (ALND) to be avoided. Although the survival outcome is still unknown, this technique has already become a standard of care for breast cancer patients. However, it is still important to discuss current techniques and some controversies. This article reviews these issues for a variety of SLNB techniques.

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Sentinel lymph node biopsy (SLNB) is standard care for patients with early-stage breast cancer, and axillary lymph node dissection (ALND) is considered unnecessary when sentinel lymph nodes (SLNs) are tumor-free. Additional non-SLN metastasis in patients with positive SLNs can be estimated using several risk factors such as primary tumor size, metastatic tumor size in SLNs, lymphatic vessel invasion, and so on. All patients with positive SLNs may be treated with further ALND based on their own risk for non-SLN metastasis. Recent randomized clinical trials have already proved less surgical morbidity and better QOL for SLNB alone compared with ALND. However, trials concerning the efficacy of ALND in positive SLNB patients in preventing local regional recurrence and improving overall survival compared with no ALND, and also, concerning the effectiveness of ALND compared with axillary radiation therapy (RT), have not yielded clear results. The prognostic significance of micrometastasis in SLNs or bone marrow also remains to be determined. So far SLNB is not acceptable for patients with positive nodes in the axilla at initial diagnosis even if their axillary metastases are down-staged to negative by neoadjuvant chemotherapy. Although basically SLNB does not need to be performed for patients with pure ductal carcinoma in situ (DCIS), it is recommended for patients with an initial diagnosis of DCIS which is large, palpable, high grade, or found in younger patients. Because these types of DCIS have higher incidences of accompanying invasive lesions. In addition if patients will undergo mastectomy, SLNB is recommended because of the inability to perform SLNB after mastectomy. SLNB may be acceptable for patients with T3 or T4b tumors, even though SLN identification is lower yet SLN involvement is higher compared with T1 or T2 tumors, and systemic adjuvant therapy is more important for patients with T3 or T4b tumors. SLNB is a bridge to further axillary treatment such as ALND or axillary RT, and which strategy, including no further treatment, is best considered individually based on recurrence risk, treatment responsiveness and use or non-use of systemic therapy.

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Background: Although non-mass lesions on breast ultrasonography have become relatively common, they remain very difficult to diagnose. The purpose of this study was to evaluate the usefulness of contrast enhanced magnetic resonance imaging (MRI) in managing non-mass lesions.
Methods: A total of 82 cases of non-mass lesions visible on breast ultrasonography who were subjected to contrast enhanced MRI (CE-MRI) were available for assessment. These lesions were evaluated in terms of the association between the enhancement pattern on contrast enhanced MRI and the pathological or cytological diagnosis.
Results: Thirty-three of 82 (40.2%) non-mass image-forming lesions were seen as enhanced lesions on CE-MRI, of which 32 revealed non-masslike enhancements. Of the 19 breast cancers detected as non-mass image-forming lesions, 18 (94.7%) had an enhancement pattern not suggestive of a mass, so breast cancers comprised 56.3 % (18/32) of the lesions. Most of the breast cancers tended to emerge in a setting of duct dilatation with internal echoes (45.5%; 5/11) or low echo areas with indistinct margins (32.4%; 11/34). Morphologically, segmental (57.9%; 11/19) and regional (21.1%; 4/19) enhancements were common patterns of breast cancer which showed up as non-mass image-forming lesions. On the other hand, 49 of 82 (59.8%) non-mass image-forming lesions were not enhanced and 28 of 49 cases underwent pathological examination. Only one case was breast cancer with category 5 microcalcifications and although about half of the remaining 21 cases were followed for at least 12 months, no breast cancers were found.
Conclusion: Contrast enhanced MRI was useful for detecting breast cancer in cases of non-mass image-forming lesions. On the other hand, except for cases in which mammography was suspicious for malignancy, lesions showing no enhanced areas may be safely followed, because the possibility of breast cancer is minute.

