Classification of Male Breast Lesions According to the IAC Yokohama System for Reporting Breast Cytopathology.

OBJECTIVE: This study aims to determine the diagnostic utility of the International Academy of Cytology (IAC) Yokohama System for reporting breast cytopathology in lesions of the male breast. STUDY DESIGN: Fine-needle aspiration biopsy (FNAB) reports between 2015 and 2019 were retrospectively recategorized according to the 5-tiered IAC Yokohama Reporting System. Our database yielded a total of 1,532 FNAB reports from breast lesions, obtained from 1,350 male patients. The risk of malignancy (ROM) and diagnostic performance of FNAB were determined using follow-up histopathological diagnosis and/or clinical follow-up, where available, for each category. RESULTS: The category distribution were as follows: inadequate, 40%; benign, 57%; atypical, 0.6%; suspicious for malignancy, 0.7%; and malignant, 1.6%. The ROM in each category was nondiagnostic, 11%; benign, 3%; atypical, 28%; suspicious for malignancy, 56%; and malignant, 100%. The sensitivity, specificity, positive predictive value, and negative predictive value were recorded as 63, 100, 100, and 84.6% respectively, when only malignant cases were considered as positive tests. CONCLUSION: This study validates the IAC Yokohama System for reporting male breast cytopathology. In accordance with the aim of the Yokohama System to establish best practice guidelines for reporting breast cytopathology, this comprehensive scheme facilitates comparisons between local and international institutions. The ROM acts as an internal audit for quality assurance within one's own laboratory and provides guidance for clinical management. It highlights inefficiencies such as high inadequacy rates for category 1 and also features strengths with impressive specificity for categories 4 and 5.

Paget disease of the breast: A national retrospective analysis of the US population.

BACKGROUND: Paget's disease of the breast is rare. The National Cancer Database (NCDB) is one of the largest tumor databases in the United States. METHODS: We queried the NCDB to identify male and female patients with Paget's disease of the breast who were treated from January 1, 2004, through December 31, 2015. No age limitations were applied. Descriptive statistical analysis and survival analysis were performed. RESULTS: We analyzed the demographic, disease, and treatment characteristics of 7,191 patients with Paget's disease of the breast. The median (range) age was 64 (20-90) years. Only 2.1% of patients were men, and 85.4% were white. The most common treatment was complete mastectomy (65.3%), followed by partial mastectomy (30.3%). Tumor destruction was performed in 0.1% of patients, and 4.3% of patients did not undergo any surgery. We examined survival in the subset of 6,864 patients who were treated surgically with complete mastectomy or partial mastectomy. The 5-year survival rate after surgery was 82.5% (95% CI, 81.1%-83.9%). Factors associated with shorter survival were older age, black race/ethnicity, higher tumor grade, regional lymph node metastasis, higher cancer stage, metastatic cancer, and larger tumor size. CONCLUSIONS: Paget's disease of the breast usually affects patients older than 60 years, and the most common treatment is complete mastectomy. The 5-year overall survival rate of patients with Paget's disease of the breast is greater than 80% but is lower among older and black people.

Impact of breast cancer molecular subtypes on the incidence, kinetics and prognosis of central nervous system metastases in a large multicentre real-life cohort.

BACKGROUND: Metastatic breast cancer (MBC) behaviour differs depending on hormone receptors (HR) and human epidermal growth factor receptor (HER2) statuses. METHODS: The kinetics of central nervous system (CNS) metastases (CNS metastasis-free survival, CNSM-FS) and subsequent patient's prognosis (overall survival, OS) according to the molecular subtype were retrospectively assessed in 16703 MBC patients of the ESME nationwide multicentre MBC database (Kaplan-Meier method). RESULTS: CNS metastases occurred in 4118 patients (24.6%) (7.2% at MBC diagnosis and 17.5% later during follow-up). Tumours were HER2-/HR+ (45.3%), HER2+/HR+ (14.5%), HER2+/HR- (14.9%) and triple negative (25.4%). Median age at CNS metastasis diagnosis was 58.1 years (range: 22.8-92.0). The median CNSM-FS was 10.8 months (95% CI: 16.5-17.9) among patients who developed CNS metastases. Molecular subtype was independently associated with CNSM-FS (HR = 3.45, 95% CI: 3.18-3.75, triple-negative and HER2-/HR+ tumours). After a 30-month follow-up, median OS after CNS metastasis diagnosis was 7.9 months (95% CI: 7.2-8.4). OS was independently associated with subtypes: median OS was 18.9 months (HR = 0.57, 95% CI: 0.50-0.64) for HER2+/HR+ , 13.1 months (HR = 0.72, 95% CI: 0.65-0.81) for HER2+/HR-, 4.4 months (HR = 1.55, 95% CI: 1.42-1.69) for triple-negative and 7.1 months for HER2-/HR+ patients (p <0.0001). CONCLUSIONS: Tumour molecular subtypes strongly impact incidence, kinetics and prognosis of CNS metastases in MBC patients. CLINICAL TRIAL REGISTRATION: NCT03275311.

