Unusual presentation of breast adenoid cystic carcinoma resembling adenomyoepithelioma with multiple distinct foci.

We describe an unusual case of multifocal breast adenoid cystic carcinoma (AdCC) with adenomyoepitheliomatous morphology. Most breast AdCCs are unifocal and only four cases of multifocal AdCC have been reported previously, however, to our best knowledge, multifocality in AdCC confirmed by molecular analysis has not been reported, so this report adds to the literature on this unique presentation. An 80-year-old woman presented with a left breast mass at 1 o'clock and non-mass enhancement lesion at 5 o'clock on imaging. Incisional biopsy at 1 o'clock showed AdCC based on histopathological features and MYB rearrangement by fluorescent in situ hybridization (FISH). As AdCC involved the margins and the non-mass enhancing lesion remained, mastectomy was performed. Microscopically, the lesion at 5 o'clock demonstrated multinodularity and a biphasic epithelial-basaloid/myoepithelial pattern. Although histological features resembled adenomyoepithelioma, MYB rearrangement was identified on FISH, so the 5 o'clock lesion was also diagnosed as AdCC showing an adenomyoepitheliomatous pattern. This unusual presentation is a potential diagnostic pitfall, so pathologists should consider AdCC as a possible differential diagnosis of multifocal basaloid breast tumors with adenomyoepitheliomatous features.

Bilateral oncoplastic breast-conserving surgery with volume replacement technique using the omental flap: a case report.

BACKGROUND: Many oncoplastic volume replacement techniques have been reported, however, it is generally difficult to utilize a single distant flap for bilateral breast carcinomas. CASE PRESENTATION: We report a case of bilateral multiple breast carcinomas successfully treated with immediate volume replacement technique with an omental flap. Bilateral partial mastectomies were performed for bilateral breast carcinomas (one in the left breast and two in the right breast). The pedicled omental flap was laparoscopically harvested, and divided at the mid-portion of the flap. The proximal half of the flap was used to fill the right defect, and the distal half of the flap filled two defects in the left breast. Cosmetic outcome was excellent with minimal donor-site scars. CONCLUSIONS: The omental flap can be considered for highly selected patients with bilateral breast carcinomas.

Predictive value of ductal carcinoma in situ with invasive breast cancer in core needle biopsies for final pathologic size of intraductal elements.

Preoperative evaluations of the size of ductal carcinoma in situ (DCIS) extension in invasive breast cancer (IBC) are problematic and markers of the actual size of DCIS remain elusive. This study aimed to quantify DCIS on core needle biopsy (CNB) and investigated its association with degree of DCIS extension on paired resection specimens, instead of with presence or absence of an extensive intraductal component or margin status as in earlier studies. This series examined 150 IBCs diagnosed from paired CNB and resection specimens. The DCIS/invasion ratio was calculated using the sum of each element size from CNB. In resection specimens, cases in which the greatest dimension of DCIS extension was longer than the greatest dimension of invasive size were defined as extended DCIS (Ext-DCIS). DCIS/invasion ratio level correlated positively with the degree of Ext-DCIS (P = 0.003). Using receiver operating characteristic curve analysis, setting cases with the subgroup of DCIS extension with greatest dimension > 2.5 times that of the invasive size in the resection specimen (Ext-DCIS > 2.5) as the positive class provided the best discrimination ability for DCIS/invasion ratio (0.375). In multivariate analysis, DCIS/invasion ratio > 0.375 was significantly associated with Ext-DCIS > 2.5 (P = 0.033). In conclusion, DCIS/invasion ratio > 0.375 in CNB was identified as a predictor of Ext-DCIS > 2.5 in resection specimens, suggesting that an approach combining DCIS/invasion ratio from CNB with preoperative staging may better predict the extent of DCIS and facilitate better surgical planning.

Spiradenoma of the breast: a rare diagnostic pitfall in the evaluation of solid-basaloid breast lesions with a dual cell population.

