Tomo Osako

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.

Accurate staging of axillary lymph nodes from breast cancer patients using a novel molecular method

Background:The one-step nucleic acid amplification (OSNA) assay is a molecular-based lymph-node metastasis detection procedure that can assess a whole node and yields semi-quantitative results for the detection of clinically relevant nodal metastases. We aimed to determine the performance of the OSNA assay as an accurate nodal staging tool in comparison with routine histological examination.Methods:Subjects comprised 183 consecutive patients with pT1-2 breast cancer who underwent axillary dissection after positive sentinel-node (SN) biopsy with the OSNA assay. Of these, for non-SN evaluation, 119 patients underwent OSNA assay evaluation, whereas 64 had single-section histology. We compared the detection rates of non-SN metastasis and upstaging rates from the SN stage according to the American Joint Committee on Cancer staging between the OSNA and histology cohorts.Results:OSNA detected more cases of non-SN metastases than histology (OSNA 66/119, 55.5% vs histology 13/64, 20.3%; P<0.001), particularly micrometastases (36/119, 30.3% vs 1/64, 1.6%; P<0.001). Total upstaging rates were similar in both cohorts (20/119, 16.8% vs 9/64, 14.1%, P=0.79).Conclusion:OSNA detects a far greater proportion of non-SN micrometastases than routine histological examination. However, upstaging rates after axillary dissection were not significantly different between both cohorts. Follow-up of the OSNA cohort is required to determine its clinical relevance.

Incidence and possible pathogenesis of sentinel node micrometastases in ductal carcinoma in situ of the breast detected using molecular whole lymph node assay

Background:The pathogenesis of lymph node metastases in preinvasive breast cancer – ductal carcinoma in situ (DCIS) – remains controversial. The one-step nucleic acid amplification (OSNA) assay is a novel molecular method that can assess a whole node and detect clinically relevant metastases. In this retrospective cohort study, we determined the performance of the OSNA assay in DCIS and the pathogenesis of node-positive DCIS.Methods:The subjects consisted of 623 patients with DCIS who underwent sentinel lymph node (SN) biopsy. Of these, 2-mm-sectioned nodes were examined using frozen-section (FS) histology in 338 patients between 2007 and 2009, while 285 underwent OSNA whole node assays between 2009 and 2011. The SN-positivity rate was compared between cohorts, and the characteristics of OSNA-positive DCIS were investigated.Results:The OSNA detected more cases of SN metastases than FS histology (12 out of 285, 4.2% vs 1 out of 338, 0.3%). Most of the metastases were micrometastases. The characteristics of high-risk DCIS (i.e., mass formation, size, grade, and comedo) and preoperative breast biopsy (i.e., methods or time to surgery) were not valid for OSNA assay–positive DCIS.Conclusion:The OSNA detects more SN metastases in DCIS than FS histology. Further examination of the primary tumours and follow-up of node-positive DCIS are needed to elucidate the pathogenesis.

Acute Radiation Dermatitis and Pneumonitis in Japanese Breast Cancer Patients with Whole Breast Hypofractionated Radiotherapy Compared to Conventional Radiotherapy

OBJECTIVE To evaluate acute morbidity, radiation dermatitis and pneumonitis, of Japanese patients treated with whole breast hypofractionated radiotherapy (RT) after breast-conserving surgery (BCS), compared to conventional RT. METHODS Japanese patients who received whole breast RT after BCS between October 2003 and September 2006 were retrospectively reviewed. Patients who had selected the conventional or hypofractionated schedule received whole breast irradiation of 50 Gy in 25 fractions plus boost or 40 Gy in 16 fractions plus boost. Radiation dermatitis and symptomatic pneumonitis were graded according to the Common Terminology Criteria for Adverse Events version 3.0. RESULTS Of 443 consecutive patients, 377 (85%) received the conventional schedule and 66 (15%) received the hypofractionated schedule. Of patients treated with the conventional schedule, Grade 0, 1, 2 and 3 radiation dermatitis were observed in 16 (4%), 278 (74%), 77 (20%) and 6 (2%), respectively. Of patients treated with the hypofractionated schedule, Grade 0, 1, 2 and 3 dermatitis were observed in 11 (17%), 49 (74%), 5 (8%) and 1 (1%), respectively. Grade 2-3 dermatitis by the hypofractionated schedule (9%) was observed less frequently than that by the conventional schedule (22%) (chi-square test; P = 0.016). Moreover, of patients treated with the conventional schedule, 4 (1%) had Grade 2 radiation pneumonitis. No patient treated with the hypofractionated schedule had symptomatic pneumonitis. CONCLUSIONS Radiation dermatitis and pneumonitis in Japanese patients treated with the hypofractionated schedule is acceptable. Especially, radiation dermatitis by the hypofractionated schedule is milder than that by the conventional schedule.