Immunophenotyping of male breast cancer - Experience at a tertiary care centre.

BACKGROUND: Male breast cancers (MBCs) are uncommon and account for 1% of all breast cancers. Medical conditions that increase the estrogen to testosterone ratio are implicated as the risk factors. Morphologically similar, but MBCs have biological differences compared with female breast cancer (FBC). PURPOSE: The present study was aimed to examine the immunophenotype of MBC, subsequent molecular subtypes, their association with clinicopathological features, and prognosis. MATERIALS AND METHODS: We analyzed clinicopathological features of 42 cases of MBC, and classified them according to molecular classification using immunohistochemistry (IHC). This is the second largest study from India. RESULTS AND CONCLUSION: Median age of patients was 61 years (age range: 41-87 years). Invasive duct carcinoma comprised 95.2% of cases. Tumor grade II and III was seen in 50% and 47.6% of cases, respectively, and advanced stage disease (III/IV) was seen in 45.2% cases (n = 39). Estrogen receptor (ER) was positive in 97.6% cases, progesterone receptor (PR) in 83.3%, androgen receptor (AR) in 76.2%, HER2 in 4.8%, Cyclin-D1 in 92.9%, Bcl2 in 66.7%, GCDFP-15 in 23.8%, p53 in 16.7%, and Ki67 index was low (<14%) in 66.7% cases. Molecular subtyping of these cases revealed 64.3% of luminal A, 35.7% of luminal B, and no HER2 rich/driven category or triple negative case. There was no statistical significance between luminal A and B category pertaining to overall stage of tumor (P = 0.905). Lymph node metastasis was more commonly associated with luminal B category (P = 0.089). p53 positivity showed significant association with luminal A cases (P = 0.002) and nodal metastasis (P = 0.042). GCDFP-15 positivity showed significant association with higher tumor grade (P = 0.042) and stage (P = 0.047). Stage was the most significant prognostic marker (P < 0.0001). On follow-up (n = 27), all the six cases that showed recurrence/persistent disease were high stage (III/IV) on presentation.

Diagnostic Value of Fine-Needle Aspiration in Male Breast Lesions.

OBJECTIVE: Differentiation between gynecomastia, a common cause of male breast enlargement, and breast cancer is crucial for appropriate management. Fine-needle aspiration biopsy has been shown to be sensitive and specific in assessing female breast lesions, comparable to core needle biopsy. Few such studies have been conducted in men. We assessed its diagnostic value in a male patient cohort. STUDY DESIGN: Men who underwent fine-needle aspiration (FNA) for palpable breast lesions at Massachusetts General Hospital from January 2007 to December 2016 were evaluated. Clinical data, radiographic findings, and cytologic diagnoses of 74 breast FNA from 71 men were reviewed. Breast aspirates were classified as nondiagnostic, benign, atypical, suspicious for malignancy, or malignant. Histology was obtained in 37 cases, and clinical and radiological data were used as follow-up in 37 patients. RESULTS: Most FNA biopsies (73%) were performed by cytopathologists, and 93.2% of the breast FNA in men were adequate; 58% showed benign processes, mostly gynecomastia (n = 22), and 28.4% (n = 21) were malignant, most often ductal carcinoma. No false-positive cytologies were obtained, and there was 1 false-negative cytology. In our study, FNA of palpable male breast lesions was 95.8% sensitive and 100% specific. CONCLUSIONS: FNA allows sensitive, specific, and safe evaluation and diagnosis of palpable male breast lesions.

Masood's and Modified Masood's Scoring Index: An Evaluation of Fine Needle Aspiration Cytology of Breast Lesions with Histopathological Correlation.

