Breast

Other nonneoplastic

Transgender breast pathology


Editorial Board Member: Kristen E. Muller, D.O.
Deputy Editor-in-Chief: Gary Tozbikian, M.D.
Gabrielle M. Baker, M.D.
Yu Jing Jan Heng, Ph.D.

Last author update: 1 February 2024
Last staff update: 1 February 2024

Copyright: 2021-2024, PathologyOutlines.com, Inc.

PubMed Search: Transgender breast pathology

Gabrielle M. Baker, M.D.
Yu Jing Jan Heng, Ph.D.
Page views in 2023: 1,235
Page views in 2024 to date: 255
Cite this page: Baker GM, Heng YJJ. Transgender breast pathology. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/breasttransgenderpath.html. Accessed February 26th, 2024.
Definition / general
  • Transgender individuals have a gender identity that differs from their assigned sex; the term includes gender nonbinary individuals who do not identify as exclusively male or female (Clin Breast Cancer 2019;19:e12)
  • This article is focused on breast pathology in transmasculine (TM) people, transgender men and gender nonbinary individuals who were assigned female at birth (AFAB) but their gender identity / expression falls in the masculine range (i.e., female to male [FtM])
  • TM people frequently pursue gender affirming testosterone therapy to induce masculinization, with or without subsequent chest contouring surgery or other gender affirming surgery (Clin Breast Cancer 2019;19:e12)
Essential features
  • Gender affirming surgery in the TM subgroup of transgender individuals includes top surgery (i.e., chest contouring surgery, mastectomy, reduction mammoplasty)
  • Testosterone therapy is often taken before and after gender affirming surgeries and has an impact on breast histopathology, particularly when taken for at least 12 months (Mod Pathol 2021;34:85)
  • Most commonly observed histologic alteration seen in patients taking testosterone is lobular atrophy
  • As top surgery does not necessarily remove all identifiable breast tissue, long term follow up studies are needed to better understand the risk of breast cancer in this population
Terminology
  • Gender dysphoria, gender incongruence, gender nonconforming individual (GNCI), transsexual, assigned female at birth (AFAB), female to male (FtM)
  • Gender affirming surgery, gender reassignment surgery, sex reassignment surgery, top surgery
ICD coding
  • ICD-10
    • F64.0 - gender dysphoria in adolescents and adults and gender identity disorder in adolescence and adulthood
    • F64.9 - gender identity disorder, unspecified
    • Z87.890 - personal history of sex reassignment
Epidemiology
  • Estimated 1.4 million (0.6%) adults in the United States identify as transgender or gender nonconforming (Plast Reconstr Surg Glob Open 2018;6:e1738)
  • Increasing social acceptance, greater health insurance policy coverage of gender affirming health care services and the implementation of the Affordance Care Act Section 1557 in 2016 has resulted in an increasing number of TM people pursuing gender affirming hormone therapy and gender affirming surgeries (Fed Regist 2016;81:31375, Transgend Health 2019;4:326, Transgend Health 2019;4:131)
  • Gender affirming surgeries in the TM subgroup of transgender individuals may include top surgery (i.e., chest contouring surgery, mastectomy, reduction mammoplasty), as well as facial masculinization and genital surgery (Plast Reconstr Surg 2019;143:857e)
  • In the United States, TM individuals tend to undergo chest contouring surgery to affirm their masculine identity at a relatively young age (< 30 years old) (Mod Pathol 2021;34:85)
Sites
  • Breast
Pathophysiology
Etiology
  • Gender affirming testosterone therapy use
Clinical features
Diagnosis
  • Diagnosed with gender dysphoria by a mental health professional
Laboratory
  • TM people receiving gender affirming testosterone therapy have circulating testosterone levels comparable to cisgender men of 300 - 1,000 ng/dL (Curr Opin Endocrinol Diabetes Obes 2013;20:553)
  • TM people receiving gender affirming testosterone therapy have circulating estradiol levels of < 50 pg/mL, lower than cisgender premenopausal women (30 - 400 pg/mL)
Radiology description
  • Screening recommendations for TM people are evolving and may include the following (AJR Am J Roentgenol 2014;202:1157)
    • Breast examination and screening mammography as for cisgender women for TM people who have undergone no chest surgery or reduction mammoplasty only
    • Annual chest wall and axillary examination for TM people following bilateral mastectomy
    • Preoperative mammography for TM people who meet standard screening criteria for cisgender women
  • Breast cancer may develop in residual breast tissue following top surgery and is most frequently identified as a palpable mass with similar radiologic appearances to tumors arising in cisgender men and women (AJR Am J Roentgenol 2014;202:1149)
Case reports
Clinical images