Breast spiradenoma is extremely rare, with only 4 cases reported previously. We describe an instructive case of breast spiradenoma resembling adenoid cystic carcinoma (AdCC). A 71-year-old woman underwent excisional biopsy of a breast mass after a conclusive diagnosis was unable to be obtained from core needle biopsy showing an AdCC-like pattern. Histopathologically, the lesion demonstrated solid and cribriform foci comprising basaloid cells, luminal cells, and eosinophilic hyaline material, reminiscent of solid-basaloid AdCC, alongside convoluted lumens, stromal edema, lymphocytic infiltration, and c-kit negativity. On molecular analysis, neither MYB fusion genes nor CYLD gene abnormalities were identified. These results were supportive of spiradenoma. Salivary gland- and skin adnexal-type tumors are challenging to diagnose due to morphological overlaps. This case, highlighting histopathological and molecular features, shows that breast spiradenoma can be a diagnostic pitfall among the differential diagnoses of AdCC.

Fat necrosis in level I oncoplastic breast-conserving surgery focusing on a modified round block technique.

The modified round block technique (MRBT) is a level I oncoplastic breast-conserving surgery (OBCS), which contains a very wide glandular flap created by extensive dual-plane undermining that is achieved by entire subcutaneous dissection and approximately 50% dissection of the breast parenchyma from the pectoralis muscle. A retrospective analysis was performed for 100 patients who underwent OBCS using MRBT from February 2009 to October 2017. The incidence of positive margin was 7.0% (seven cases), and there has been no local recurrence during a median follow-up period of 68 months. Short- and long-term complications included fat necrosis (11.0%), infection (4.0%), and hematoma formation (4.0%). When patients were divided into two groups based upon the preoperative mammography findings, fat necrosis occurred in 5.2% of the patients with extremely dense or heterogeneously dense mammography, and in 19.0% of patients with scattered fibroglandular or entire fat mammography, which showed a statistically significant difference. Therefore, in level I OBCS, the extent of dual-plane undermining should be minimized to less than 50% of the total parenchyma in fatty breasts.

Quantitative digital image analysis of tumor-infiltrating lymphocytes in HER2-positive breast cancer.

As visual quantification of the density of tumor-infiltrating lymphocytes (TILs) lacks in precision, digital image analysis (DIA) approach has been applied in order to improve. In several studies, TIL density has been examined on hematoxylin and eosin (HE)-stained sections using DIA. The aim of the present study was to quantify TIL density on HE sections of core needle biopsies using DIA and investigate its association with clinicopathological parameters and pathological response to neoadjuvant chemotherapy in human epidermal growth factor receptor 2 (HER2)-positive breast cancer. The study cohort comprised of patients with HER2-positive breast cancer, all treated with neoadjuvant anti-HER2 therapy. DIA software applying machine learning-based classification of epithelial and stromal elements was used to count TILs. TIL density was determined as the number of TILs per square millimeter of stromal tissue. Median TIL density was 1287/mm2 (range, 123-8101/mm2). A high TIL density was associated with higher histological grade (P = 0.02), estrogen receptor negativity (P = 0.036), and pathological complete response (pCR) (P < 0.0001). In analyses using receiver operating characteristic curves, a threshold TIL density of 2420/mm2 best discriminated pCR from non-pCR. In multivariate analysis, high TIL density (> 2420/mm2) was significantly associated with pCR (P < 0.0001). Our results indicate that DIA can assess TIL density quantitatively, machine learning-based classification algorithm allowing determination of TIL density as the number of TILs per unit area, and TIL density established by this method appears to be an independent predictor of pCR in HER2-positive breast cancer.

A Genome-Wide Association Study Identifies Five Novel Genetic Markers for Trastuzumab-Induced Cardiotoxicity in Japanese Population.

