https://orcid.org/0000-0002-7788-8074
Abstract
Gender diversity, especially pertaining to transgender and gender-diverse (TGD) populations, is often stigmatized. A small but not insignificant number of adults in the United States identify as TGD, including transgender, nonbinary, and other gender identities than cisgender. Accessing health care remains a significant challenge for TGD individuals because many health care systems adhere to a gender binary model and many TGD individuals experience negative interactions when interfacing with health care. There is also a scarcity of literature addressing their unique health care needs, limiting our current understanding of breast cancer risks and screening recommendations for TGD patients. This article reviews important considerations when providing care to TGD patients. It covers background information on gender identity and sexuality, explores gender-affirming care, discusses histopathologic findings of breast biopsy specimens, examines breast cancer risks, and presents current breast cancer screening recommendations for TGD patients. Education on TGD breast cancer risks and screening and creating a standardized screening protocol for TGD patients who may receive gender-affirming care through hormonal and surgical therapies could help improve their health care equity and access.
Highlighting the need for consensus guidelines, transgender and gender-diverse individuals are a growing patient population, and radiologists can better engage by being informed of their breast care needs and communicating them in an effective and appropriate manner.
Transmasculine individuals can generally follow the breast cancer screening guidelines of their natal sex unless they receive bilateral mastectomy, or “top surgery,” in which case they may not need further screenings without other risk factors.
Transfeminine individuals generally do not need screenings for breast cancer unless they receive 5 or more years of gender-affirming hormonal therapy or have other risk factors.
Introduction
Gender identity refers to an individual’s concept of self and can be broken down into 2 main categories of cisgender (cis) and transgender (trans). Cis individuals identify with the sex that they were assigned at birth based on their anatomic characteristics. For example, a cis man will be assigned male at birth (AMAB) based on external genitalia. Trans individuals identify with a sex other than the one assigned to them at birth. For example, a trans man may have been assigned female at birth (AFAB) (1). Notably, intersex persons, defined as individuals having differences in sex development with traits that do not correspond to a single sex, can develop gender dysphoria relative to the sex they are assigned at birth, similar to trans persons (2,3). People who do not identify within the male-female binary may prefer the term “nonbinary” (NB). Sexual orientation is a separate trait that describes to whom a person is attracted (4). Gender-diverse (GD) identities encompass all gender identities beyond the male-female binary, including some (but not all) trans and NB individuals. Overall, trans and gender-diverse (TGD) individuals vary in their identities, and clinicians should always ask how, relative to gender, a patient identifies (4). It is crucial to understand these nuances such that appropriate recommendations are made for TGD individuals who may require breast cancer imaging.
The distress caused by a discrepancy between one’s gender identity and that assigned sex at birth is known as gender dysphoria (2). Not all TGD individuals experience gender dysphoria, and many do not ever desire gender-affirming medical or surgical treatment; nor do all TGD individuals undergo a “traditional” binary medical transition in their lifetime. However, a person experiencing significant gender dysphoria may require medical interventions such as mental health counseling, medical therapies, and surgical therapies (4). Estimated to make up 0.5% to 1.6% of the adult population in the United States, TGD persons face high levels of societal stigma, discrimination, and violence (5,6). Additionally, many have had negative experiences within the health care system and thus may have distrust of their clinicians (6). Providing culturally competent care to TGD patients is an ongoing effort in the field of breast radiology. Some examples of creating an inclusive environment for TGD patients include using gender-inclusive language in all aspects of providing care, creating gender-neutral facilities (eg, avoiding “all-pink” color schemes), and widespread adoption of gender-inclusive breast cancer risk assessment surveys by breast imaging centers with infrastructure for long-term data collection (7–9).
Although there is an increase in the transgender population, data related to transgender breast imaging are still sparse (8). Thus, this article will review the current literature on the gender-affirming care that TGD individuals may receive and considerations for breast radiologists to make for these patients. In particular, the article will review gender-affirming care related to breast cancer, breast cancer risks in TGD populations, histopathologic features seen in TGD patient breast biopsy specimens, and current recommendations on TGD breast cancer screening. It is essential to acknowledge that, although this article will review the literature in breast radiology about trans patients, these topics are not intended to exclude other GD patients (eg, gender-fluid, NB, etc) who may require similar breast cancer care. The literature discussed will focus on the care of adults.