Images hosted on other servers:
Pre and postoperative photographs Pre and postoperative photographs Pre and postoperative photographs

Pre and postoperative photographs

Gross description
  • Breast parenchyma is typically without macroscopic abnormality
  • If macroscopically within normal limits, representative sections of fibrous breast tissue, skin and nipple areolar complex (if present) may be sampled for microscopic evaluation
  • As guidelines for the gross examination and subsequent tissue submission have not been standardized, one's institutional protocol for reduction mammoplasty specimens may be followed with additional tissue evaluated if atypical proliferations are identified on the initially submitted tissue (Mod Pathol 2021;34:85, Arch Pathol Lab Med 2020;144:888)
Gross images

Contributed by Kelsey McGinley PA (ASCP) and Gabrielle M. Baker, M.D.
Mastectomy specimen; gender dysphoria, trans man

Mastectomy
specimen

Microscopic (histologic) description
  • Full spectrum of benign and malignant histologic alterations seen in cisgender breast tissue may be seen in the transgender setting
  • Same diagnostic criteria are applied in breast tissue from cisgender and transgender patients
  • Most common histologic alteration observed in breast specimens from TM people taking testosterone is a variable degree of lobular atrophy (Mod Pathol 2021;34:85)
  • Gynecomastoid change is also commonly seen in breast tissue from TM people taking testosterone (Histopathology 2017;71:859, Mod Pathol 2021;34:85)
  • Singly dispersed Toker cells and Toker cell hyperplasia (clusters of 3 or more Toker cells or Toker cells in acinar formation) is common in the nipple areolar complex of TM people who take testosterone therapy (Mod Pathol 2023;36:100121)
Microscopic (histologic) images

Contributed by Yaileen Guzman, M.D. and Gabrielle M. Baker, M.D.
DCIS; gender dysphoria, trans man

Ductal carcinoma in situ

29 year old transgender man with ADH

Atypical ductal hyperplasia

Toker cells

Toker cells

Toker cell hyperplasia

Toker cell hyperplasia

Immunofluorescence images

Contributed by Gabrielle M. Baker, M.D. and Yu Jing Jan Heng, Ph.D.
Toker cell hyperplasia Toker cell hyperplasia

Toker cell hyperplasia

Positive stains
  • Toker cell CK7 (> 90%)
  • Toker cell AR (> 90%)
  • Toker cell ER (very variable, 0 - 90%)
  • Note that Toker cells with or without intraepidermal gland formation may demonstrate some degree of HER2 expression in order to avoid making an erroneous diagnosis of Paget disease
  • Reference: Mod Pathol 2023;36:100121
Negative stains
Sample pathology report
  • Right breast, mastectomy:
    • Breast tissue, portion of nipple areolar complex and skin with no significant pathologic change (see comment)
    • Comment: The lobules appear atrophic, consistent with the patient's reported use of testosterone therapy.
Differential diagnosis
  • Gynecomastia (Endocrine 2017;55:37, Am J Clin Pathol 1972;57:431):
    • May affect 1 or both breasts
    • Increase in the number of ducts, with or without associated dilation
    • Lobule formation may occur
    • Pseudoangiomatous stromal hyperplasia (PASH) is common and may be conspicuous
    • May be divided into early and late stages
      • Early stage
        • Cellular, loose, vascular periductal stroma
        • Epithelial hyperplasia may be florid and commonly exhibits tapered tips
      • Late stage
        • Periductal fibrosis
        • Stroma may be hyalinized
        • Epithelial atrophy
  • Normal physiologic alterations in postmenopausal women (Maturitas 2004;49:2):
    • Variable degrees of lobular atrophy
    • Relative increase in adipose tissue with relative decrease in collagenous stroma and glandular components
  • Paget disease:
    • Single or cluster of cells with pale cytoplasm, large irregular nuclei with prominent nucleoli present throughout the epidermis
    • May display gland formation
    • Underlying carcinoma is commonly of high grade invasive carcinoma or DCIS
Board review style question #1
Which of the following is the most commonly observed histologic alteration in breast specimens from transmasculine individuals taking testosterone?

