Effect of testosterone therapy on breast tissue composition and mammographic breast density in trans masculine individuals.

BACKGROUND: The effect of gender-affirming testosterone therapy (TT) on breast cancer risk is unclear. This study investigated the association between TT and breast tissue composition and breast tissue density in trans masculine individuals (TMIs). METHODS: Of the 444 TMIs who underwent chest-contouring surgeries between 2013 and 2019, breast tissue composition was assessed in 425 TMIs by the pathologists (categories of lobular atrophy and stromal composition) and using our automated deep-learning algorithm (% epithelium, % fibrous stroma, and % fat). Forty-two out of 444 TMIs had mammography prior to surgery and their breast tissue density was read by a radiologist. Mammography digital files, available for 25/42 TMIs, were analyzed using the LIBRA software to obtain percent density, absolute dense area, and absolute non-dense area. Linear regression was used to describe the associations between duration of TT use and breast tissue composition or breast tissue density measures, while adjusting for potential confounders. Analyses stratified by body mass index were also conducted. RESULTS: Longer duration of TT use was associated with increasing degrees of lobular atrophy (p < 0.001) but not fibrous content (p = 0.82). Every 6 months of TT was associated with decreasing amounts of epithelium (exp(ß) = 0.97, 95% CI 0.95,0.98, adj p = 0.005) and fibrous stroma (exp(ß) = 0.99, 95% CI 0.98,1.00, adj p = 0.05), but not fat (exp(ß) = 1.01, 95%CI 0.98,1.05, adj p = 0.39). The effect of TT on breast epithelium was attenuated in overweight/obese TMIs (exp(ß) = 0.98, 95% CI 0.95,1.01, adj p = 0.14). When comparing TT users versus non-users, TT users had 28% less epithelium (exp(ß) = 0.72, 95% CI 0.58,0.90, adj p = 0.003). There was no association between TT and radiologist's breast density assessment (p = 0.58) or LIBRA measurements (p > 0.05). CONCLUSIONS: TT decreases breast epithelium, but this effect is attenuated in overweight/obese TMIs. TT has the potential to affect the breast cancer risk of TMIs. Further studies are warranted to elucidate the effect of TT on breast density and breast cancer risk.

Toker Cell Hyperplasia in the Nipple-Areolar Complex of Transmasculine Individuals.

We previously reported breast histopathologic features associated with testosterone therapy in transmasculine chest-contouring surgical specimens. During that study, we observed a high frequency of intraepidermal glands in the nipple-areolar complex (NAC) formed by Toker cells. This study reports Toker cell hyperplasia (TCH)-the presence of clusters of Toker cells consisting of at least 3 contiguous cells and/or glands with lumen formation-in the transmasculine population. Increased numbers of singly dispersed Toker cells were not considered TCH. Among the 444 transmasculine individuals, 82 (18.5%) had a portion of their NAC excised and available for evaluation. We also reviewed the NACs from 55 cisgender women who were aged <50 years old and had full mastectomies. The proportion of transmasculine cases with TCH (20/82; 24.4%) was 1.7-fold higher than cisgender women (8/55; 14.5%) but did not achieve significance (P = .20). However, in cases with TCH, the rate of gland formation is 2.4-fold higher in transmasculine cases, achieving borderline significance (18/82 vs 5/55; P = .06). Among transmasculine individuals, TCH was significantly more likely to be present in those with higher body mass index (P = .03). A subset of 5 transmasculine and 5 cisgender cases were stained for estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), androgen receptor (AR), cytokeratin 7, and Ki67. All 10 cases were cytokeratin 7+ and Ki67-; 9 out of 10 cases were AR+. Toker cells in transmasculine cases demonstrated variable expression of ER, PR, and HER2. For cisgender cases, Toker cells were consistently ER+, PR-, and HER2-. In conclusion, there is a higher rate of TCH in the transmasculine than cisgender population, particularly among transmasculine individuals with high body mass index and taking testosterone. To our knowledge, this is the first study to demonstrate that Toker cells are AR+. Toker cell features display variable ER, PR, and HER2 immunoreactivity. The clinical significance of TCH in the transmasculine population remains to be elucidated.

Testosterone therapy and breast histopathological features in transgender individuals.