Gender-affirming hormonal treatments
Gender-affirming hormonal therapy (GAHT) aims to modify the patient’s endogenous serum sex steroid levels for their desired phenotypic outcome (eg, ceasing menses, changing hair growth patterns, etc) and alleviate gender dysphoria (10,11).
Gender-affirming transfeminine hormonal therapies
Gender-affirming hormonal therapy for transfeminine individuals is intended to reduce male patterns of hair growth, decrease muscle mass, redistribute subcutaneous fat, and induce breast growth (10,11). These effects do not alter the effects of androgens before treatment, such as changes in puberty (11). Estrogen therapy with supraphysiologic dosages can suppress androgen production by inhibiting the hypothalamic-pituitary-gonadal (HPG) axis and preventing the release of gonadotropins for testosterone production (10,11). Oral estradiol is the most commonly prescribed GAHT because it is inexpensive and easy to monitor via serum estradiol levels (10,11). Typically, treatment regimens will use other testosterone-lowering agents with antiandrogens such as spironolactone and gonadotropin-releasing hormone agonist therapy, owing to an increased risk of thrombosis with estrogen therapy (10,11). Although surgical androgen suppression with orchiectomy is an option, most transfeminine individuals elect not to pursue this operation and therefore require higher doses of estrogen therapy (10,11). These hormonal treatments can lead to significant breast growth (11), warranting recommendations from the American College of Radiology (ACR) to publish the ACR Appropriateness Criteria Transgender Breast Cancer Screening guidelines in November 2021, which will be referred to moving forward as the “ACR guidelines” (12).
Gender-affirming transmasculine hormonal therapies
Transmasculine GAHT also aims to inhibit the HPG axis to induce physical changes that align with the patient’s gender identity. Androgen therapy (AT) using testosterone is effective, inexpensive, and easy to monitor with serum testosterone levels (10,11). Androgen therapy is titrated to achieve and maintain physiologically similar testosterone levels as cis AMAB individuals, around 300 to 1000 ng/dL. This may differ for NB individuals, who may receive AT primarily to avoid hypogonadism (10,11,13). There are many routes of administration, all of which increase the risk of thrombosis, stroke, pulmonary embolism, and cardiovascular disease as inherent properties of testosterone (10,14). Most other risks are route and/or dosage dependent, such as skin irritation from testosterone patches (10,14).
There is a correlation between increased endogenous testosterone levels and an increased breast cancer risk (15,16). However, AT has been investigated as prophylactic in both pre- and postmenopausal cis women for breast cancer risk reduction (17–19). Additionally, there is very little literature on breast cancer risk in transmasculine patients receiving AT (20). Consequently, the ACR guidelines emphasize surgical gender-affirming care as the primary risk stratification factor for TGD patients receiving transmasculine therapies (12).
Gender-affirming surgical treatments
Surgical therapies for gender affirmation are primarily performed to accentuate features concordant with one’s gender identity and most often involve facial, chest/breast, and/or genital reconstruction. Approximately half of all TGD individuals receiving GAHT also undergo surgical treatment (11).
Gender-affirming transfeminine surgical therapies
Breast augmentation is the primary surgical treatment for transfeminine gender-affirming care encountered by breast radiologists (21). Similar to transmasculine GAHT, breast augmentation is not a known risk factor for breast cancer in either cis AFAB or TGD patients (21), and the ACR does not account for it in their TGD screening criteria for breast cancer (12). Instead, it is recommended that these TGD individuals be screened for breast cancer using the existing screening guidelines (10).
Breast augmentation can be done with the use of implants; however, this limits the visualization of the whole breast tissue. In some circumstances, due to social and economic reasons or limited access to proper health care, the use of nonregulated materials or methods for augmentation is seen as injections of free silicone, paraffin oil, polyacrylamide hydrogel, or implantation of substances including ivory, glass balls, or rubber. The use of these materials is illicit worldwide, but it can be seen more often outside the United States. The use of nonregulated material to augment breasts significantly lowers the sensitivity of the imaging studies, posing a great challenge for screening and also being a potential harm to health due to the risk of complications (22,23). The use of textured silicone implants is also associated with anaplastic large cell lymphoma and squamous cell carcinoma, but there are sparse data regarding these tumors in a transgender population (24).