OBJECTIVE: As fine needle aspiration cytology (FNAC) is the primary tool for evaluation of breast lesions, it is essential to segregate lesions with low and high risk of malignancy. To address this, Masood proposed a cytological scoring system for categorization, Masood's Scoring Index (MSI), which was modified later (Modified Masood's Scoring Index [MMSI]). This study analyses the effectiveness of MMSI over MSI and assesses the concordance between cytological scoring and histopathology. STUDY DESIGN: All breast FNACs over a period of 2 years were categorized based on MSI and MMSI by 2 reviewers independently. The agreement rate along with specificity, sensitivity, positive predictive value, negative predictive value and diagnostic accuracy were calculated. Correlation and concordance analyses between cytological and histopathological categories were conducted. RESULTS AND DISCUSSION: Out of 415 cases of breast FNACs, histopathology was available for 310 for which MSI and MMSI were evaluated. The sensitivity, specificity, positive predictive value, negative predictive value and diagnostic accuracy were 95, 100, 100, 97.6 and 98.3%, respectively. The difference between the concordance rate of MSI and of MMSI for various cytological categories was found to be statistically significant. CONCLUSION: MMSI has a better concordance with histopathological diagnosis than MSI. MMSI can serve as a uniform standardized scoring system for breast cytology for better categorization of proliferative breast diseases.

Aberrant miRNAs expressed in HER-2 negative breast cancers patient.

BACKGROUND: Breast cancer is a highly heterogeneous pathology, exhibiting a number of subtypes commonly associated with a poor outcome. Due to their high stability, microRNAs are often regarded as non-invasive cancer biomarkers, having an expression pattern specific for their 'cell of origin'. METHOD: Triple negative breast cancer (TNBC: ER-, PR-, Her-2-) and double positive breast cancer (DPBC: ER+, PR+, Her-2) miRNA expression patterns were obtained by analysis of the TCGA (The Cancer Genome Atlas) data, followed by PCR-array analysis on plasma samples from 20 TNBC patients, 14 DPBC patients and 11 controls. RESULTS: Three downregulated and nine upregulated miRNAs were obtained from the TNBC analysis. Five overexpressed miRNAs were identified in the DPBC group. Four of the dysregulated miRNAs (miR-10a, miR-125b, miR-210 and miR-489) were common for both groups. The cluster miR-17-92 (miR-17, miR-20a, miR-20b, and miR-93), along with miR-130, miR-22 and miR-29a/c, were found to differentiate between TNBC and DPBC. A panel of five transcripts (miR-10a, miR-125, miR-193b, miR-200b and miR-489) was validated in a new set of plasma samples. The overlapping of TCGA and plasma profiling data revealed miR-200b, miR-200c, miR-210 and miR-29c as common signature. MiR-200b was validated on additional normal and tumor tissue samples. The expression level of this transcript from the TCGA data was correlated with lung and bone metastatic genes. CONCLUSION: The miR-200b presents a great potential for the future advancements in the diagnostic/prognostic and therapeutic approach of TNBC, along with other coding or non-coding transcripts. However, this needs to be further integrated in a regulatory network that acts in conjunction with other markers that affect the patients' prognosis or response to therapy.

Morphology and genomic hallmarks of breast tumours developed by ATM deleterious variant carriers.

BACKGROUND: The ataxia telangiectasia mutated (ATM) gene is a moderate-risk breast cancer susceptibility gene; germline loss-of-function variants are found in up to 3% of hereditary breast and ovarian cancer (HBOC) families who undergo genetic testing. So far, no clear histopathological and molecular features of breast tumours occurring in ATM deleterious variant carriers have been described, but identification of an ATM-associated tumour signature may help in patient management. METHODS: To characterise hallmarks of ATM-associated tumours, we performed systematic pathology review of tumours from 21 participants from ataxia-telangiectasia families and 18 participants from HBOC families, as well as copy number profiling on a subset of 23 tumours. Morphology of ATM-associated tumours was compared with that of 599 patients with no BRCA1 and BRCA2 mutations from a hospital-based series, as well as with data from The Cancer Genome Atlas. Absolute copy number and loss of heterozygosity (LOH) profiles were obtained from the OncoScan SNP array. In addition, we performed whole-genome sequencing on four tumours from ATM loss-of-function variant carriers with available frozen material. RESULTS: We found that ATM-associated tumours belong mostly to the luminal B subtype, are tetraploid and show LOH at the ATM locus at 11q22-23. Unlike tumours in which BRCA1 or BRCA2 is inactivated, tumours arising in ATM deleterious variant carriers are not associated with increased large-scale genomic instability as measured by the large-scale state transitions signature. Losses at 13q14.11-q14.3, 17p13.2-p12, 21p11.2-p11.1 and 22q11.23 were observed. Somatic alterations at these loci may therefore represent biomarkers for ATM testing and harbour driver mutations in potentially 'druggable' genes that would allow patients to be directed towards tailored therapeutic strategies. CONCLUSIONS: Although ATM is involved in the DNA damage response, ATM-associated tumours are distinct from BRCA1-associated tumours in terms of morphological characteristics and genomic alterations, and they are also distinguishable from sporadic breast tumours, thus opening up the possibility to identify ATM variant carriers outside the ataxia-telangiectasia disorder and direct them towards effective cancer risk management and therapeutic strategies.