Trastuzumab has been administered to patients with human epidermal growth factor receptor 2 (HER2)-positive cancer, however, the cardiotoxicity is identified as one of the life-threatening toxicities. Clinically useful biomarker for trastuzumab-induced cardiotoxicity has been expected to be developed. To identify a novel genetic marker(s) determining the risk of trastuzumab-induced cardiotoxicity, we performed a first genome-wide association study (GWAS) in Japanese population. We enrolled 481 patients who had been treated with trastuzumab and carried out a GWAS using 11 cases (with cardiotoxicity) and 257 controls (without cardiotoxicity). Top 100 single nucleotide polymorphisms (SNPs) which revealed the smallest p values in GWAS (p = 7.60 × 10-7 - 2.01 × 10-4) were further examined using replication samples consisted of 14 cases and 199 controls. The combined analysis of the GWAS and replication study indicated possible association of five loci with trastuzumab-induced cardiotoxicity (rs9316695 on chromosome 13q14.3, rs28415722 on chromosome 15q26.3, rs7406710 on chromosome 17q25.3, rs11932853 on chromosome 4q25, and rs8032978 on chromosome 15q26.3, Pcombined = 6.00 × 10-6, 8.88 × 10-5, 1.07 × 10-4, 1.42 × 10-4, 1.60 × 10-4, respectively). Furthermore, we developed a risk prediction model for trastuzumab-induced cardiotoxicity using the five marker SNPs. The incidence of trastuzumab-induced cardiotoxicity in patients with risk score ≥5 was significantly higher (42.5%) compared to that in patients with score ≤ 4 (1.8%) (p = 7.82 × 10-15, odds ratio = 40.0). These findings suggest the potential to improve the ability of physicians to avoid the trastuzumab-induced cardiotoxicity for patients with HER2-positive cancer.

Participants in a randomized controlled trial had longer overall survival than non-participants: a prospective cohort study.

PURPOSE: While some studies show improved outcomes in clinical trial participants as compared to non-participants, existence of such a trial effect has not been proved precisely. METHODS: This was a prospective cohort study to compare the prognoses for participants in the randomized controlled trial (SELECT BC) and non-participants. SELECT BC compared S-1 and taxane as first-line treatment for metastatic breast cancer. Non-participants were all patients who met the eligibility criteria of SELECT BC and who had been requested to participate in that trial by attending doctors and declined. The study aimed to compare the prognoses between participants and non-participants. The primary endpoint was median overall survival. RESULTS: The median OS in participants was significantly superior to that in non-participants with a statistically significant difference (36.8 months vs. 25.2 months. HR 1.48, p = 0.022). A similar result was obtained when only patients who received the same chemotherapy (S-1 or taxane) used in SELECT BC after declining participation were assumed as non-participants (36.8 months vs. 22.0 months. HR 2.03, p = 0.006). CONCLUSIONS: This study may suggest the existence of a trial effect, in which, for a given treatment, participation in a clinical trial is associated with a better outcome.

A genome-wide association study identifies three novel genetic markers for response to tamoxifen: A prospective multicenter study.

PURPOSE: Although association studies of genetic variations with the clinical outcomes of breast cancer patients treated with tamoxifen have been reported, genetic factors which could determine individual response to tamoxifen are not fully clarified. We performed a genome-wide association study (GWAS) to identify novel genetic markers for response to tamoxifen. EXPERIMENTAL DESIGN: We prospectively collected 347 blood samples from patients with hormone receptor-positive and human epidermal growth factor receptor 2-negative, invasive breast cancer receiving preoperative tamoxifen monotherapy for 14 to 28 days. We used Ki-67 response in breast cancer tissues after preoperative short-term tamoxifen therapy as a surrogate marker for response to tamoxifen. We performed GWAS and genotype imputation using 275 patients, and an independent set of 72 patients was used for replication study. RESULTS: The combined result of GWAS and the replication study, and subsequent imputation analysis indicated possible association of three loci with Ki-67 response after tamoxifen therapy (rs17198973 on chromosome 4q34.3, rs4577773 on 6q12, and rs7087428 on 10p13, Pcombined = 5.69 x 10-6, 1.64 x 10-5, and 9.77 x 10-6, respectively). When patients were classified into three groups by the scoring system based on the genotypes of the three SNPs, patients with higher scores showed significantly higher after/before ratio of Ki-67 compared to those with lower scores (P = 1.8 x 10-12), suggesting the cumulative effect of the three SNPs. CONCLUSION: We identified three novel loci, which could be associated with clinical response to tamoxifen. These findings provide new insights into personalized hormonal therapy for the patients with breast cancer.

