Kiyomi Kimura

Intraoperative molecular assay for sentinel lymph node metastases in early stage breast cancer: a comparative analysis between one-step nucleic acid amplification whole node assay and routine frozen section histology.

Conventional histopathological examination is limited in measuring accurate total metastatic volume in a lymph node. Recently, a molecular‐based procedure to detect lymph node metastases, one‐step nucleic acid amplification (OSNA) assay, has been developed. OSNA assay can assess a whole lymph node and yields semiquantitative results. The authors compared the performance in intraoperative detection of sentinel lymph node metastases with OSNA assay using a whole lymph node versus routine frozen section (FS) histology with a 2 mm‐sectioned lymph node.

Sentinel node tumour burden quantified based on cytokeratin 19 mRNA copy number predicts non-sentinel node metastases in breast cancer: Molecular whole-node analysis of all removed nodes

OBJECTIVE The one-step nucleic acid amplification (OSNA) assay can assess an entire lymph node and detect clinically relevant metastases quantified based on cytokeratin 19 (CK19) mRNA copy number. The OSNA assay of all sentinel lymph nodes (SNs) and non-sentinel nodes (non-SNs) allows for the accurate measurement of tumour burden in either situation. We aim to reveal the usefulness of the OSNA assay regarding the prediction of non-SN metastasis. METHODS The subjects consisted of 185 breast cancer patients who underwent axillary dissection after a metastatic SN biopsy and whose SNs and non-SNs were examined using the OSNA whole-node assay between 2009 and 2011. The non-SN tumour burden was classified as macrometastasis (CK19 mRNA ≥ 5000 copies/μl) or micrometastasis (250-5000 copies/μl). The relationship between SN and non-SN tumour burdens and predictors of non-SN metastasis were investigated. RESULTS Among these 185 patients, 38 patients (20.5%) had macrometastasis and 58 (31.4%) had micrometastasis only in the non-SNs. Non-SN macrometastasis rates increased in direct proportion to the SN copy number: approximately 5% in patients with SNs with 250-500 copies; 20%, 500-5000 copies and 30%, ≥ 5000 copies. However, non-SN micrometastasis rates were approximately 30% regardless of the SN copy number. In multivariate analyses, the mean SN copy number, number of macrometastatic SN and lymphovascular invasion were significant for identifying non-SN macrometastases. CONCLUSIONS The SN tumour burden quantified using the OSNA assay predicts non-SN metastases. A novel mathematical model to predict the non-SN tumour burden can be generated using the results of the OSNA assay.

Ductal carcinoma in situ and sentinel lymph node metastasis in breast cancer

BackgroundThe impact of sentinel lymph node biopsy on breast cancer mimicking ductal carcinoma in situ (DCIS) is a matter of debate.MethodsWe studied the rate of occurrence of sentinel lymph node metastasis in 255 breast cancer patients with pure DCIS showing no invasive components on routine pathological examination. We compared this to the rate of occurrence in 177 patients with predominant intraductal-component (IDC) breast cancers containing invasive foci equal to or less than 0.5 cm in size.ResultsMost of the clinical and pathological baseline characteristics were the same between the two groups. However, peritumoral lymphatic permeation occurred less often in the pure DCIS group than in the IDC-predominant invasive-lesion group (1.2% vs. 6.8%, p = 0.002). One patient (0.39%) with pure DCIS had two sentinel lymph nodes positive for metastasis. This rate was significantly lower than that in patients with IDC-predominant invasive lesions (6.2%; p < 0.001).ConclusionsBecause the rate of sentinel lymph node metastasis in pure DCIS is very low, sentinel lymph node biopsy can safely be omitted.

Influence of Lymphatic Invasion on Locoregional Recurrence Following Mastectomy: Indication for Postmastectomy Radiotherapy for Breast Cancer Patients With One to Three Positive Nodes