Male breast cancer: Looking for better prognostic subgroups.

PURPOSE: Male Breast Cancer (MBC) remains a poor understood disease. Prognostic factors are not well established and specific prognostic subgroups are warranted. PATIENTS/METHODS: Retrospectively revision of 111 cases treated in the same Cancer Center. Blinded-central pathological revision with immunohistochemical (IHQ) analysis for estrogen (ER), progesterone (PR) and androgen (AR) receptors, HER2, ki67 and p53 was done. Cox regression model was used for uni/multivariate survival analysis. Two classifications of Female Breast Cancer (FBC) subgroups (based in ER, PR, HER2, 2000 classification, and in ER, PR, HER2, ki67, 2013 classification) were used to achieve their prognostic value in MBC patients. Hierarchical clustering was performed to define subgroups based on the six-IHQ panel. RESULTS: According to FBC classifications, the majority of tumors were luminal: A (89.2%; 60.0%) and B (7.2%; 35.8%). Triple negative phenotype was infrequent (2.7%; 3.2%) and HER2 enriched, non-luminal, was rare (≤1% in both). In multivariate analysis the poor prognostic factors were: size >2 cm (HR:1.8; 95%CI:1.0-3.4 years, p = 0.049), absence of ER (HR:4.9; 95%CI:1.7-14.3 years, p = 0.004) and presence of distant metastasis (HR:5.3; 95%CI:2.2-3.1 years, p < 0.001). FBC subtypes were independent prognostic factors (p = 0.009, p = 0.046), but when analyzed only luminal groups, prognosis did not differ regardless the classification used (p > 0.20). Clustering defined different subgroups, that have prognostic value in multivariate analysis (p = 0.005), with better survival in ER/PR+, AR-, HER2-and ki67/p53 low group (median: 11.5 years; 95%CI: 6.2-16.8 years) and worst in PR-group (median:4.5 years; 95%CI: 1.6-7.8 years). CONCLUSION: FBC subtypes do not give the same prognostic information in MBC even in luminal groups. Two subgroups with distinct prognosis were identified in a common six-IHQ panel. Future studies must achieve their real prognostic value in these patients.

Copy number profiling by array comparative genomic hybridization identifies frequently occurring BRCA2-like male breast cancer.

Genomic aberrations can be used to subtype breast cancer. In this study, we investigated DNA copy number (CN) profiles of 69 cases of male breast cancer (MBC) by array comparative genomic hybridization (aCGH) to detect recurrent gains and losses in comparison with female breast cancers (FBC). Further, we classified these profiles as BRCA1-like, BRCA2-like or non-BRCA-like profiles using previous classifiers derived from FBC, and correlated these profiles with pathological characteristics. We observed large CN gains on chromosome arms 1q, 5p, 8q, 10p, 16p, 17q, and chromosomes 20 and X. Large losses were seen on chromosomes/chromosome arms 1p, 6p, 8p, 9, 11q, 13, 14q, 16q, 17p, and 22. The pattern of gains and losses in estrogen receptor positive (ER+) MBC was largely similar to ER+ FBC, except for gains on chromosome X in MBC, which were uncommon in FBC. Out of 69 MBC patients, 15 patients (22%) had a BRCA2-like profile, of which 2 (3%) were also BRCA1-like. One patient (1%) was only BRCA1-like; the remaining 53 (77%) patients were classified as non-BRCA-like. BRCA2-like cases were more often p53 accumulated than non-BRCA-like cases (P = 0.014). In conclusion, the pattern of gains and losses in ER+ MBC was largely similar to that of its ER+ FBC counterpart, except for gains on chromosome X in MBC, which are uncommon in FBC. A significant proportion of MBC has a BRCA2-like aCGH profile, pointing to a potentially hereditary nature, and indicating that they could benefit from a drug regimen targeting BRCA defects as in FBC.

Genome methylation patterns in male breast cancer - Identification of an epitype with hypermethylation of polycomb target genes.