[A Case of Pneumocystis Pneumonia during Adjuvant Dose-Dense Chemotherapy for Breast Cancer].

A 47-year-old woman received adjuvant chemotherapy for breast cancer. On the 13th day of 4 courses of dose-dense AC therapy, she developed a fever. She was orally administered an antibioticfor febrile neutropenia treatment. She showed no improvement of symptoms and gradually presented with new symptoms, including a non-productive cough and dyspnea. After admission, she underwent a further examination, and was provided a diagnosis of pneumocystis pneumonia. It is reported that patients receiving chemotherapy for solid tumors are less likely to develop opportunistic infections. However, patients receiving dose-dense chemotherapy may have a higher risk for developing opportunistic infections than those receiving conventional chemotherapy.

Oncoplastic surgery with omental flap reconstruction: a study of 200 cases.

BACKGROUND: There are several small case series on use of a laparoscopically harvested omental flap (LHOF) for breast reconstruction. However, the long-term oncological safety and clinical benefits of the LHOF remain uncertain, especially in use of the flap in oncoplastic breast surgery. STUDY DESIGN: A retrospective chart review was performed for 200 patients who underwent oncoplastic breast surgery using a LHOF at our institution from April 2002 to March 2016. Laparoscopy-associated complications, local recurrence, and cosmetic outcomes were evaluated. RESULTS: Most of the patients underwent partial breast reconstruction immediately after breast-conserving surgery (BCS). The success rate of laparoscopic harvesting of the omental flap was 99.5%. The rate of complications was 12.0% and laparoscopy-associated complications occurred in four cases (2.0%). The rate of a positive margin was 6.5%. Two cases (1.0%) had local recurrence during a median follow-up period of 90 months. In 24 patients (12.0%), the volume of the flap was insufficient. When applied to total reconstruction, volume insufficiency occurred in 32.6% of patients. Cosmetic outcomes were mostly satisfactory. Approximately 80% of patients were rated as good or excellent by evaluation using a 4-point scale and Breast Cancer Conservative Treatment cosmetic results (BCCT.core) software. Donor-site scars were negligible, as in laparoscopic cholecystectomy. CONCLUSIONS: The LHOF has minimal donor-site morbidity and deformity, and oncological safety is promising. There is a limit to the adaptable volume, but the LHOF is an attractive option in partial breast reconstruction after BCS.

Significant Effect of Polymorphisms in CYP2D6 on Response to Tamoxifen Therapy for Breast Cancer: A Prospective Multicenter Study.

Purpose: CYP2D6 is the key enzyme responsible for the generation of the potent active metabolite of tamoxifen, "endoxifen." There are still controversial reports questioning the association between CYP2D6 genotype and tamoxifen efficacy. Hence, we performed a prospective multicenter study to evaluate the clinical effect of CYP2D6 genotype on tamoxifen therapy.Experimental Design: We enrolled 279 patients with hormone receptor-positive and human epidermal growth factor receptor 2-negative, invasive breast cancer receiving preoperative tamoxifen monotherapy for 14 to 28 days. Ki-67 response in breast cancer tissues after tamoxifen therapy was used as a surrogate marker for response to tamoxifen. We prospectively investigated the effects of allelic variants of CYP2D6 on Ki-67 response, pathological response, and hot flushes.Results: Ki-67 labeling index in breast cancer tissues significantly decreased after preoperative tamoxifen monotherapy (P = 0.0000000000000013). Moreover, proportion and Allred scores of estrogen receptor-positive cells in breast cancer tissues were significantly associated with Ki-67 response (P = 0.0076 and 0.0023, respectively). Although CYP2D6 variants were not associated with pathologic response nor hot flushes, they showed significant association with Ki-67 response after preoperative tamoxifen therapy (P = 0.018; between two groups, one with at least one wild-type allele and the other without a wild-type allele).Conclusions: This is the first prospective study evaluating the relationship between CYP2D6 variants and Ki-67 response after tamoxifen therapy. Our results suggest that genetic variation in CYP2D6 is a key predictor for the response to tamoxifen in patients with breast cancer. Clin Cancer Res; 23(8); 2019-26. ©2016 AACR.