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Background: Lymphatic vessel invasion (LVI) has been conventionally assessed on hematoxylin-eosin (HE) stained sections, but this assessment tends to be subjective. The aim of this study is to investigate the significance of LVI in invasive breast cancers, primarily using immunohistochemical lymphatic endothelial markers.
Methods: We studied 69 invasive breast carcinoma cases. Using D2-40 and podoplanin, we investigated the distribution of lymphatic vessels around the tumor and LVI, and they were compared with the HE sections. The correlation between LVI, lymph node metastasis and disease free survival (DFS) was also investigated.
Results: Lymphatic vessels were most frequently seen outside the tumor (86%), whereas lymphatic vessels were not seen in the central zone of the tumor. LVI was found in 22 cases, of which nineteen was seen in the peripheral zone (87%). For both HE and lymphatic markers, the rates of mild LVI tended to be high. The concordance rate between D2-40 and podoplanin was 94.2% (65/69). LVI assessed on HE sections was corresponded to 54/69 cases (78.2%) using either D2-40 or podoplanin. There were 25 axillary lymph node positive cases. Lymph node metastasis significantly correlated with LVI assessed by HE section, but did not correlate with LVI assessed by the lymphatic markers. The tumor recurred in 19 cases during the mean follow-up period of 47.5 months. Disease free survival was significantly better for LVI negative cases on HE analysis, and LVI negative or mildly positive by any staining procedure.
Conclusion: The lymphatic endothelium markers, D2-40 and podoplanin, are very useful for detecting LVI, but careful examination by routine HE sections may be enough for routine practice. Moderate or marked degree of LVI may be of value to predict survival.

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Background: Fine-needle aspiration cytology (FNA) is less traumatic and technically easy to apply to small breast tumors.
Methods: A total of 382 cases of palpable breast lesions that had undergone fine needle aspiration and histopathologic diagnosis were reviewed with an emphasis on the rate of false positive diagnoses in benign breast lesions.
Results: A diagnosis of “ malignant ” was made in 98 of the 382 specimens (25.6%). The predictive value for malignancy was 97.9%. The sensitivity, specificity, and accuracy of FNA were 86.3%, 98.2%, and 93.2%, respectively, when the “ suspicious ” group was considered positive for malignancy. The histologic subtypes of the 4 false-positive cases were epithelial proliferative lesions, ductal or lobular hyperplasia. None of these 4 cases were definitely diagnosed as “ malignant ” by radiological studies. Four false-negative cases by FNA were suspicious for malignancy radiologically. There was no specific pathological subtype associated with false-negative status on FNA in this study.
Conclusion: Palpable breast tumors can be definitively diagnosed based on a combination of physical examination, radiological studies and FNA, when the radiological studies concur with the diagnosis by FNA.

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Background: To establish tailor-made therapy for breast cancer, we investigated the possibility of predicting chemotherapy sensitive cases based on pre-therapeutic histological features.
Methods: A total of 87 breast cancer patients underwent neoadjuvant chemotherapy with a paclitaxel (80mg/m²/q1w, 12courses)or an epirubicin regimen (90 mg/m²/q3wks, 4courses). We investigated the chemo-sensitivity of invasive ductal carcinoma, solid-tubular carcinoma consisting of highly malignant cancer cells with many mitoses. We refer to this type of carcinoma as “ chemo-sensitive carcinoma ” and compared the histological therapeutic effects of chemo-sensitive and chemo-insensitive carcinomas.
Results:1) Out of 87 patients, 20 cases (23%) showed the histological features of chemo-sensitive carcinomas on pre-therapeutic needle biopsy specimens. The remaining 67 cases (77%) were classified as chemo-insensitive carcinoma. 2) Histologically marked or complete response were observed in 50% (10/20) of chemo-sensitive carcinomas and 10% (7/67) of chemo-insensitive carcinomas (χ²=15.33, p=0.0001). Multivariate analysis of chemo-sensitive carcinoma, including HER2, hormone receptor and p53 status, revealed that chemo-sensitive carcinoma had a significant correlation with the histological therapeutic effects (p=0.01119). 3) Pathological complete response (pCR) was achieved in 35% (7/20) of chemo-sensitive carcinomas and 1.5% (1/67)of chemo-insensitive carcinomas (χ²=20.71, p<0.0001). Multivariate analysis revealed that chemo-sensitive carcinoma had a significant correlation with pCR (p=0.0091).
Conclusion: The histological features of chemo-sensitive carcinoma were significant predictive factors for chemotherapeutic efficacy.