Gender-affirming transmasculine surgical therapies
Mastectomies done for surgical transmasculine gender-affirming care are often subtotal to contour the chest for a masculine aesthetic, leaving behind residual breast tissue that can develop breast cancer (25). The ACR guidelines stratify breast cancer screening criteria for this population based on the extent of mastectomy, age, and other medical history risk factors common to cis patients (12). Patients who undergo bilateral mastectomy are generally no longer at a high enough risk to be appropriate candidates for breast cancer screening without other risk factors (10,12).
Histopathologic features
Pathology departments rarely receive breast tissue specimens from TGD patients who have received gender-affirming care, and it is still an ongoing effort to obtain more information on the histopathologic findings of breast biopsy specimens in TGD patients (26). Estrogen GAHT can lead to the development of ducts, lobules, and acini that are histologically identical to those of cis women (27,28). This must be differentiated from gynecomastia, a benign condition found in cis men caused by an increased ratio of estrogen to progesterone, which shows only ductal and stromal hyperplasia (28,29). Breast biopsies performed in trans women studied by de Blok et al in 2021 found an 88:12 ratio of benign vs malignant breast lesions (30). In this study, the most frequent breast lesions found in the group of trans women receiving GAHT undergoing biopsy at a median of 20 years after starting therapy were fibroadenomas, followed by breast cancer, fibrosis, fibrosis, and cysts (30). A similarly sized group of trans women with silicone breast implants had biopsies often done for implant-related issues, and most biopsy specimen results found a reaction to silicone (30). Finally, a smaller group of trans women received breast biopsies before starting GAHT, often for palpable abnormalities resulting in a diagnosis of gynecomastia (30). It is important to note that, although this study is the largest of its size, only 5% of TGD patients had breast biopsies done, and samples were much smaller once further stratified by gender-affirming care types and indication for biopsy. Additionally, this study had a low positive predictive value (PPV) of approximately 10% compared with the 20% to 40% seen in cis women at most centers. Such a low PPV could be due to the study’s young population, with a median age of 30 years, or a preference for US or physical examination to recommend a biopsy, consequently increasing the false positive rates. The use of imaging was also limited among trans patients with implants because many of them underwent biopsies for clinically detected abnormalities such as capsular contractions or preoperative biopsies before implant replacement, implant leakage or recall, cosmetic reasons, or complications due to silicone injections. Only 42% of the patients in this cohort had imaging abnormalities (30).
In trans men, AT decreases breast glandular and overall adipose tissue while increasing breast fibrous connective tissue (31). An increase in fibrous tissue can lead to increased breast density on mammography, which may be confused with fibroglandular tissue growth. In a recent study by Wolters et al, a histopathologic analysis of 314 breast specimens from trans men showed a higher proportion of fibrous tissue, fewer lobules, and a higher degree of lobular atrophy than in cis women (26). This effect was particularly apparent in trans men who have undergone AT. They also found a statistically significant lower prevalence of cysts, calcifications, and cellular atypia; however, the sample sizes for these additional findings were small (26). Histologically, the breast tissue in trans men receiving AT resembles that of postmenopausal cis women (31).
Breast cancer risks
Risks for trans women
Estrogen GAHT is known to increase the risk of breast cancer (32). Trans women with additional risk factors such as BRCA-related mutations and being on GAHT for many years have a higher risk of breast cancer compared with cis men; however, incidence rates are still much lower than in cis women (33). The development of ER+ tumors has long been linked to long-term estrogen exposure in postmenopausal cis women, an association that may also occur in trans men (34). Little is known about the association between genetic mutations and breast cancer in trans women. Similar risk factors likely exist for trans women as cis men, particularly hereditary BRCA1 and BRCA2 mutations (35).
