Investigation of imaging features in contrast-enhanced magnetic resonance imaging of benign and malignant breast lesions.

PURPOSE: This study aimed to enhance the diagnostic accuracy of contrast-enhanced breast magnetic resonance imaging (MRI) using gadobutrol for differentiating benign breast lesions from malignant ones. Moreover, this study sought to address the limitations of current imaging techniques and criteria based on the Breast Imaging Reporting and Data System (BI-RADS). MATERIALS AND METHODS: In a multicenter retrospective study conducted in Japan, 200 women were included, comprising 100 with benign lesions and 100 with malignant lesions, all classified under BI-RADS categories 3 and 4. The MRI protocol included 3D fast gradient echo T1- weighted images with fat suppression, with gadobutrol as the contrast agent. The analysis involved evaluating patient and lesion characteristics, including age, size, location, fibroglandular tissue, background parenchymal enhancement (BPE), signal intensity, and the findings of mass and non-mass enhancement. In this study, univariate and multivariate logistic regression analyses were performed, along with decision tree analysis, to identify significant predictors for the classification of lesions. RESULTS: Differences in lesion characteristics were identified, which may influence malignancy risk. The multivariate logistic regression model revealed age, lesion location, shape, and signal intensity as significant predictors of malignancy. Decision tree analysis identified additional diagnostic factors, including lesion margin and BPE level. The decision tree models demonstrated high diagnostic accuracy, with the logistic regression model showing an area under the curve of 0.925 for masses and 0.829 for non-mass enhancements. CONCLUSION: This study underscores the importance of integrating patient age, lesion location, and BPE level into the BI-RADS criteria to improve the differentiation between benign and malignant breast lesions. This approach could minimize unnecessary biopsies and enhance clinical decision-making in breast cancer diagnostics, highlighting the effectiveness of gadobutrol in breast MRI evaluations.

Effectiveness and tasks of breast MRI surveillance for high-risk women with cancer susceptibility genes other than BRCA1/2: a single institution study.

BACKGROUND: In Japan, with the introduction of multigene panel testing, there is an urgent need to build a new medical system for hereditary breast cancer patients that covers pathogenic variants other than BRCA1/2. The aim of this study was to reveal the current status of breast MRI surveillance for high-risk breast cancer susceptibility genes other than BRCA1/2 and the characteristics of detected breast cancer. METHODS: We retrospectively examined 42 breast MRI surveillance with contrast performed on patients with hereditary tumors other than BRCA1/2 pathogenic variants at our hospital from 2017 to 2021. MRI exams were evaluated independently by two radiologists. Final histopathological diagnosis for malignant lesions were obtained from surgical specimen. RESULTS: A total of 16 patients included TP53, CDH1, PALB2, ATM pathogenic variants and 3 variant of unknown significance. 2 patients with TP53 pathogenic variants were detected breast cancer by annual MRI surveillance. The rate of cancer detection was 12.5% (2/16). One patient was detected synchronous bilateral breast cancer and unilateral multiple breast cancers (3 lesions in 1 patient), so there were 4 malignant lesions in total. Surgical pathology of 4 lesions were 2 ductal carcinoma in situ, 1 invasive lobular carcinoma, and 1 invasive ductal carcinoma. MRI findings of 4 malignant lesions were detected as 2 non mass enhancement, 1 focus and 1 small mass. All of 2 patients with PALB2 pathogenic variants had previously developed breast cancer. CONCLUSIONS: Germline TP53 and PALB2 were strongly associated with breast cancer, suggesting that MRI surveillance is essential for breast cancer-related hereditary predisposition.

Incidence of germline variants in Lynch syndrome-related genes among Japanese endometrial cancer patients aged 40 years or younger.