PURPOSE The indication for postmastectomy radiotherapy (PMRT) in breast cancer patients with one to three positive lymph nodes has been in discussion. The purpose of this study was to identify patient groups for whom PMRT may be indicated, focusing on varied locoregional recurrence rates depending on lymphatic invasion (ly) status. METHODS AND MATERIALS Retrospective analysis of 1,994 node-positive patients who had undergone mastectomy without postoperative radiotherapy between January 1990 and December 2000 at our hospital was performed. Patient groups for whom PMRT should be indicated were assessed using statistical tests based on the relationship between locoregional recurrence rate and ly status. RESULTS Multivariate analysis showed that the ly status affected the locoregional recurrence rate to as great a degree as the number of positive lymph nodes (p < 0.001). Especially for patients with one to three positive nodes, extensive ly was a more significant factor than stage T3 in the TNM staging system for locoregional recurrence (p < 0.001 vs. p = 0.295). CONCLUSION Among postmastectomy patients with one to three positive lymph nodes, patients with extensive ly seem to require local therapy regimens similar to those used for patients with four or more positive nodes and also seem to require consideration of the use of PMRT.

Incidence and prediction of invasive disease and nodal metastasis in preoperatively diagnosed ductal carcinoma in situ

For breast cancer patients with a preoperative diagnosis of ductal carcinoma in situ (DCIS), sentinel lymph node (SN) biopsy has been proposed as an axillary staging procedure in selected patients with a higher likelihood of having occult invasive lesions. With detailed histological examination of primary tumors and molecular whole‐node analysis of SNs, we aimed to validate whether this selective application accurately identifies patients with SN metastasis. The subjects were 336 patients with a preoperative needle‐biopsy diagnosis of DCIS who underwent SN biopsy using the one‐step nucleic acid amplification assay in the period 2009–2011. The incidence and preoperative predictors of upstaging to invasive disease on final pathology and SN metastasis, and their correlation, were investigated. Of the 336 patients, 113 (33.6%) had invasive disease, and 6 (1.8%) and 17 (5.0%) had macro‐ and micrometastasis in axillary nodes respectively. Of the 113 patients with invasive disease, 4 (3.5%) and 9 (8.0%) had macro‐ and micrometastasis. Predictors of invasive disease included palpability, mammographic mass, and calcifications (spread >20 mm), and intraductal solid structure, but no predictor was found for SN metastasis. Therefore, even though occult invasive disease was found at final pathology, most of the patients had no metastasis or only micrometastasis in axillary nodes. Predictors of invasive disease and SN metastasis were not completely consistent, so the selective SN biopsy for patients with a higher risk of invasive disease may not accurately identify those with SN metastasis. More accurate application of SN biopsy is required for patients with a preoperative diagnosis of DCIS.

A case of diabetic mastopathy with multiple lesions mimicking breast cancer.

We report a case of diabetic mastopathy with multiple unilateral lesions in an insulin dependent patient. The patient was a 62-year-old woman with two hard tumors in the right breast, who had been treated with insulin for diabetes mellitus. Mammography revealed a highly dense tumor in the right breast, while ultrasonography showed two irregular hypoechoic lesions with marked posterior acoustical shadowing, suggesting scirrhous carcinoma. On magnetic resonance imaging the two lesions had slightly heterogeneous enhancement. Aspiration breast cytology showed insufficient cellular material for evaluation. Excisional biopsy was performed because the patient wanted confirmation and treatment. Fibrosis with dense lymphocytic infiltration around the lobules and ducts was diagnosed histopathologically. These findings were compatible with diabetic fibrous mastopathy. Although this disease is thought to be a diabetes-induced reaction of autoimmune origin, multiple lesions are rare. This is the first case of unilateral multiple lesions of diabetic mastopathy.

Detection of occult invasion in ductal carcinoma in situ of the breast with sentinel node metastasis

By definition, ductal carcinoma in situ (DCIS) – pre‐invasive breast cancer – does not metastasize to the lymph nodes. However, since the introduction of molecular whole‐node analysis using the one‐step nucleic acid amplification assay for sentinel node (SN) biopsies, the number of patients with DCIS and SN metastasis has increased. The pathogenesis and clinical management of DCIS with SN metastasis remain controversial. In this case–control study, in order to elucidate the pathogenesis of SN metastasis in DCIS, we compared occult invasions between the SN‐positive and SN‐negative DCIS and investigated predictive factors of occult invasion. The subjects were 24 patients selected from 285 patients with a routine postoperative diagnosis of DCIS who had undergone SN biopsy using the one‐step nucleic acid amplification whole‐node assay between 2009 and 2011. Of these 24 patients, 12 were SN‐positive, and 12 were SN‐negative. The 12 SN‐negative patients make up the control group and were selected from the 273 SN‐negative patients based on patient characteristics. All paraffin blocks of the primary tumor from each patient were step‐sectioned with 500‐μm intervals until the block was exhausted and histopathologically examined. We analyzed 1830 step‐sectioned slides and found occult invasions were more frequent in the SN‐positive group (7/12, 58.3%) than in the SN‐negative group (3/12, 25.0%). All occult invasions were <5 mm. There was no correlation between occult invasion and SN tumor burden, non‐SN metastasis, or patient characteristics. Our results suggest true metastasis from occult invasion may be a potent pathogenesis indicating nodal metastasis in postoperatively diagnosed DCIS. Patient follow‐up is required to elucidate the prognostic impact of nodal metastasis and occult invasion.