Male breast cancer (MBC) is a rare disease that shares both similarities and differences with female breast cancer (FBC). The aim of this study was to assess genome-wide DNA methylation profiles in MBC and compare them with the previously identified transcriptional subgroups of MBC, luminal M1 and M2, as well as the intrinsic subtypes of FBC. Illumina's 450K Infinium arrays were applied to 47 MBC and 188 FBC tumors. Unsupervised clustering of the most variable CpGs among MBC tumors revealed two stable epitypes, designated ME1 and ME2. The methylation patterns differed significantly between the groups and were closely associated with the transcriptional subgroups luminal M1 and M2. Tumors in the ME1 group were more proliferative and aggressive than ME2 tumors, and showed a tendency toward inferior survival. ME1 tumors also displayed hypermethylation of PRC2 target genes and high expression of EZH2, one of the core components of PRC2. Upon combined analysis of MBC and FBC tumors, ME1 MBCs clustered among luminal B FBC tumors and ME2 MBCs clustered within the predominantly luminal A FBC cluster. The majority of the MBC tumors remained grouped together within the clusters rather than being interspersed among the FBC tumors. Differences in the genomic location of methylated CpGs, as well as in the regulation of central canonical pathways may explain the separation between MBC and FBC tumors in the respective clusters. These findings further suggest that MBC is not readily defined using conventional criteria applied to FBC.

Clinicopathological and Immunohistochemical Characteristics in Male Breast Cancer: A Retrospective Case Series.

BACKGROUND: Due to its rarity, male breast cancer (mBC) remains an inadequately characterized disease, and current evidence for treatment derives from female breast cancer (FBC). METHODS: We retrospectively analyzed the clinicopathological characteristics, treatment patterns, and outcomes of mBCs treated from 2000 to 2013. RESULTS: From a total of 97 patients with mBC, 6 (6.2%) with ductal in situ carcinoma were excluded, and 91 patients with invasive carcinoma were analyzed. Median age was 65 years (range: 25-87 years). Estrogen receptors were positive in 88 patients (96.7%), and progesterone receptors were positive in 84 patients (92.3%). HER-2 was overexpressed in 13 of 85 patients (16%). Median follow-up was 51.5 months (range: 0.5-219.3 months). Five-year progression-free survival (PFS) was 50%, whereas overall survival (OS) was 68.1%. Patients with grades 1 and 2 presented 5-year PFS of 71% versus 22.5% for patients with grade 3 disease; 5-year OS was 85.7% for patients with grades 1 and 2 versus 53.3% of patients with grade 3. Ki-67 score >20% and adjuvant chemotherapy were also statistically significant for OS on univariate analyses. Twenty-six of 87 patients (29.8%) experienced recurrent disease and 16 of 91 patients (17.6%) developed a second neoplasia. CONCLUSION: Male breast cancer shows different biological patterns compared with FBC, with higher positive hormone-receptor status and lower HER-2 overexpression. Grade 3 and Ki-67 >20% were associated with shorter OS. IMPLICATIONS FOR PRACTICE: There is little evidence that prognostic features established in female breast cancer, such as grading and Ki-67 labeling index, could be applied to male breast cancer as well. This study found that grade 3 was associated with shorter overall survival and a trend for Ki-67 >20%; this could help in choosing the best treatment option in the adjuvant setting. Many questions remain regarding the impact of HER-2 positivity on survival and treatment with adjuvant anti-HER-2 therapy. Regarding metastatic male breast cancer, the results suggest that common regimens of chemo-, endocrine and immunotherapy used in female breast cancer are safe and effective for men. Male breast cancer patients show a higher incidence of second primary tumors, especially prostate and colon cancers and should therefore be carefully monitored.

Combined microRNA and ER expression: a new classifier for familial and sporadic breast cancer patients.