[Objective] Lynch syndrome (LS) is an autosomal dominant inherited disorder caused by a germline pathogenic variant in DNA mismatch repair (MMR) genes. Endometrial cancer frequently precedes another LS-associated tumor. This study aimed to clarify the incidence and features of LS in young Japanese endometrial cancer patients.[Methods] Sixty-five patients aged 40 years or younger, who were diagnosed with endometrial cancer, were enrolled in this study. Targeted sequencing of a hereditary colorectal cancer-related gene panel including the MMR genes MLH1, MSH2, MSH6, and PMS2 was conducted on DNA samples extracted from blood cells.[Results] Overall, 6 missense variants (2 in MSH2, 2 in MSH6, and 2 in PMS2), 1 inframe deletion variant in MSH2, 1 splice variant in MSH2, and 1 two-base substitution in the 3' untranslated region in MLH1 were detected in 9 (13.8%) patients. Among these, the splice variant c.1276G > T (p.Ile411_Gly426del16) in MSH2 was annotated as pathogenic, while other variants were of uncertain significance. The patient with the pathogenic variant had a family history of endometrial and colorectal cancer and was diagnosed with endometrial cancer at age 35.[Conclusion] The incidence of LS among Japanese endometrial cancer patients of reproductive age (≤ 40 years) in this study was at least 1.5%; however, 12.3% of patients had variants of uncertain significance in MMR genes.

Myofibroblastoma of the breast showing rare palisaded morphology and uncommon desmin- and CD34-negative immunophenotype: A case report.

Myofibroblastoma is a rare benign mesenchymal tumor typically arising in the breast. We report a diagnostically challenging case of myofibroblastoma of the breast showing a rare palisaded morphology and an uncommon desmin- and CD34-negative immunophenotype. A 73-year-old man underwent an excision for an 8 mm-sized breast mass. Histology revealed that the tumor was composed of fascicles of bland spindle cells showing prominent nuclear palisading and Verocay-like bodies. First, schwannoma, malignant peripheral nerve sheath tumor, and synovial sarcoma were suspected given the palisaded morphology. However, none of them was confirmed by immunohistochemical or molecular analyses. Next, a palisaded variant of myofibroblastoma was suspected by the morphology and coexpression of estrogen, progesterone and androgen receptors, BCL2 and CD10 in immunohistochemistry. However, the key diagnostic markers, desmin and CD34, were both negative. Finally, the diagnosis of myofibroblastoma was confirmed by detecting RB1 loss in immunohistochemistry and monoallelic 13q14 deletion (RB1 and FOXO1 loss) by fluorescence in situ hybridization assay. For the correct diagnosis of myofibroblastoma, it is important for pathologists to recognize the wide morphological spectrum, including a palisaded morphology, and the immunophenotypical variations, including desmin- and CD34-negative immunophenotypes, and to employ a comprehensive diagnostic analysis through combined histological, immunohistochemical and molecular evaluations.

Metastatic ovarian cancer spreading into mammary ducts mimicking an in situ component of primary breast cancer: a case report.

BACKGROUND: Accurate diagnosis of metastatic tumors in the breast is crucial because the therapeutic approach is essentially different from primary tumors. A key morphological feature of metastatic tumors is their lack of an in situ carcinoma component. Here, we present a unique case of metastatic ovarian carcinoma spreading into mammary ducts and mimicked an in situ component of primary carcinoma. To our knowledge, this is the second case (and the first adult case) confirming the in situ-mimicking growth pattern of a metastatic tumor using immunohistochemistry. CASE PRESENTATION: A 69-year-old Japanese woman was found to have a breast mass with microcalcifications. She had a known history of ovarian mixed serous and endocervical-type mucinous (seromucinous) carcinoma. Needle biopsy specimen of the breast tumor revealed adenocarcinoma displaying an in situ-looking tubular architecture in addition to invasive micropapillary and papillary architectures with psammoma bodies. From these morphological features, metastatic serous carcinoma and invasive micropapillary carcinoma of breast origin were both suspected. In immunohistochemistry, the cancer cells were immunoreactive for WT1, PAX8, and CA125, and negative for GATA3, mammaglobin, and gross cystic disease fluid protein-15. Therefore, the breast tumor was diagnosed to be metastatic ovarian serous carcinoma. The in situ-looking architecture showed the same immunophenotype, but was surrounded by myoepithelium confirmed by immunohistochemistry (e.g. p63, cytokeratin 14, CD10). Thus, the histogenesis of the in situ-like tubular foci was could be explained by the spread of metastatic ovarian cancer cells into existing mammary ducts. CONCLUSION: Metastatic tumors may spread into mammary duct units and mimic an in situ carcinoma component of primary breast cancer. This in situ-mimicking growth pattern can be a potential pitfall in establishing a correct diagnosis of metastasis to the breast. A panel of breast-related and extramammary organ/tumor-specific immunohistochemical markers may be helpful in distinguishing metastatic tumors from primary tumors.