  1. Collagenous spherulosis
  2. Intraductal papillomas
  3. Invasive ductal carcinoma
  4. Lobular atrophy
Board review style answer #1
D. Lobular atrophy. The most common histologic alteration observed in breast specimens from transmasculine people taking testosterone is a variable degree of lobular atrophy. Longer duration of testosterone therapy is associated with higher degrees of lobular atrophy, independent of age at surgery, ethnicity, BMI and presurgical oophorectomy. Answers A - C are incorrect because although collagenous spherulosis, papilloma and invasive carcinoma can occur with testosterone therapy, they are not most common.

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Reference: Transgender breast pathology
Board review style question #2
Which of the following is true regarding the risk of breast cancer in transmasculine individuals who are taking testosterone and have undergone top surgery?

  1. Long term follow up studies are needed to better understand the risk of breast cancer in this population
  2. These individuals are known to have a higher risk of developing breast cancer than cisgender females
  3. These individuals are known to have a lower risk of developing breast cancer than cisgender males
  4. These individuals have no risk of developing subsequent breast cancer
Board review style answer #2
A. Long term follow up studies are needed to better understand the risk of breast cancer in this population. There is a need for long term follow up as well as culturally sensitive and appropriate screening algorithms to determine risk.  Answers B - D are incorrect because data remains limited regarding the influence of exogenous testosterone on hormone sensitive tissues, such as the breast and the risk of subsequent malignancy; therefore, risk under these conditions has yet to be definitively determined.

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Reference: Transgender breast pathology
Board review style question #3

What is the most likely finding depicted in this image taken from the nipple areolar complex of a transgender man on long term testosterone therapy, now undergoing chest contouring surgery?

  1. Invasive ductal carcinoma
  2. Nipple adenoma
  3. Paget disease
  4. Toker cell hyperplasia with gland formation
Board review style answer #3
D. Toker cell hyperplasia with gland formation. The image demonstrates intraepidermal gland formation composed of cytologically bland epithelial cells predominantly located at the base of the epidermis, findings that support the diagnosis of Toker cell hyperplasia with gland formation. Answer C is incorrect because Paget disease is defined as a proliferation of malignant glandular epithelial cells within the epidermis of the nipple areolar complex; the neoplastic cells of Paget disease are typically of high nuclear grade. Although Paget disease is most often characterized by the presence of singly dispersed cells or clusters of malignant epithelial cells with variable upward (i.e., pagetoid) scatter throughout the epidermis, gland formation may occur. Answer A is incorrect because the intraepidermal gland formation depicted here is cytologically benign; additionally, while invasive ductal carcinoma involving the breast parenchyma proper may secondarily involve the dermis and epidermis, there is no evidence of an underlying carcinoma in the provided image. Answer B is incorrect because in contrast to the image shown here, a nipple adenoma is generally characterized by a well demarcated but variably complex proliferation of epithelial elements in the dermis of the nipple areolar complex; of note, in some cases the glandular proliferation may involve the overlying epidermis and Toker cell hyperplasia has been reported to arise in association with an underlying nipple adenoma.

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Reference: Transgender breast pathology
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