Oncoplastic volume replacement technique for the upper inner quadrant using the omental flap.

BACKGROUND: In breast-conserving surgery (BCS), a large defects in the upper inner quadrant (UIQ) named the no man's land of the breast will cause shift the nipple in an unnatural upward or medial fashion. We have developed oncoplastic volume replacement techniques using a laparoscopically harvested omental flap (OF). This paper presents our experiences performing partial breast reconstruction for the defect in the UIQ using the OF. METHODS: A wide excision (>20% of the breast tissue) was performed mainly through a periareolar incision. The pedicled OF was harvested laparoscopically. A small incision was made along the medical inframammary fold and a subcutaneous tunnel was created towards the xyphoid process. The OF was extracted through the tunnel, and used to fill the defect in the UIQ. RESULTS: Thirty patients were included in this study. The median resected breast volume was 142 g. A donor-site complication was only one ventral hernia. The surgical margins were positive in one patient (3.3%), and neither local nor systemic recurrence has occurred during medial follow-up periods of 64 months. Cosmetic outcomes were mostly satisfactory with negligible donor-site scars, and more than 80% of the patients scored excellent or good. CONCLUSIONS: The OF is a useful volume replacement technique for the UIQ which is the most difficult quadrant for the other distant flaps.

Cosmetic evaluation methods adapted to asian patients after breast-conserving surgery and examination of the necessarily elements for cosmetic evaluation.

PURPOSE: Although various strategies have been reported, there are no defined criteria for cosmetic evaluation methods after breast-conserving surgery (BCS). Since Asians tend to have smaller breasts, indistinct inframammary folds, and conspicuous scars, differences in the cosmetic results are expected. So we examined two subjective methods and one objective method to determine the differences, and elements necessary for a cosmetic evaluation after BCS. METHODS: Frontal photographs of 190 Japanese were evaluated using the Harris scale (Harris) and the evaluation method proposed by the Japanese Breast Cancer Society Sawai group (Sawai group) as the subjective methods, and the Breast Cancer Conservation Treatment cosmetic results (BCCT.core) as the objective method, respectively. In order to examine the necessary elements for developing a new ideal method, 100 out of 190 were selected and assessed separately by six raters using both the Harris and modified Sawai group methods in the observer assessment. The correlation between the two methods was examined using the Spearman rank-correlation coefficient. RESULTS: The results of the BCCT.core and the other two methods were clearly different. In the observer assessment, the consensuses of the six raters were evaluated as follows: 27, 27, 26, and 20 cases were evaluated as "excellent," "good," "fair," and "poor," respectively. For the Spearman rank-correlation coefficient, values higher than 0.7 indicated a strong correlation, as seen by the values of 0.909 for the breast shape and 0.345 for the scar. The breast shape accounted for the most significant part of the evaluation, and the scar had very little correlation. CONCLUSION: In this study, we recognized a clear difference between the subjective and objective evaluation methods, and identified the necessary elements for cosmetic evaluation. We would like to continue developing an ideal cosmetic evaluation that is similar to subjective one and is independent from raters.

Can we improve breast cancer mortality in Okinawa? Consensus of the 7th Okinawa Breast Oncology Meeting.