Locally advanced triple negative breast cancer arising from fibroadenoma with complete response to neoadjuvant chemotherapy: A case report.

INTRODUCTION: Breast cancer arising from benign fibroadenoma (FA) is rare. The histological type of the former was either carcinoma in situ or early-stage invasive breast carcinoma with hormone receptor positive/HER2 (human epidermal growth factor receptor-2)-negative phenotype. Meanwhile, advanced breast cancer of triple negative (TN) phenotype such as our case is extremely uncommon and clinically challenging. PRESENTATION OF CASE: We experienced a case of a 53-year-old woman that had invasive ductal carcinoma of TN phenotype in FA with multiple lymph node metastases. After receiving neoadjuvant chemotherapy (NAC), she underwent breast mastectomy and axillary dissection. The pathological examination on postoperative specimens revealed the dense fibrous stroma in the FA without any residual viable tumor cells and was considered as pathological complete response (pCR). DISCUSSION: This is the first report presenting a case of NAC treatment for invasive ductal carcinoma (IDC) in FA. Furthermore, the patient achieved pCR even if IDC was located within FA. Diagnosing breast cancer in FA may be challenging as the carcinoma component may be hidden by the FA component. If imaging of FA became larger or abnormal changes during follow-up examinations, needle biopsy should be recommended for assessment of the lesion positively. CONCLUSION: This is the first report presenting a case of advanced breast cancer in FA of TN phenotype with multiple lymph node metastases who achieved pCR even if IDC was located within FA.

Giant cell tumor of soft tissue of the breast: Case report with H3F3A mutation analysis and review of the literature.

Giant cell tumors of soft tissue (GCT-ST) arising in the breast are extremely rare. We report a unique case of breast GCT-ST coincident with ductal carcinoma in situ (DCIS), diagnosed with histological, immunohistochemical, and H3F3A (Histone H3.3) mutation analyses. A 59-year-old woman preoperatively diagnosed with DCIS underwent total mastectomy for a cystic mass. Histology revealed a tumor composed of mononuclear cells interspersed with numerous osteoclast-like giant cells, resembling giant cell tumor of bone (GCT-B), with apocrine DCIS in proximity to the tumor. The mononuclear and giant cells were immunoreactive for CD68 and negative for cytokeratins. Granulomatous diseases, carcinomas with giant cells, and giant cell-type sarcomas were excluded by histological and immunophenotypic features. Lack of H3F3A mutation eliminated the possibility of GCT-B metastasizing to the breast. These findings were consistent with GCT-ST of the breast. To our knowledge, this is the ninth reported case of breast GCT-ST, but the first case that accompanied DCIS or involved H3F3A mutation status investigation. For correct diagnosis of this rare tumor, it is important for pathologists to raise the possibility of GCT-ST when encountering giant cell-rich breast lesions and to exclude other differential diagnoses by combining the results of histological, immunohistochemical, and genetic analyses.

The Japanese Breast Cancer Society Clinical Practice Guidelines for Breast Cancer Screening and Diagnosis, 2018 Edition.

This article updates readers as to what is new in the Japanese Breast Cancer Society Clinical Practice Guidelines for Breast Cancer Screening and Diagnosis, 2018 Edition. Breast cancer screening issues are covered, including matters of breast density and possible supplemental modalities, along with appropriate pre-operative/follow-up diagnostic breast imaging tests. Up-to-date clinical practice guidelines for breast cancer screening and diagnosis should help to provide patients and clinicians with not only evidence-based breast imaging options, but also accurate and balanced information about the benefits and harms of intervention, which ultimately enables shared decision making about imaging test plans.