Four types of Ipsilateral Breast Tumor Recurrence (IBTR) after breast-conserving surgery: Classification of IBTR based on precise pathological examination

We classified ipsilateral breast tumor recurrences (IBTRs) based on strict pathological rules. Ninety‐six women who were surgically treated for IBTR were included. IBTRs were classified according to their origins and were distinguished based on strict pathological rules: relationship between the IBTR and the primary lumpectomy scar, surgical margin status of the primary cancer, and the presence of in situ lesions of IBTR. The prognosis of these subgroups were compared to that of new primary tumors (NP) in the narrow sense (NPn) that occurred far from the scar. Distant‐disease free survival of IBTR that occurred close to the scar with in situ lesions and a negative surgical margin of the primary cancer (NP occurred close to the scar, NPcs) was similar to that of NPn. In contrast, IBTR that occurred close to the scar without in situ lesions (true recurrence (TR) that arose from residual invasive carcinoma foci, TRinv) had significantly poorer prognosis than NPn. IBTR that occurred close to the scar with in situ lesions and a positive surgical margin of the primary cancer (TR arising from a residual in situ lesion, TRis) had more late recurrences than NPcs. Precise pathological examinations indicated four distinct IBTR subtypes with different characteristics.

Monotherapy with Paclitaxel as Third-Line Chemotherapy against Anthracycline-Pretreated and Docetaxel-Refractory Metastatic Breast Cancer

We describe a patient with anthracycline-pretreated and docetaxel-refractory metastatic breast cancer who achieved a complete response after third-line chemotherapy with paclitaxel. A 59-year-old woman underwent modified radical mastectomy for advanced cancer in her left breast after local arterial neoadjuvant chemotherapy with anthracycline. Postoperatively anthracycline-containing adjuvant therapy was administered. Pulmonary metastases occurred 15 months after surgery, which did not respond to 4 cycles of second-line chemotherapy with docetaxel, given at 60 mg/m2 every 3 weeks. Therefore 210 mg/m2 of paclitaxel was given every 3 weeks as third-line monotherapy and induced a complete response with grade 3 neutropenia and hair loss as the major adverse effects.We suggest that paclitaxel is potentially effective as third-line monotherapy for anthracycline-resistant and docetaxel-refractory metastatic breast cancer.

Maximum Density of Tumor Staining Obtained by Preoperative IV-DSA as a Prognostic Indicator for Node-Negative Breast Cancer.

BackgroundWe previously demonstrated that the density of tumor enhancement by intravenous digital subtraction angiography (IV-DSA) is correlated with the number of tumor microvessels and that the incidence of distant metastasis is high in patients with breast cancer who show a high maximum density of tumor enhancement (MAX) on IV-DSA. In the present study, we evaluated the prognostic value of MAX for node-negative breast cancer patients.Patients and MethodsA total of 128 node-negative breast cancer patients underwent preoperative IV-DSA, and the region of interest (ROI) was set in the areas enhanced by IV-DSA of the breast. MAX was calculated by the time-density curve. Patients were divided into two subgroups: those with MAX ≥9 (n=35) and those with MAX <9 (n=93).ResultsPatients with recurrence had a significantly higher MAX value than those without recurrence (11.8±3.8 vs 7.1 ±3.0, p<0.01). The disease-free survival rate was significantly worse in patients with higher MAX values than in those with lower MAX values (p<0.001). Multivariate analysis showed that MAX was the strongest predictor of disease-free survival (p=0.026).ConclusionsThese results suggest that the maximum density obtained by IV-DSA is a strong, independent prognostic indicator for node-negative breast cancer patients.