Some medications, such as cyclosporine, have also been linked to the development of benign breast masses such as fibroadenomas, fibrocystic changes, intraductal papillomatosis, invasive cancers, and phyllodes tumors (36–38). However, diuretics such as spironolactone, which are often part of GAHT, were not found to be independent risk factors for breast cancer (39). Breast cancer in trans women is rare, with only 21 cases of non–implant-associated breast cancer reported since 1968 (40). Among the 21 cancers reported in transgender women, there were 17 adenocarcinomas or invasive ductal carcinomas, 1 ductal carcinoma in situ, 1 secretory carcinoma, and 2 unspecified cases (40). In most of these cases, patients most commonly presented with a breast lump, and most tumors were ER+ (40).
Risks for trans men
Trans men who do not undergo gender-affirming surgery, regardless of AT usage, have a similar lifetime risk of breast cancer as cis women (12.4%) (10–12). Assigned female at birth individuals who undergo bilateral mastectomy have a decreased risk of breast cancer by nearly 90%, regardless of gender identity (12,41,42). Notably, this is still higher than a cis AMAB individual’s risk of developing breast cancer (12). The reported incidence of breast cancer in trans men is 5.9 cases per 100 000 person-years compared with 154.7 cases per 100 000 person-years in cis women (43).
Current breast cancer screening guidelines
Transgender and GD breast cancer screening guidelines are frequently updated as more individuals receive gender-affirming care. There are varied institutional breast cancer screening guidelines for transgender patients based on their individual needs and history of gender-affirming hormonal and/or surgical therapies. Further information on screening criteria (eg, age, gender-affirming care, screening modality) are discussed in these referenced guidelines (12,44,45). However, these guidelines are based on limited data and expert opinions. It is difficult to obtain significant evidence-based data on TGD individuals due to historical marginalization, barriers to health care access, younger average patient age than most breast cancer screening guidelines, loss to follow-up, and lack of clinician experience (6,13,46,47).
According to the ACR and the Society of Breast Imaging (SBI), breast cancer screening needs depend on several factors as sex assigned at birth, age, personal risk of breast cancer, breast development, history of breast surgery (for transmasculine populations) and the use and duration of GAHT (for transfeminine populations) (Tables 1,2). An annual screening mammogram at age 40 may be appropriate for transfeminine patients who have used hormones for ≥5 years (Figures 1,2) and is recommended for transmasculine patients who have not had a complete bilateral mastectomy (Figure 3) (48). Additionally, the National Comprehensive Cancer Network endorses the consensus-based guidelines developed by the ACR Appropriateness Criteria (49). For BRCA1 or BRCA 2 gene mutation carriers in a TGD population, the ACR and SBI recommend similar screening protocols as for others with these mutations (48). For other gene mutations carriers, there are no specific screening guidelines for the transgender population. Health care providers being well informed on these emerging guidelines can help TGD patients receive timely and effective breast care. The ACR and the American College of Breast Surgeons also recommend that all women should be examined for breast cancer risk yearly by age 25 using a variety of risk assessment models, but it is unclear whether this recommendation should be extended to TGD populations (48).
Recommended Screening Guidelines—Transfeminine Patients
| Average cancer riska AND no or <5 years of GAHT | Increased cancer riska AND no or <5 years of GAHT | Increased cancer riska AND past or ≥5 years of GAHT | Average cancer riska AND past or ≥5 years of GAHT | ||
|---|---|---|---|---|---|
| Any age | 25–30 y old | 25–30 y old | ≥30 y old | ≥40 y old | |
| Mammogram/DBT | Usually not appropriate | May be appropriate | Usually appropriate | Usually appropriate | May be appropriate |
| Breast MRI | Usually not appropriate | Usually not appropriate | Usually not appropriate | May be appropriate | Usually not appropriate |
| Breast US | Usually not appropriate | Usually not appropriate | Usually not appropriate | May be appropriate | Usually not appropriate |
| Average cancer riska AND no or <5 years of GAHT | Increased cancer riska AND no or <5 years of GAHT | Increased cancer riska AND past or ≥5 years of GAHT | Average cancer riska AND past or ≥5 years of GAHT | ||
|---|---|---|---|---|---|
| Any age | 25–30 y old | 25–30 y old | ≥30 y old | ≥40 y old | |
| Mammogram/DBT | Usually not appropriate | May be appropriate | Usually appropriate | Usually appropriate | May be appropriate |
| Breast MRI | Usually not appropriate | Usually not appropriate | Usually not appropriate | May be appropriate | Usually not appropriate |
| Breast US | Usually not appropriate | Usually not appropriate | Usually not appropriate | May be appropriate | Usually not appropriate |
aAverage risk is <15% lifetime risk of breast cancer. Abbreviations: DBT, digital breast tomosynthesis; GAHT, gender-affirming hormonal therapy.