Efficacy of Scalp Cooling in Preventing and Recovering From Chemotherapy-Induced Alopecia in Breast Cancer Patients: The HOPE Study.

Purpose: This study aimed to assess the efficacy of scalp-cooling devices in preventing chemotherapy-induced alopecia in Japanese breast cancer patients and investigate whether a scalp-cooling device improves hair volume recovery over a 12 weeks period after completing chemotherapy. Methods: This multicenter controlled trial included women with breast cancer undergoing chemotherapy in Japan between February 2016 and March 2018. The primary endpoint was the proportion of patients with no alopecia at the end of chemotherapy. The secondary endpoint included hair volume at 12 weeks after completing chemotherapy. Results: A total of 48 patients were enrolled; of them, 34 and 14 were sequentially allocated to the scalp-cooling group using the Paxman Hair Loss Prevention System and the control group, respectively. There was no significant difference in average age between the scalp-cooling and the control groups (50.0 ± 9.6 vs. 49.0 ± 9.0 years). More than 50% of patients in each group had stage II breast cancer (scalp-cooling group: 53.1%; control group: 64.3%), more than 90% received adjuvant chemotherapy (scalp-cooling group: 96.9%; control group: 92.9%), and more than 60% were treated with a docetaxel/cyclophosphamide regimen (scalp-cooling group: 75.0%; control group: 64.3%). There were more patients judged to have no alopecia at the end of chemotherapy in the scalp-cooling group than in the control group (26.7% [8/30] vs. 0% [0/13]; P = 0.011). The proportion of patients with alopecia who experienced an increase in hair volume of ≥50% within 12 weeks duration after chemotherapy was 85.7% (24/28) in the scalp-cooling group and 50.0% (6/12) in the control group. No patient developed serious adverse events related to the scalp-cooling device. Conclusions: The use of a scalp-cooling device prevented alopecia with acceptable safety for Japanese patients. In addition, scalp cooling resulted in faster recovery of hair volume after chemotherapy, even in patients for whom scalp cooling failed to prevent chemotherapy-induced alopecia.

Routine genetic testing of lung cancer specimens derived from surgery, bronchoscopy and fluid aspiration by next generation sequencing.

After the development of EGFR tyrosine kinase inhibitors (TKIs), genetic testing of EGFR became required for effective treatment of lung cancer. Initially, the testing was conducted separately for each mutated region. However, many EGFR mutations have since been identified that determine the efficacy of EGFR-TKIs. Therefore, genetic testing of EGFR by next generation sequencing (NGS) may be a suitable strategy for lung cancer. Here we examined the applicability of the NGS method in regard to sensitivity, time and cost. A total of 939 specimens were obtained from 686 lung cancer patients at our hospital. DNA and RNA were simultaneously extracted from specimens derived from surgery, bronchoscopy, and fluid aspiration. Specimens included cerebrospinal fluid, pleural effusion, abdominal fluid, and pericardial effusion. From RNA, target regions (EGFR, KRAS, ALK fusion and RET fusion) were enriched by RT-PCR and sequenced with MiSeq. From DNA, PCR or PCR-RFLP conventional methods were performed. NGS and conventional methods were carried out routinely per week. Among the total 939 specimens, 38 specimens could not be examined with NGS. Among these, 34 specimens were analyzed by conventional testing with simultaneously extracted DNA. The remaining four specimens could not be tested with either method. Compared with the conventional method, the concordance rate of mutations was 99% (892/901), excluding specimens with NGS failure. The time period required from processing of specimens to results was 4 days, and the cost per sample was sufficiently low. In conclusion, the genetic testing with NGS method was useful for lung cancer treatment. The cost, sensitivity and time were able to tolerate routine examinations.

The silent mutation MLH1 c.543C>T resulting in aberrant splicing can cause Lynch syndrome: a case report.