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Background: The dose-response curve for anticancer agents cannot be evaluated by studying patients directly. To investigate individual differences in the dose-response curve for paclitaxel in breast cancer, we utilized the histoculture drug response assay (HDRA) technique.
Materials and Methods: Twenty specimens obtained from breast cancer patients who underwent surgical resection were used in this study. The inhibition rates of paclitaxel at several concentrations were measured and fitted to a sigmoid dose-response curve, using non-linear least squares analysis with the fitting equation y=A(1-1/(1+exp(B(x-log(C))))), where A denotes maximal response; B, slope factor; and C, ED50.
Results: A dose-response curve was obtained in all tumors. The mean value (±SD) of maximum response, slope factor, and ED50 were 90.2±5.5%, 9.4±4.3, and 36.8±17.2µg/ml, respectively. The slope factor was higher in nuclear grade 3 tumors compared with nuclear grade 1 and 2 tumors.
Conclusion: An individual dose-response curve for paclitaxel in breast cancer can be obtained using the HDRA technique. Nuclear grade 3 tumors appeared to have more uniform chemosensitivity to paclitaxel compared with nuclear grade 1 and 2 tumors.

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Background: Skin-sparing mastectomy (SSM) is a type of breast cancer surgery presupposed as breast reconstruction surgery. Cosmetically, it is an extremely effective breast cancer operation because the greater part of the breast's native skin and infra-mammary fold are conserved. All cases of SSM and immediate breast reconstruction performed by the senior author during the last five years were reviewed.
Methods: There are three implant options for breast reconstruction, namely, deep inferior epigastric perforator (DIEP) flap, latissimus dorsi myocutaneous (LDM) flap, and breast implant, and one of these was used for reconstruction after comprehensive evaluation.
Results: From 2001 to 2005, immediate reconstructions following SSM were performed on 124 cases (128 breasts) by the same surgeon. Partial necrosis of the breast skin occurred in 4 cases of SSM. The mean follow-up was 33.6 months. During the follow-up, there was local recurrence following surgery in 3 cases. The overall aesthetic results of immediate breast reconstruction after SSM are better than those after non-SSM.
Conclusion: SSM preserves the native breast skin and infra-mammary fold, and is an extremely useful breast cancer surgery for breast reconstruction. SSM is an excellent breast cancer surgical technique. We think this procedure should be considered in more facilities conducting breast reconstruction in Japan.

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We report a rare case of primary small cell carcinoma of the breast. A 44-year-old woman was admitted to our hospital with a mass in her left breast. Fine-needle biopsy revealed small cell carcinoma with neuroendocrine differentiation resembling small cell carcinoma of the lung. Systemic computed tomography (CT) and magnetic resonance imaging (MRI) revealed no primary site in the lung or any other organ. A modified radical mastectomy with removal of the axillary lymph node (Bt + Ax, R2) was performed. Histological examination revealed that the tumor was composed of small round to oval cells with a large nuclear-cytoplasmic ratio. The tumor cells were positive for neuroendocrine differentiation markers such as synaptophysin, CD56, and neuron-specific enolase (NSE), but negative for thyroid transcription factor-1 (TTF-1), leukocyte common antigen (LCA), estrogen receptor (ER), and progesterone receptor (PR). Interestingly, the tumor cells lacked immunoreactivity for epithelial markers, including cytokeratin AE1⁄3, CAM5.2, and epithelial membrane antigen (EMA). The patient was given adjuvant chemotherapy for axillary lymph node metastasis. There were no signs of recurrence 22 months after surgery.

