Incidence of High Risk and Malignant Pathological Findings in Transgender and Gender Diverse Individuals Undergoing Gender-Affirming Mastectomy

Our study population was comprised of 865 individuals (1610 breasts) with a median age at the time of surgery of 27 years [interquartile range (IQR) = 21–30]. Most participants identified as female to male (658, 75.6%), followed by nonbinary (181, 20.8%), with a small number identifying as female (2, 0.2%) or other (28, 3.2%). The ethnic composition was predominantly Caucasian (699, 80.1%), with smaller representations from African American (76, 8.8%), Latin-x (42, 4.8%), Asian (18, 2.1%), Native American/Alaskan Native (9, 1.0%), or other (21, 2.4%) backgrounds.

Concerning body mass index (BMI) at the time of surgery, the distribution was relatively spread across different ranges, with 25.5% of patients having a BMI of 26–30 kg/m², followed closely by 25.2% in the 21–25 kg/m² range, and 18.5% in the 31–35 kg/m² range. Smaller percentages were distributed among the other BMI categories, reflecting a broad diversity in body compositions within our study cohort.

A significant portion of the participants (688, 79.2%) were undergoing testosterone therapy at the time of surgery, with the median duration of testosterone use prior to surgery being 14 months with an inner quartile range of 4–29 months. The rate of oophorectomy in this population was low, at 1.7%, which aligns with the selection criteria focusing primarily on top surgery. Other forms of hormone suppression or replacement were uncommon, indicating that testosterone therapy was the predominant hormone treatment in this group (Table 1).

In the analysis of pathologic findings, we observed a spectrum of lesions with varying implications for breast cancer risk. Among the specimens evaluated, benign nonproliferative lesions constituted 6.2% of the findings, encompassing fibrocystic changes (2.7%), fibroadenoma (1.5%), and apocrine metaplasia (2%). Proliferative diseases without atypia, indicative of a slightly elevated risk for developing breast cancer, were identified in 2.4% of cases, including usual ductal hyperplasia (1.4%), sclerosing adenosis (0.2%), columnar cell changes (0.4%), and intraductal papilloma (0.4%). Moreover, the presence of proliferative disease with atypia, which confers a higher risk for breast cancer, was noted in a smaller fraction of the population, with atypical ductal hyperplasia and atypical lobular hyperplasia being found in 0.1% and 0.2% of specimens, respectively. Malignant lesions were rare, with only two cases identified: one instance of ductal carcinoma in situ (DCIS) and one case of Paget’s disease, each constituting 0.1% (see Table 2). All malignant lesions and 50% of proliferative lesions with atypia were found in patients aged 35 years or older (see Table 3).

Three patients were found to have atypical lobular hyperplasia. One patient was 49 years old and had already had total abdominal hysterectomy and bilateral salpingo-oophorectomy with one paternal uncle with a history of an unknown malignancy. This patient received risk reduction counseling and was instructed to perform breast self-examination every 2–3 months with an annual breast exam from their primary care physician. A second 51-year-old patient with atypical lobular hyperplasia on a single pathology slide and a longstanding history of smoking and family history of breast cancer opted for 5 years of tamoxifen therapy for risk reduction. The third patient with atypical lobular hyperplasia was 20 years old and was lost to follow-up. One patient aged 34 years with an incidental locus of atypical ductal hyperplasia was found to have no additional loci on further analysis of their specimen and was advised to carry out the same self and clinical examinations described above. A 51-year-old patient was found to have ductal carcinoma in situ and was recommended to have additional surgery to remove breast tissue and to start endocrine therapy but declined treatment. One patient was found to have Paget’s disease on their top surgical specimen at the nipple terminal ducts and had the affected free nipple graft removed. The free nipple graft did not contain additional foci of cancer on pathologic analysis.

Ordered logistic regression analysis found that the variables of gender, smoking, alcohol use, personal or family history of cancer, and BMI were not associated with breast cancer risk in our cohort. Age was associated with increased risk, with those undergoing surgery at 45 or older having over a 300% increased risk of having an incidental finding on pathology compared with those aged 26–34 years [odds ratio (OR) 3.11, p < 0.01, confidence interval (CI) 1.37–7.09). This is in keeping with older age being a known risk factor for development of breast lesions and for our current institutional standard of required baseline mammographic screening of any patient 40 years and older prior to GAM. Additionally, patients aged 25 or younger were 70% less likely to have an incidental finding on pathological analysis with no patients in the present cohort having an occult malignancy (OR 0.3, p < 0.01, CI 0.18–0.50). GAHT use was not associated with an increased risk of having an incidental finding on pathological analysis. In the presented population, patients taking GAHT for a year or less were significantly less likely to have a pathological finding compared with those who were not (OR 0.5, p = 0.05, CI 0.25–0.99). This may represent an initial finding of the protective significance of testosterone therapy, although this does not hold true for the other cohorts and will require larger cohort studies (see Table 4).