The proband was a 67-year-old man with transverse and sigmoid colon cancer. Microsatellite instability analysis revealed a high frequency of microsatellite instability, and immunohistochemical staining showed the absence of both MLH1 and PMS2 proteins in the sigmoid colon cancer tissue specimens from the patient. DNA sequencing revealed a nucleotide substitution c.543C>T in MLH1, but this variant did not substitute an amino acid. The MLH1 c.543C>T variant was located 3 bases upstream from the end of exon 6 and created a new splice donor site 4 bases upstream from the end of exon 6. Consequently, the last 4 bases of exon 6 were deleted and frameshift occurred. Thus, the MLH1 c.543C>T silent mutation is considered 'pathogenic'.

Cytotoxic evaluation of natural and synthetic callipeltins: a revision of cytotoxicity of callipeltin B.

The cytotoxic evaluation of natural and synthetic callipeltins is described. Cyclic depsipeptide callipeltin B and linear peptides callipeltins E and M synthesized by us showed no cytotoxic activity. In contrast, natural callipeltin B purified from Callipelta sp. showed CC50 = 130 µM against Hela cells. We found that purified callipeltin B included the contamination of callipeltins C and H at a ratio of approximately 15%. These results suggested that the cytotoxicity of natural callipeltin B was derived from callipeltins C and H.

The significance of combined CK5/6 and p63 immunohistochemistry in predicting the risks of subsequent carcinoma development in intraductal papilloma of the breast.

Prediction of subsequent risks of breast carcinoma (BC) development in intraductal papilloma (IDP) has remained controversial with the exception of atypical papilloma (AP). The potential value of immunohistochemistry (IHC) of cytokeratin 5/6 [CK5/6] and p63 have been proposed but its standardization has also remained controversial. We studied 17 patients initially diagnosed as IDP or AP who subsequently developed BC with 34 age-matched controls. We compared histological features, results of IHC (estrogen receptor [ER], progesterone receptor [PR], human epidermal growth factor receptor 2 [HER2], p63, CK5/6, Ki67), and ultrasound findings. Univariate conditional logistic regression analysis revealed that the status of both CK5/6 and p63/CK5/6 were significantly associated with subsequent BC development (P < 0.05). BC development in CK5/6 positive patients was 17.9% and p63/CK5/6 double positive patients 8.6%, respectively. Ultrasound evaluation was not significantly associated with any of the parameters examined and subsequent carcinoma development. Despite CK5/6 positivity, the subsequent incidence of BC development was nearly 20%. However p63/CK5/6 double positive status could predict a significantly lower subsequent carcinoma incidence, indicating a more accurate prognostic utility. Combining p63/CK5/6 with histological findings could be easily applied and could predict the subsequent BC development of the patients diagnosed as IDP at biopsy.

MRI and ultrasound evaluation of invasive lobular carcinoma of the breast after primary systemic therapy.

AIM: To assess magnetic resonance imaging (MRI) and ultrasound (US) evaluation of invasive lobular carcinoma after primary systemic therapy compared to the primary surgery group. METHODS: A total of 218 breasts with invasive lobular carcinoma (ILC), which were diagnosed by core needle biopsy and underwent surgery between 2004 and 2010 in St. Luke's International Hospital, were reviewed. Of these, 44 breasts received primary systemic therapy (PST) and the residual 174 breasts underwent surgery first. Before surgery, MRI and second-look US were performed. Patients whose extent of lesion from MRI and US was over 90° were recommended to receive total mastectomy. Diagnostic image evaluation was categorized from the final pathology. A negative margin of breast-conserving surgery (BCS) and mastectomy which has over 90° tumor extent in pathology were regarded as "appropriate". A positive margin of BCS was regarded as "underestimated". "Overestimation" was determined when the pathological extension was small enough for BCS although MRI and US diagnosis was over 90°. RESULTS: Of 44 breasts which received PST, 26 breasts received BCS as initial surgery. Of these, 14 (53.8 %) breasts were "underestimated". Of these 14, 5 breasts received additional total mastectomy. Of 174 breasts that received surgery first, 121 (69.5 %) breasts received BCS as the initial surgery. Of these, 46 (38.0 %) breasts were "underestimated" and 6 breast of these 46 received additional total mastectomy. "Underestimated" rate was similar in the two groups, but the additional total mastectomy rate was significantly higher in the PST group (p = 0.025). There were no "overestimations". The "appropriate" rate was similar between the PST (68.2 %) and surgery-first groups (73.6 %). CONCLUSIONS: Although 68.2 % of ILC patients were evaluated "appropriately" even after PST, higher additional total mastectomy rates should be considered when selecting the surgical procedure.