Testosterone therapy (TT) is administered to enhance masculinization in transgender individuals. The long-term effect of exogenous testosterone on breast tissues remains unclear. Our study evaluated the modulation of breast morphology by TT in transgender individuals with special attention to duration of TT. We reviewed 447 breast surgical specimens from gender affirming chest-contouring surgery, and compared histopathological findings including degree of lobular atrophy, and atypical and non-atypical proliferations between subjects who did (n = 367) and did not (n = 79) receive TT. TT for one patient was unknown. TT for >12 months was associated with seven histopathological features. Longer duration of TT was significantly associated with higher degrees of lobular atrophy (p < 0.001). This relationship remained significant after accounting for age at surgery, ethnicity, body mass index, and presurgical oophorectomy (adjusted p < 0.001). Four types of lesions were more likely to be absent in breast tissues exposed to longer durations of TT: cysts (median = 16.2 months; p < 0.01; adjusted p = 0.01), fibroadenoma (median = 14.8 months; p = 0.02; adjusted p = 0.07), pseudoangiomatous stromal hyperplasia (median = 17.0 months; p < 0.001; adjusted p < 0.001), and papillomas (median = 14.7 months; p = 0.04; adjusted p = 0.20). Columnar cell change and mild inflammation were also less likely to occur in subjects receiving TT (p < 0.05), but were not linked to the duration of TT. Atypia and ductal carcinoma in situ were detected in 11 subjects (2.5%) all of whom received TT ranging from 10.1 to 64.1 months. The incidental findings of high-risk lesions and carcinoma as well as the risk of cancer in residual breast tissue after chest-contouring surgery warrant the consideration of culturally sensitive routine breast cancer screening protocols for transgender men and masculine-centered gender nonconforming individuals. Long-term follow-up studies and molecular investigations are needed to understand the breast cancer risk of transgender individuals who receive TT.

Contrast-Enhanced Mammography: A Systematic Guide to Interpretation and Reporting.

OBJECTIVE: The purpose of this article is to discuss the essential steps involved in performing, interpreting, managing, and reporting findings on contrast-enhanced mammography for successful implementation into clinical practice. CONCLUSION: To successfully implement contrast-enhanced mammography into clinical practice, an understanding about the acquisition of images, image interpretation, and reporting of the spectrum of negative, benign, and malignant findings is essential.

Increased Cancer Detection Rate and Variations in the Recall Rate Resulting from Implementation of 3D Digital Breast Tomosynthesis into a Population-based Screening Program.

PURPOSE: To compare the recall and cancer detection rates (CDRs) at screening with digital breast tomosynthesis (DBT) with those at screening with two-dimensional (2D) mammography and to evaluate variations in the recall rate (RR) according to patient age, risk factors, and breast density and among individual radiologists at a single U.S. academic medical center. MATERIALS AND METHODS: This institutional review board-approved, HIPAA-compliant prospective study with a retrospective cohort included 85 852 asymptomatic women who presented for breast cancer screening over a 3-year period beginning in 2011. A DBT unit was introduced into the existing 2D mammography screening program, and patients were assigned to the first available machine. Ten breast-subspecialized radiologists interpreted approximately 90% of the examinations. RRs were calculated overall and according to patient age, breast density, and individual radiologist. CDRs were calculated. Single and multiple mixed-effect logistic regression analyses, χ(2) tests, and Bonferroni correction were utilized, as appropriate. RESULTS: The study included 5703 (6.6%) DBT examinations and 80 149 (93.4%) 2D mammography examinations. The DBT subgroup contained a higher proportion of patients with risk factors for breast cancer and baseline examinations. DBT was used to detect 54.3% more carcinomas (+1.9 per 1000, P < .0018) than 2D mammography. The RR was 7.51% for 2D mammography and 6.10% for DBT (absolute change, 1.41%; relative change, -18.8%; P < .0001). The DBT subgroup demonstrated a significantly lower RR for patients with extremely or heterogeneously dense breasts and for patients in their 5th and 7th decades. CONCLUSION: Implementing DBT into a U.S. breast cancer screening program significantly decreased the screening RR overall and for certain patient subgroups, while significantly increasing the CDR. These findings may encourage more widespread adoption and reimbursement of DBT and facilitate improved patient selection.

Breast imaging in the transgender patient.

OBJECTIVE: Limited information exists regarding breast health in the transgender population. In this article, we review transgender terminology, barriers faced by transgender patients, current breast care screening recommendations, and normal and abnormal imaging findings in this population. CONCLUSION: Health disparities in the transgender population continue. Educating physicians on the breast health care needs of transgender patients is important for improving their care.

Effect of testosterone therapy on breast tissue composition and mammographic breast density in trans masculine individuals.