Recommended Screening Guidelines—Transfeminine Patients
| Average cancer riska AND no or <5 years of GAHT | Increased cancer riska AND no or <5 years of GAHT | Increased cancer riska AND past or ≥5 years of GAHT | Average cancer riska AND past or ≥5 years of GAHT | ||
|---|---|---|---|---|---|
| Any age | 25–30 y old | 25–30 y old | ≥30 y old | ≥40 y old | |
| Mammogram/DBT | Usually not appropriate | May be appropriate | Usually appropriate | Usually appropriate | May be appropriate |
| Breast MRI | Usually not appropriate | Usually not appropriate | Usually not appropriate | May be appropriate | Usually not appropriate |
| Breast US | Usually not appropriate | Usually not appropriate | Usually not appropriate | May be appropriate | Usually not appropriate |
| Average cancer riska AND no or <5 years of GAHT | Increased cancer riska AND no or <5 years of GAHT | Increased cancer riska AND past or ≥5 years of GAHT | Average cancer riska AND past or ≥5 years of GAHT | ||
|---|---|---|---|---|---|
| Any age | 25–30 y old | 25–30 y old | ≥30 y old | ≥40 y old | |
| Mammogram/DBT | Usually not appropriate | May be appropriate | Usually appropriate | Usually appropriate | May be appropriate |
| Breast MRI | Usually not appropriate | Usually not appropriate | Usually not appropriate | May be appropriate | Usually not appropriate |
| Breast US | Usually not appropriate | Usually not appropriate | Usually not appropriate | May be appropriate | Usually not appropriate |
aAverage risk is <15% lifetime risk of breast cancer. Abbreviations: DBT, digital breast tomosynthesis; GAHT, gender-affirming hormonal therapy.
Recommended Screening Guidelines—Transmasculine Patients
| History of bilateral mastectomy | Breast tissue present AND BRCA mutation | Breast tissue present AND increased cancer riska | Breast tissue present AND average cancer riska | |
|---|---|---|---|---|
| Any age | 25–30 y old | ≥30 y old | ≥40 y old | |
| Mammogram/DBT | Usually not appropriate | Usually appropriate | Usually appropriate | Usually appropriate |
| Breast MRI | Usually not appropriate | Usually appropriate | May be appropriate | Usually not appropriate |
| Breast US | Usually not appropriate | May be appropriate | May be appropriate | Usually not appropriate |
| History of bilateral mastectomy | Breast tissue present AND BRCA mutation | Breast tissue present AND increased cancer riska | Breast tissue present AND average cancer riska | |
|---|---|---|---|---|
| Any age | 25–30 y old | ≥30 y old | ≥40 y old | |
| Mammogram/DBT | Usually not appropriate | Usually appropriate | Usually appropriate | Usually appropriate |
| Breast MRI | Usually not appropriate | Usually appropriate | May be appropriate | Usually not appropriate |
| Breast US | Usually not appropriate | May be appropriate | May be appropriate | Usually not appropriate |
aAverage risk is <15% lifetime risk of breast cancer. Abbreviation: DBT, digital breast tomosynthesis.