BACKGROUND: The role of miRNAs in familial breast cancer (fBC) is poorly investigated as also in the BRCA-like tumors. To identify a specific miRNA expression pattern which could allow a better fBC classification not only based on clinico-pathological and immunophenotypical parameters we analyzed miRNA profile in familial and sporadic samples. Moreover since BRCA1 tumors and sporadic triple negative (TN) breast tumors share similarities regarding clinical outcomes and some histological characteristics, we focused on TN and not TN cases. METHODS: The sample set included fresh frozen tissue samples, including 39 female fBCs (19 BRCA-related and 20 BRCAX) and 12 male fBC (BRCAX). Moreover, we considered TN and non TN (NTN), 21 BRCA-related and 27 sporadic BCs. MiRNA profiling was performed through GeneChip miRNA v.1.0 Array (Affymetrix). ANOVA, hierarchical and consensus clustering analyses allowed identification of pattern of expression of miRNAs and pathway enrichment analysis, considering validated target genes, was carried out to achieve a deeper biological understanding. RESULTS: ANOVA test led to the identification of 53 deregulated miRNAs; hierarchical and consensus clustering of female fBCs (fFBCs) and male fBCs (fMBCs) highlighted the presence of 3 sample clusters named FBC1, FBC2 and FBC3. We found a correlation between ER-status and the three sample clusters. The three clusters are distinct by a different expression of two clusters of miRNAs (CLU1 and CLU2), which resulted to be different in targeted pathways. In particular, CLU1 targets cellular pathways and CLU2 is involved in epigenetic activities. Considering TN and NTN BRCA-related and sporadic tumors, a hierarchical clustering identified two clusters of miRNAs, which were not so different from CLU1 and CLU2, both in miRNA content and targeted pathways. CONCLUSIONS: Our results highlighted the importance of miRNA regulation to better clarify similarities and differences between familial and sporadic BC groups.

Molecular profiling of male breast cancer - lost in translation?

Breast cancer is the most common cancer form in women and it has been extensively studied on the molecular level. Male breast cancer (MBC), on the other hand, is rare and has not been thoroughly investigated in terms of transcriptional profiles or genomic aberrations. Most of our understanding of MBC has therefore been extrapolated from knowledge of female breast cancer. Although differences in addition to similarities with female breast cancer have been reported, the same prognostic and predictive markers are used to determine optimal management strategies for both men and women diagnosed with breast cancer. This review is focused on prognosis for MBC patients, prognostic and predictive factors and molecular subgrouping; comparisons are made with female breast cancer. Information was collected from relevant literature on both male and female breast cancer from the MEDLINE database between 1992 and 2014. MBC is a heterogeneous disease, and on the molecular level many differences compared to female breast cancer have recently been revealed. Two distinct subgroups of MBC, luminal M1 and luminal M2, have been identified which differ from the well-established intrinsic subtypes of breast cancer in women. These novel subgroups of breast cancer therefore appear unique to MBC. Furthermore, several studies report inferior survival for men diagnosed with breast cancer compared to women. New promising prognostic biomarkers for MBC (e.g. NAT1) deserving further attention are reviewed. Further prospective studies aimed at validating the novel subgroups and recently proposed biomarkers for MBC are warranted to provide the basis for optimal patient management in this era of personalized medicine. This article is part of a Directed Issue entitled: Rare Cancers.

Clinico-pathological and molecular subtypes of male breast carcinoma according to immunohistochemistry.

INTRODUCTION: Male breast carcinoma is a rare condition, but with a trend of increase frequency. In our study, we investigate the clinico-pathological features and overall survival at 35 male cases of primary invasive breast carcinoma correlated with molecular subtypes defined by immunohistochemical profile. METHODS: Based on immunohistochemical expression profiles of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor 2 (HER2) and Ki67, EGFR and CK5/6, the male breast cancers were classified into the following molecular subtypes: Luminal A, Luminal B, HER2+, triple negative and unclassified. RESULTS: In our study, we identified 65.7% as Luminal A subtype and 28.6% as Luminal B subtype. The difference was represented by two (5.7%) cases of triple negative subtype, but due to low number of patients, no correlations or prognostic significance could be assessed in these cases. No HER2 or unclassified subtypes were identified. CONCLUSIONS: Luminal A tumors are the most frequent subtype in MBC, with a better outcome than Luminal B subtype. We recorded high levels of ER and PR expression, which predict a better response to adjuvant hormonal therapy. At the time of diagnosis, most of the patients were aged and with an advance clinical stage, this requiring implementation of screening programs and increase education of population in order to an early detection.

Rare non-epithelial primary breast neoplasms: a ten-year experience at a Greek University Hospital.