Total synthesis of callipeltin B and M, peptidyl marine natural products.

Total synthesis of callipeltins B and M, peptidyl cytotoxic agents isolated from marine sponges, by the combination of Fmoc solid-phase peptide synthesis and cyclization and global deprotection in the solution phase is described. Eight amino acids, including several unusual amino acids, were assembled on a solid support, and effective TFA-mediated deprotection was employed to reach callipeltin M. Callipeltin B was accomplished via the macrolactonization between the side chain of d-aThr and the C-terminus carboxylic acid of protected callipeltin M.

A new method for differentiating benign and malignant pleomorphic clustered calcifications in mammography.

OBJECTIVE: Retrospective study to determine whether new mammography imaging characteristics can improve identification of an isolated cluster of coarse heterogeneous and fine pleomorphic calcifications as benign or malignant. MATERIALS AND METHODS: Institutional review board approval and informed consent were obtained. The study included 123 women (mean age, 50 years: age range, 34-79 years), in whom mammograms had found pleomorphic clustered calcifications, but without abnormal ultrasound findings and who underwent stereotactically-guided vaccum-assisted breast biopsy. Pleomorphic clustered calcifications were classified on the basis of 5 characteristics density, heterogeneity of density, number, heterogeneity of size, and distribution area size (DAS) of calcifications in the mediolateral oblique view (multiplication of the greatest length by the width of the total zone of clustered calcifications in mm(2)), and correlated with pathological findings. RESULTS: The chi-square test showed significant differences in whether a calcification was malignant or benign only in terms of DAS of calcification (p 0.009). There were significant differences in the association with malignancy of a DAS of 32- to 55 mm(2) (p=0.023, odds ratio=4.22), and the association more likely with a DAS of 56 mm(2) or larger (p=0.01, odds ratio=5.55) than with a DAS smaller than 18 mm(2) as a reference. CONCLUSION: The DAS is a new and reliable variable for differentiating between benign and malignant pleomorphic clustered calcifications. The DAS improves diagnostic accuracy and is useful for determining whether to proceed with biopsies.

Opportunistic breast cancer screening by mammography in Japan for women in their 40s at our preventive medical center: harm or benefit?

BACKGROUND: After recent revised grading by the US Preventive Services Task Force of mammography (MMG) recommendations for women in their 40s, it is urgent to collect data on the benefits and harm of MMG screenings in Japan. In this paper, we study the actual status and effectiveness of opportunistic breast cancer screening by MMG for women in their 40s. METHODS: From January to December 2008, the total number of opportunistic breast cancer screenings by MMG at our institute was 12823. Of them, 398 (3.1 %) who were diagnosed as category 3 or more on MMG required further exams. The data were compared between two groups (women in their 40s, women aged 50 and older). Recall rate, detection rate of breast cancers, and implementation rate of further exams were evaluated. RESULTS: Recall rate was 4.0 % (166/4138) for women in their 40s and 2.4 % (166/6949) for women aged 50 and older. Detection rate of breast cancers was higher in women in their 40s (0.56 %) than women aged 50 and older (0.26 %). Non-cancer rate among women receiving invasive examination was higher in women in their 40s (0.76 %) than women aged 50 and older (0.42 %) (p = 0.02). The number of false positives required to detect one true cancer patient was smaller in women in their 40s (4.5) than women aged 50 and older (5.3). CONCLUSION: The results from our single institute revealed that opportunistic breast cancer screening by MMG for women in their 40s shows higher net benefits than for women aged 50 and older.