Recommended Screening Guidelines—Transmasculine Patients
| History of bilateral mastectomy | Breast tissue present AND BRCA mutation | Breast tissue present AND increased cancer riska | Breast tissue present AND average cancer riska | |
|---|---|---|---|---|
| Any age | 25–30 y old | ≥30 y old | ≥40 y old | |
| Mammogram/DBT | Usually not appropriate | Usually appropriate | Usually appropriate | Usually appropriate |
| Breast MRI | Usually not appropriate | Usually appropriate | May be appropriate | Usually not appropriate |
| Breast US | Usually not appropriate | May be appropriate | May be appropriate | Usually not appropriate |
| History of bilateral mastectomy | Breast tissue present AND BRCA mutation | Breast tissue present AND increased cancer riska | Breast tissue present AND average cancer riska | |
|---|---|---|---|---|
| Any age | 25–30 y old | ≥30 y old | ≥40 y old | |
| Mammogram/DBT | Usually not appropriate | Usually appropriate | Usually appropriate | Usually appropriate |
| Breast MRI | Usually not appropriate | Usually appropriate | May be appropriate | Usually not appropriate |
| Breast US | Usually not appropriate | May be appropriate | May be appropriate | Usually not appropriate |
aAverage risk is <15% lifetime risk of breast cancer. Abbreviation: DBT, digital breast tomosynthesis.
Images of a 45-year-old trans woman (she/her) who was assigned male at birth and started gender-affirming hormonal therapy 7 years before the current examination with a family history of breast cancer diagnosed in her sister at age 34 years. She was found to have a positive PALB2 mutation, warranting annual screenings alternating between breast mammogram and breast MRI. After 6 years of negative screening examination results, the current breast MRI (maximum intensity projection) (A) demonstrated a mass in the right breast at 12 o’clock measuring up to 27 mm with delayed phase plateau kinetics (arrow). Craniocaudal view (B) from the prior mammogram of the right breast was negative, with the subsequent screening examination 1 year later (C) demonstrating a new obscured oval mass in the retro areolar region (arrows). Breast US (D) demonstrates the corresponding hypoechoic circumscribed oval mass. US-guided core needle biopsy yielded a fibroepithelial neoplasm showing stromal hypercellularity and a rare mitotic figure. Excisional biopsy later yielded a benign phyllodes tumor with negative margins.
Images of a 49-year-old trans woman (she/her) who was assigned male at birth, started on gender-affirming hormonal therapy with estradiol transdermal patches and spironolactone in July 2022. This was the first screening mammogram done in June 2023, and both craniocaudal (A) and mediolateral oblique (B) views show no evidence of imaging abnormalities.
Images of a 48-year-old trans man (he/him) who was assigned female at birth, started on gender-affirming hormonal therapy with testosterone therapy 3 years before the examination. Craniocaudal (A) and mediolateral oblique (B) views from the most recent screening mammogram were negative. He is scheduled to be seen for gender-affirming surgical treatment with plastic surgery.
When considering different imaging modalities, there are no relevant data on the use of digital breast tomosynthesis (DBT) for breast cancer screening of TGD individuals; however, it is expected that DBT may be beneficial if considering data from cis women that demonstrate reduced false positive recall rates. There are no sufficient data for all the clinical scenarios regarding MRI with intravenous (IV) contrast involving TGD populations, but it could be reasonably expected to be beneficial in patients with high lifetime risk of breast cancer. MRI without IV contrast is not useful in any scenario other than evaluating silicone implant integrity. Regarding whole-breast screening US, there are no sufficient data to support most of the scenarios in transgender screening, but for patients with high risk and/or dense breasts, it may be beneficial. There are no data regarding the use of automated breast US or contrast-enhanced mammography in this population (12).
Conclusion
There is currently little literature regarding screening TGD individuals for breast cancer. Current screening guidelines are affected by many factors, such as gender-affirming care status, age, gender identity, genetic predispositions, and medications. Breast cancer risks in TGD patients are poorly understood and require further study.
Acknowledgments
We would like to thank Oliver Mesa-Burton, Sophia Xiao, Morgan Leff, Aastha Chandra, and Alaina Berg for proofreading and cultural perspective.
Funding
None declared.
Conflict of interest statement
None declared.
Author contributions
Ajmain Chowdhury (Investigation, Validation, Writing – original draft, Writing – review & editing), Assim Saad Eddin (Conceptualization, Data curation, Investigation, Writing – original draft), Su Kim Hsieh (Conceptualization, Data curation, Validation, Writing – review & editing), and Fabiana C. Policeni (Conceptualization, Data curation, Project administration, Resources, Supervision, Validation, Writing – review & editing)