PURPOSE: Non-epithelial breast neoplasms cover a large spectrum of histopathological entities. The demographics and clinical features are similar to epithelial breast lesions but the diagnosis, prognosis and management options are often very different. METHODS: During 2001-2010, 1362 patients were examined at the Pathology Department of the Aretaieion General Hospital for various breast lesions. All specimens were processed routinely and slides stained with hematoxylin-eosin were re-examined. The patient clinical records were examined for demographics, clinical presentation and therapeutic approach. RESULTS: In 23/1362 cases (1.68%) pathological examination showed non-epithelial lesions: in 12/1362 cases (0.8%) haemangiomas (11 women, one man), in 4 /1362 cases (0.3%) myofibroblastomas (MFB), in 2/1362 cases (0.1%) primary breast non-Hodgkin's lymphoma (NHL), in 3 /1362 cases (0.2%) granular cell tumor (GCT), and in 2/1362 cases (0.1%) angiosarcomas (one developed after radiotherapy for breast cancer). CONCLUSIONS: Non-epithelial primary breast tumors are rare (1.68%) and present significant difficulty in accurate preoperative diagnosis and in certain cases in pathological diagnosis as well, which is necessary for the selection of the appropriate treatment. Avoidance of inappropriate therapies requires a multidisciplinary management approach.

Male breast cancer according to tumor subtype and race: a population-based study.

BACKGROUND: Breast cancer occurs rarely in men. To the authors' knowledge, no population-based estimates of the incidence of human epidermal growth factor receptor 2 (HER2)-positive breast cancer or of the distribution of breast cancer subtypes among male breast cancer patients have been published to date. Therefore, the objective of the current study was to explore breast tumor subtype distribution by race/ethnicity among men in the large, ethnically diverse population of California. METHODS: This study included men who were diagnosed with invasive breast cancer between 2005 and 2009 with known estrogen receptor (ER) and progesterone receptor (PR) (together, hormone receptor [HR]) status and HER2 status reported to the California Cancer Registry. Among the men with HR-positive tumors, survival probabilities between groups were compared using log-rank tests. RESULTS: Six hundred six patients were included. The median age at diagnosis was 68 years. Four hundred ninety-four men (81.5%) had HR-positive tumors (defined as ER-positive and/or PR-positive and HER2-negative). Ninety men (14.9%) had HER2-positive tumors, and 22 (3.6%) had triple receptor-negative (TN) tumors. Among the patients with HR-positive tumors, non-Hispanic black men and Hispanic men were more likely to have PR-negative tumors than non-Hispanic white men. No statistically significant differences in survival were observed according to tumor subtype (P = .08). Differences in survival according to race/ethnicity were observed among all patients (P = .087) and among those with HR-positive tumors (P = .0170), and non-Hispanic black men had poorer outcomes. CONCLUSIONS: In this large, representative cohort of men with breast cancer, the distribution of tumor subtypes was different from that reported for women and varied by patient race/ethnicity. Non-Hispanic black men were more likely to have TN tumors and ER-positive/PR-negative tumors than white men.

Male breast cancer: immunohistochemical subtypes and clinical outcome characterization.

AIM: The aim of this study was to assess the molecular subtype profiles of male breast cancer (MBC) and subsequent clinical outcome using a validated 6-marker immunohistochemical panel. METHODS: A total of 43 cases of MBC were examined retrospectively using a semiquantitative immunohistochemical analysis of estrogen receptor (ER), progesterone receptor (PR), Ki-67, human epidermal growth factor receptor 2 (Her2), epidermal growth factor receptor and cytokeratin 5/6. Patients were classified into the following categories: luminal A, luminal B, Her2-positive or basal-like subtypes. RESULTS: The median age of patients was 63 years (r: 32-89). The predominant histology was invasive ductal carcinoma (91%). Only 1 patient had advanced breast cancer at diagnosis. Ninety-three percent were ER-positive and 84% were PR-positive. Two patients had tumors that were ER- and PR-negative. The distribution of tumor molecular subtypes was 19 (44%) luminal A, 22 (51%) luminal B and 2 (5%) basal-like. The Her2-positive tumor subtype was not identified. The clinicopathological characteristics did not differ significantly between tumor subtypes A and B. There were no significant differences in 6-year disease-free survival (74 vs. 82%, p = 0.77) or overall survival (74 vs. 82%, p = 0.69) between luminal A and luminal B subtypes, respectively. CONCLUSION: The most common subtypes in our cohort of MBC were luminal B followed by luminal A, and no differences were found between both tumor subtypes in terms of clinicopathologic characteristics and patient outcome.

Papillary lesions of the breast: impact of breast pathology subspecialization on core biopsy and excision diagnoses.