The rate of breast cancer mortality in Okinawa has gradually been increasing up to 2010. Now Okinawa has the second worst mortality rate in Japan, in part due to the enormous dietary changes resulting from the post-World War II US military occupation, high incidence of obesity, high non-optimal treatment rate, and low breast-cancer screening rate. To reduce breast cancer mortality in Okinawa, we established the Okinawa Breast Oncology Meeting (OBOM) in 2012. At the 7th OBOM held on January 10th, 2014, we discussed the breast cancer mortality in Okinawa focusing on lifestyle, breast cancer screening and optimal treatments. The Okinawan women who were overweight and/or obese during premenopausal and postmenopausal ages had a statistically significant higher risk of breast cancer development compared to those with non-overweight and/or obese women. The traditional diet of Okinawa consists of foods low in calories but rich in nutritional value. Therefore, we recommend Okinawan people not to forget the Okinawan traditional lifestyle, and to reduce their bodyweight to prevent breast cancer. One of the main goals of the OBOM is to raise breast cancer screening attendance rates to 50% (29.2% in 2010). We should standardize the quality control for breast cancer screening in Okinawa. It is important to continue enlightening the Okinawan population to receive optimal treatment. In addition, we are striving to establish systematic medical cooperation between the hospitals specializing in breast cancer treatment with rural hospitals. The OBOM group endeavors to contribute to the improvement of breast cancer mortality in Okinawa.

Partial breast reconstruction for the medial quadrants using the omental flap.

BACKGROUND: The indications for breast-conserving surgery have increased due to the establishment of various volume-replacement techniques. We have used the omental flap for partial breast reconstruction. Unlike other autologous flaps, the medial quadrants represent a suitable field for the omental flap. We report a technique for partial breast reconstruction using the omental flap. METHODS: For tumors in the lower medial quadrant, wide excision was performed through an inframammary skin incision. The omental flap was harvested laparoscopically, and a subcutaneous tunnel was created towards the xyphoid process. The omental flap was extracted through the tunnel and used to fill the defect directly. For tumors in the upper medial quadrant, a periareolar incision was usually used for wide excision, and an additional small inframammary incision was made to extract the omental flap. The pedicle of the flap was made as slim as possible by defatting, and the subcutaneous fat tissue around the tunnel was excised to avoid bulging caused by the subcutaneous tunnel. RESULTS: A total of 51 patients with tumors in the medial quadrants underwent partial breast reconstruction with the omental flap between April 2002 and July 2013. The surgical margin was positive in two patients, and there was only one case of local recurrence. The complication rate was 7.8 %, and all of them were minor. Cosmetic results were mostly satisfactory with minimal donor-site scars. CONCLUSIONS: The omental flap is an attractive volume replacement technique for difficult quadrants of the breast with minimal donor-site morbidities and deformities.

A new scarless oncoplastic breast-conserving surgery: modified round block technique.

Round block technique (RBT) is often utilized in breast-conserving surgery, but has problems of late-onset scar widening and changes in the shape or the position of the areola. We have modified RBT (MRBT) to resolve those problems. A circumferential incision was made without excision of the periareolar skin, and subcutaneous dissection was extended to the entire breast. The wound could be widened and moved onto the distant tumor by application of a wound retractor. Partial mastectomy was then performed under direct vision. The wound was easily closed without tension. Forty breast cancer patients were treated with MRBT. The median distance between the nipple and the tumor was 5.2 cm, and the median areolar size was 2.8 cm. Cosmetic results were satisfactory with minimal scar formation. There were neither subsequent changes in the shape nor the position of the areola. MRBT is a useful oncoplastic technique in patients with small areolae, and/or when the tumor location is distant from the nipple.

The challenge to reduce breast cancer mortality in Okinawa: consensus of the first Okinawa breast oncology meeting.

Breast cancer mortality is gradually increasing in Okinawa. The 1st Okinawa Breast Oncology Meeting was held on 6 July 2012 and discussions on how to curb the rising trend were focused on breast cancer screening, adjuvant treatment, socioeconomic and geographic issues, and the problem of complementary and alternative medicine. The consensus of the 1st Okinawa Breast Oncology Meeting was that ultrasonography screening is an acceptable screening system for Okinawan women because of the geographic disadvantage of having many small islands and rural areas. Educational and economic support is needed for women in rural areas to get correct information, for access to urban areas and to be treated by evidence-based optimal therapy for breast cancer. In addition, new approaches are needed for Okinawan people to successfully educate patients to correctly interpret evidence-based information.