Secretory carcinoma of the breast and its histopathological mimics: value of markers for differential diagnosis

Secretory carcinoma (SC) is a rare histological type of breast cancer, and ETV6–NTRK3 gene fusion is highly specific to it. The differential diagnoses of SC include acinic cell carcinoma (ACCA) and cystic hypersecretory carcinoma (CHC), as well as invasive ductal carcinoma (IDC). For patients with these rare but distinctive histological subtypes, SC and its histopathological mimics should be differentiated from each other. However, differential markers have not yet been assessed systematically, and we aimed to identify and evaluate novel and existing markers.

Clinicopathological significance of invasive micropapillary carcinoma component in invasive breast carcinoma

Invasive micropapillary carcinoma (IMP) of the breast is a rare variant of invasive breast carcinoma and most cases of IMP are associated with nodal metastasis and lymphatic invasion. Lesions composed of an IMP component alone are rare and almost always coexist with other pathological components. However, few reports have documented IMP along with its proportion and the coexistent pathological type. We analyzed the total 486 breast cancer lesions operated in our hospital in 1998. We classified the lesions into five groups by the proportion of the IMP component in each lesion. Then we evaluated the incidence of nodal metastasis and lymphatic invasion in each group. The incidence of the invasive carcinoma containing any IMP components was 8.4%. The incidence of nodal metastasis and lymphatic invasion in lesions with an IMP component were significantly higher than that in those with no IMP. No correlation was seen between the incidence of nodal metastasis and the coexistent pathological type, shape of tumor clusters, nuclear grade and the expression of estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2 and gross cystic disease fluid protein‐15 in IMP components. The presence of IMP components was a significant predictive factor for nodal metastasis, even if it is detected in only a small proportion of the tumor.

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.

Flare-up of dermatomyositis along with recurrence of breast cancer.

Abstract:  Dermatomyositis is an idiopathic inflammatory myopathy with characteristic cutaneous manifestations. The association between dermatomyositis and malignancy is becoming more clearly delineated. A sort of dermatomyositis is thought to be paraneoplastic syndrome and dermatomyositis may follow clinical course of malignancy. We report a 68‐year‐old woman with dermatomyositis, whose clinical onset of dermatomyositis was apparently concomitant with breast cancer. Dermatomyositis had settled down and oral steroid could be tapered after the resection of breast cancer. Creatine kinase value was elevated before the detection of the first and second recurrence and in the terminal state. At the second recurrence, skin lesions and creatine kinase value had flared up and immediate metastatic check‐up revealed the recurrence. Our case shows dermatomyositis, which was thought to be paraneoplastic syndrome, that followed clinical course of malignancy and suggests immediate check‐up is needed for early detection of recurrence when dermatomyositis flares up after the resection of the malignancy.

Molecular detection of lymph node metastasis in breast cancer patients treated with preoperative systemic chemotherapy: a prospective multicentre trial using the one-step nucleic acid amplification assay.

Background:For patients with breast cancer treated with preoperative chemotherapy, residual tumour burden in lymph nodes is the strongest prognostic factor. However, conventional pathological examination has limitations that hinder the accurate and reproducible measurement. The one-step nucleic acid amplification (OSNA) assay is a novel molecular method for detecting nodal metastasis. In this prospective multicentre trial, we assessed the performance of the OSNA assay in detecting nodal metastasis after chemotherapy.Methods:In total, 302 lymph nodes from 80 breast cancer patients who underwent axillary dissection after chemotherapy were analysed. Each node was cut into two or four slices. One piece or alternate pieces were evaluated by pathology, and the other(s) were examined using the OSNA assay. The results of the two methods were compared. Stromal fibrosis, histiocytic aggregates, and degenerated cancer cells were regarded as chemotherapy-induced histological changes.Results:The overall accuracy, sensitivity, and specificity of the OSNA assay compared with the reference pathology were 91.1%, 88.3%, and 91.7%, respectively. Of the 302 lymph nodes, 66 (21.9%) exhibited chemotherapy-induced histology. For these nodes, the accuracy, sensitivity, and specificity were 90.9%, 88.9%, and 93.3%, respectively.Conclusion:The OSNA assay can detect the residual tumour burden as accurately as conventional pathology, although chemotherapy-induced histological changes are present.