To our knowledge, the present study represents the largest single-center series of pathological gender-affirming top surgery samples of TGD patients. Of 1654 specimens, 123 were found to have incidental pathology with 34 patients having a proliferative lesion, 4 patients having proliferative lesions with atypia, and 2 having malignancies. The absolute number of cancers among this relatively young and healthy population is low. Typical risks for breast cancer still apply in transgender patients with age being the single most significant risk factor for breast cancer regardless of gender identity.¹² Other studies seeking to identify risks in this population also found that older age was the primary risk and that TGD patients develop breast cancer at similar rates to their cisgender counterparts.^6,9,13

Screening guidelines for breast cancer in TGD patients are lacking, with the American College of Radiology having the only formal guidance for clinicians to reference. These guidelines are somewhat vague, largely rely on expert opinion with data from a single study, and leave final shared decision making in the hands of practitioners and patients.^9,10 Previous studies and the present data suggest that GAHT may not increase a patient assigned female at birth’s baseline risk for breast malignancy and should not affect screening guidelines for breast cancer in this population.^6,9,14 Our study of the largest TGD pathologic specimen cohort suggests a similar risk of breast cancer development in this population of individuals assigned female at birth compared with their cis-gender counterparts. When it comes to screening recommendations, our institution screens all those undergoing GAM for breast cancer development risk. If there are patients of concern, we offer a multidisciplinary approach where they are referred to a breast surgeon who evaluates the patient’s risk of breast cancer development with the BCRAT from the National Cancer Institute. Those at high risk of breast cancer development (score > 20%) may benefit from additional mammographic and MRI screening prior to GAM. At our institution, this level of multidisciplinary care has led to several high-risk patients undergoing risk reducing mastectomies instead of GAM and one patient undergoing concurrent risk reducing mastectomies and chest masculinization with the combined efforts of the plastic surgeon and the breast surgeon.

Given the possibility of detecting possible malignancy in gender-affirming mastectomy patients, some advocate for pathological examination for every breast specimen.^15,16 Oftentimes, detection of low-grade aberrant breast lesions does not alter immediate management or guide screening decisions. The present analysis found that those 25 years or younger in our cohort were 70% less likely to have any incidental pathology findings, suggesting that increasing age should be the central consideration for pathological evaluation. Therefore, it is our recommendation that high-risk patients based on BCRAT scores or those patients older than 25 years of age should have pathological analysis done on their breast tissue. Further investigation will likely show that this age recommendation is conservative but is substantiated by our analysis and reduces resource allocations.

The costs associated with pathological breast examination have been calculated at US$233 per specimen in the literature, and it has been suggested that cis-gender patients 18 years of age and younger are unlikely to benefit from pathological analysis.¹⁷ In our cohort these suggestions would have decreased the number of pathological analyses by as many as 600 breasts (300 patients) at an estimated savings of roughly US$140,000. This is particularly pertinent in this patient population who often pay out of pocket for GAM.

All studies have inherent limitations. The present sample is comprised of relatively young patients with few comorbid conditions from a single institution which may limit the generalizability of our results; however, current estimates show that our population is closely aligned with national samples of patients undergoing this surgery.¹⁸ Additionally, this study is retrospective in nature and long-term follow-up for all patients was not possible. All included patients had relevant pathology data and GAHT history, ensuring the presented data’s reliability and value.

Data-driven consensus recommendations for breast cancer screening and pathologic analysis among TGD patients who have received GAM surgery are lacking. The present study sought to compile and analyze data to contribute to the generation of specific guidelines to manage breast cancer screening and pathologic specimen management in this population. Our findings suggest that the overall incidence of cancer in TGD patients seeking top surgery is low. Thus, tailoring screening to patients 40 and older or patients with higher risk of breast cancer development and pathological tissue analyses to patients above the age of 25 in a multidisciplinary management model may represent early steps towards conscientious resource allocation and more evidence-based patient management.