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Background: We encountered two patients with inflammatory breast carcinoma who developed symptomatic brain metastases after achieving local pathological complete responses (pCR) with neoadjuvant chemotherapy (NAC).
Case presentations: The first patient is a 39-year-old woman (Case 1), who underwent NAC with AC (doxorubicin + cyclophosphamide)followed by weekly paclitaxel. After achieving a clinical CR (cCR), we conducted a modified radical mastectomy. Pathological evaluation confirmed no residual malignant cells within the breast tissue or lymph nodes. However, she developed neurological symptoms from brain metastases one month postoperatively. The second patient is a 44-year-old woman (Case 2). Again, no residual malignant cells were detected within the breast tissue or lymph nodes following NAC, but the patient developed symptomatic brain metastases eight months postoperatively. When primary breast tumors are locally advanced, it may be worthwhile to rule out brain metastases even if pCR is obtained after NAC.

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Benign epithelial inclusions are uncommonly found in lymph nodes, and ectopic breast tissue in axillary lymph nodes is particularly uncommon. The patient is a 48-year-old woman who had an adenoma of the nipple removed 10 years previously. A swollen lymph node with amorphous calcifications in a clustered distribution on mammogram was found in the left axilla. Fine needle aspiration cytology showed only cystic change. Excisional biopsy was performed and microscopic examination demonstrated that the node contained benign mammary epithelial and glandular inclusions, and no evidence of malignancy.
Such cases will be increasingly found due to the widespread use of mammography screening and biopsy of axillary sentinel lymph nodes. Ectopic breast tissue in lymph nodes may be mistaken for malignant lesions. It is most important to identify correctly the epithelial inclusions in lymph nodes to prevent an erroneous diagnosis.

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A case of an intracystic adenomyoepithelioma of the breast mimicking intracystic carcinoma is described. Preoperative examination with mammography, sonography, computed tomography, and magnetic resonance imaging showed an intracystic tumor with an indistinct margin and several swollen lymph nodes in the ipsilateral axilla. Because the results of fine-needle aspiration cytology of the tumor were interpreted as carcinoma, partial mastectomy with dissection of the axillary nodes was performed. Histopathologic and immunohistochemical examination revealed an intracystic adenomyoepithelioma without nodal involvement. The imaging features of this rare tumor may vary widely, which may result in an incorrect diagnosis of breast carcinoma. Indeed, adenomyoepithelioma has metastatic potential; however, lymphatic spread is rare and axillary intervention may be over-treatment for most cases. While the imaging descriptions of intracystic adenomyoepitheliomas are very limited, this tumor should be considered in the differential diagnosis to avoid unnecessarily aggressive treatment.

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Epidermal inclusion cysts are uncommon in the breast, but the consequences can be severe when these cysts occur in the breast parenchyma. Here, we report two such cases. The patient in case 1 was an 85-year-old woman with a 3-cm palpable mass in the right breast. Mammography revealed a round and smoothly outlined mass, which indicated a benign tumor, and sonography showed an irregularly shaped and heterogeneous hypoechoic mass. Breast cancer was suspected on the basis of the sonographic findings and the age of the patient, but excisional biopsy revealed an epidermal inclusion cyst. The patient in case 2 was a 45-year-old woman with a 9-cm lesion in the left breast. Mammography revealed a round, dense, smoothly outlined mass, and sonography showed a well-defined, central hyperechoic mass. A phyllodes tumor or a giant fibroadenoma was suspected on the basis of clinical and imaging findings, but the resected specimen revealed an epidermal inclusion cyst.

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