Objective: Determine the association between TT and breast tissue composition and breast tissue density in trans masculine individuals (TMIs). Design: This is a cross-sectional study. Setting: TMIs (n=444) underwent chest-contouring surgeries to treat their gender dysphoria between 2013 and 2019 at an urban medical center. Participants: Of the 444 TMIs, 425 had pathology images analyzed by our deep-learning algorithm to extract breast tissue composition. A subset of 42/444 TMIs had mammography prior to surgery; mammography files were available for 25/42 TMIs and analyzed using a breast density software, LIBRA. Main Outcomes and Measures: The first outcome was the association of duration of TT and breast tissue composition assessed by pathologists (categories of lobular atrophy and stromal composition) or by our algorithm (% epithelium, % fibrous stroma, and % fat). The second outcome is the association of TT and breast density as assessed by a radiologist (categorical variable) or by LIBRA (percent density, absolute dense area, and absolute non-dense area). Results: Length of TT was associated with increasing degrees of lobular atrophy ( p <0.001) but not fibrous content ( p =0.821) when assessed by the pathologists. Every six months of TT was associated with decreased amounts of both epithelium (exp(ß)=0.97, 95% CI 0.95-0.98, adj p =0.005) and stroma (exp(ß)=0.99, 95% CI 0.98-1.00, adj p =0.051), but not fat (exp(ß)=1.01, 95%CI 0.98-1.05, p =0.394) in fully adjusted models. There was no association between TT and radiologist's breast density assessment ( p =0.575) or LIBRA measurements ( p >0.05). Conclusions: TT decreases breast epithelium and fibrous stroma, thus potentially reducing the breast cancer risk of TMIs. Further studies are warranted to elucidate the effect of TT on breast density and breast cancer risk. Summary Box: Very little is known about the effect of gender-affirming testosterone therapy on cancer risks, such as breast cancer.Epidemiological studies had different conclusions about the association between testosterone and breast cancer in cisgender women (positive association) and trans masculine individuals (inverse association).More laboratory-based research are needed to understand the effect of testosterone on breast cancer risk in the understudied trans masculine population.Our study provides quantitative histological evidence to support prior epidemiological reports that testosterone may reduce breast cancer risk in trans masculine individuals.

Invasive Ductal Carcinoma of the Breast in a Transgender Man: A Case Report.

There is limited literature about breast cancer in the transgender population. Very little is known about how gender-affirming hormone therapy affects their breast cancer risk. On the other end, for those diagnosed with breast cancer, there are no clinical guidelines to manage their breast cancer, specifically, how to manage their gender-affirming hormone therapy during breast cancer treatment. Here, we report a 52-year-old transman diagnosed with a grade 2 invasive ductal carcinoma (ER+/PR+/HER2-), and ductal carcinoma in situ (DCIS) of intermediate grade. We discussed his risk factors as well as treatment options.

Pearls and Pitfalls of Contrast-Enhanced Mammography.

Contrast-enhanced mammography (CEM) is a promising new imaging modality that uses a dual-energy acquisition to provide both morphologic and vascular assessment of breast lesions. Although no official BI-RADS lexicon exists, interpretation entails using the mammographic BI-RADS lexicon in combination with that for breast MRI. CEM has comparable performance to breast MRI, with sensitivity of 93-100% and specificity of 80-94%. Currently FDA approved for diagnostic imaging, this technology can be helpful in determining disease extent in patients with newly diagnosed breast malignancy, monitoring response to neoadjuvant therapy, identifying mammographically occult malignancies, and diagnostic problem-solving. Studies are ongoing about its role in screening, especially in women with dense breasts or at elevated risk. There are some challenges to successful implementation into practice, but overall, patients tolerate the study well, and exam times are less than the full breast MRI protocol.

Establishing a Cohort of Transgender Men and Gender Nonconforming Individuals to Understand the Molecular Impact of Testosterone on Breast Physiology.

Purpose: To characterize a cohort of transgender men and masculine-centered gender nonconforming individuals who underwent gender-affirming chest-contouring surgeries at our institution between 2013 and 2018. Methods: Demographics, medical history, and breast histopathological assessment for 340 patients were retrieved from medical records. Results: Most of our patients were white, non-Hispanic (75.0%), were taking testosterone (83.2%), and opted for chest-contouring surgery after 12-14 months of testosterone therapy. Ten patients were parous (2.9%). Seventy-nine (23.2%) and 27 (7.9%) patients had a family history of breast cancer or ovarian cancer, respectively. One transgender man was incidentally diagnosed with ductal carcinoma in situ at chest-contouring surgery. Conclusion: Future studies on this cohort will provide valuable insights about the impact of testosterone on breast physiology.