BACKGROUND: Classifying papillary lesions of the breast on core biopsy (CB) is challenging. Although traditionally all such lesions were surgically excised, at present, conservative management of benign lesions is being advocated; therefore, accurately classifying papillary lesions on CB is all the more imperative. The extent to which subspecialty training in breast pathology might mitigate such difficulties in diagnosis has not yet been reported. We investigated change in diagnoses from CB to surgical excision according to subspecialist training in breast pathology and interobserver agreement between specialized breast pathologists (BPs) and nonbreast pathologists (NBPs) in classifying these lesions. DESIGN: CBs of 281 papillary lesions from 266 patients diagnosed between 2000 and 2010 were classified by both a BP and NBP into benign, atypical, ductal carcinoma in situ/encapsulated papillary carcinoma, or invasive carcinoma categories. Rates of change in diagnostic category in the surgical excision specimen were calculated on the basis of: (i) the original diagnosis, (ii) diagnosis made by the BP, and (iii) diagnosis made by the NBP. Comparisons were made using the χ test. Kappa values were calculated for interobserver agreement. RESULTS: Of 162 lesions with subsequent excision, 90 were originally diagnosed as benign, 38 as atypical, 25 as ductal carcinoma in situ/encapsulated papillary carcinoma, and 9 as invasive on CB. The upgrade rate for benign papillomas to an atypical or malignant lesion on surgical excision was 22.2% according to the original diagnosis. This rate fell to 16.3% when the BP diagnoses were considered, compared with 26.3% for the NBP diagnoses. There was no significant difference between BPs and NBPs in the rate of upgrade from a benign to an atypical/malignant diagnosis, although downgrades from atypical/malignant to benign papillomas were more commonly seen among NBPs (P=0.002). Overall, the BP diagnosis on CB was less likely to differ from the excision diagnosis (P=0.0001). Benign papillomas upgraded on excision were more likely to occur with larger radiologic mass size (P=0.033) compared with those that were not upgraded. Of 8 benign papillomas upgraded to a malignant lesion on excision, 7 were discordant on radiology. Interobserver agreement between BP and NBP diagnoses was in the "fair agreement" range (κ=0.38), with perfect agreement in 66.4% of cases. CONCLUSIONS: Correlation between CB and excision diagnoses for breast papillary lesions is significantly greater for BPs than for NBPs. This is largely because of a tendency to overcall atypia or malignancy on CB by NBPs. However, upgrades from benign to atypical or malignant did not significantly differ according to subspecialization. With accurate pathologic assessment and radiologic-pathologic correlation, the upgrade rate of benign papillomas to malignancy can be minimized significantly.

Gene expression profiling of primary male breast cancers reveals two unique subgroups and identifies N-acetyltransferase-1 (NAT1) as a novel prognostic biomarker.

INTRODUCTION: Male breast cancer (MBC) is a rare and inadequately characterized disease. The aim of the present study was to characterize MBC tumors transcriptionally, to classify them into comprehensive subgroups, and to compare them with female breast cancer (FBC). METHODS: A total of 66 clinicopathologically well-annotated fresh frozen MBC tumors were analyzed using Illumina Human HT-12 bead arrays, and a tissue microarray with 220 MBC tumors was constructed for validation using immunohistochemistry. Two external gene expression datasets were used for comparison purposes: 37 MBCs and 359 FBCs. RESULTS: Using an unsupervised approach, we classified the MBC tumors into two subgroups, luminal M1 and luminal M2, respectively, with differences in tumor biological features and outcome, and which differed from the intrinsic subgroups described in FBC. The two subgroups were recapitulated in the external MBC dataset. Luminal M2 tumors were characterized by high expression of immune response genes and genes associated with estrogen receptor (ER) signaling. Luminal M1 tumors, on the other hand, despite being ER positive by immunohistochemistry showed a lower correlation to genes associated with ER signaling and displayed a more aggressive phenotype and worse prognosis. Validation of two of the most differentially expressed genes, class 1 human leukocyte antigen (HLA) and the metabolizing gene N-acetyltransferase-1 (NAT1), respectively, revealed significantly better survival associated with high expression of both markers (HLA, hazard ratio (HR) 3.6, P = 0.002; NAT1, HR 2.5, P = 0.033). Importantly, NAT1 remained significant in a multivariate analysis (HR 2.8, P = 0.040) and may thus be a novel prognostic marker in MBC. CONCLUSIONS: We have detected two unique and stable subgroups of MBC with differences in tumor biological features and outcome. They differ from the widely acknowledged intrinsic subgroups of FBC. As such, they may constitute two novel subgroups of breast cancer, occurring exclusively in men, and which may consequently require novel treatment approaches. Finally, we identified NAT1 as a possible prognostic biomarker for MBC, as suggested by NAT1 positivity corresponding to better outcome.