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Prostate Cancer in a Transgender Woman 41 Years After Initiation of Feminization
To the Editor: The development of prostate cancer after orchiectomy is rare. In transgender women, the longest duration between initiation of estrogen therapy and diagnosis previously reported was 12 years.1-2 We report a case of a male-to-female transgender woman with locally advanced prostate cancer diagnosed 41 years after feminization.
Report of a Case
In May 2005, a 60-year-old transgender woman presented with gross hematuria. She had started feminizing estrogen therapy at 19 years of age. After 5 years of weekly estrogen injections (details unknown), she used conjugated estrogen tablets (Premarin, 2.5 mg daily) until bilateral orchiectomy at age 34 years. Thereafter, she took conjugated estrogen tablets (Premarin, 1.25 mg daily) except between the ages of 50 and 56 years, when she took no estrogen because of acquisition difficulties. Family history was negative for prostate cancer.
A large anterior mass was palpated on digital neovaginal examination. Her serum prostate-specific antigen (PSA) level was 240 ng/mL; no previous PSA level had been measured. The total serum testosterone level was 44 ng/dL (1.5 nmol/L) (expected castrate level <50 ng/dL [1.7 nmol/L]3). Hormone levels were consistent with a feminized male (Figure), with the detectable androgens presumed to be of adrenal origin.3
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Figure. Treatment Course, PSA Values, and Serum Hormone Levels for a Transgender Woman With Prostate Cancer
Serum hormone levels were obtained prior to and at completion of treatment (estradiol was not measured at week 35). External beam radiotherapy was delivered weeks 8 to 16. The whole pelvis received 45 Gy (conventional 4-field technique). The gross tumor received an additional 27 Gy (intensity-modulated). PSA indicates prostate-specific antigen; DHEA, dehydroepiandrosterone. SI conversion factors: to convert testosterone to nmol/L, multiply by 0.0347; estradiol to pmol/L, multiply by 3.671. (Reference ranges, age-adjusted: PSA, 0-4 ng/mL; testosterone, male: 280-800 ng/dL, female, 8-82 ng/dL; DHEA, male: 51.7-295 µg/dL, female, 18.9-205 µg/dL; estradiol, male: 8-43 pg/mL, female [premenopausal], 13-211 pg/mL, female [postmenopausal], 0-55 pg/mL).
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Magnetic resonance imaging demonstrated a 6.3 x 5.2 x 6.0 cm prostate mass infiltrating the bladder. Transrectal ultrasound-guided biopsy revealed Gleason 8 prostate adenocarcinoma in 6 out of 6 cores (80% involvement). Immunohistochemistry showed abundant (3+) androgen receptor (AR) expression in all cancer cells, but no estrogen  (ER) or progesterone (PR) receptor expression (Santa Cruz Biotech, Santa Cruz, Calif; antibodies SC-816 [AR], SC-543 [ER], and SC-538 [PR] at 1:50 dilution).
Antiandrogen treatment with oral bicalutamide (50 mg daily) and oral dutasteride (0.5 mg daily) was given for 35 weeks. She continued taking conjugated estrogen tablets (Premarin, 1.25 mg daily). After 6 weeks of treatment, her PSA level had decreased by 68%, to 77 ng/mL (Figure). During weeks 8 through 16 of antiandrogen treatment, she received radiation (72 Gy in 1.8-Gy fractions). After radiation (week 17 of treatment), her PSA level was 4.6 ng/mL. After completing antiandrogen treatment in week 35, her PSA level was 0.4 ng/mL. On magnetic resonance imaging, the prostate size had decreased to 4.5 x 4.2 x 3.7 cm. At week 56, her PSA level was 0.4 ng/mL.
Comment
Early castration has been assumed to protect against prostate cancer because androgens regulate prostate cancer cell growth.1, 3-5 Two case series of eunuchs with an average age of 57.5 years and an average duration of castration of 44 years demonstrated small or nonpalpable prostate glands on examination (n = 36) and an atrophic prostate on autopsy (n = 1).4
Although male-to-female gender reassignment surgery generally does not include prostatectomy, a small cross-sectional study suggested that prostate disease may not be common. Prostate ultrasonography and biopsy demonstrated atrophy in 9 transgender women aged 51 to 71 years a mean of 15.8 years after estrogen initiation and 13.4 years after orchiectomy.6 Three cases of prostate cancer in transgender women have been reported. In contrast to this patient who was feminized 41 years prior to diagnosis, these patients started estrogen therapy after 50 years of age and were diagnosed within 12 years.1-2
The prompt PSA response to antiandrogen treatment prior to radiation in this patient implies an active AR pathway. Bicalutamide (an antiandrogen) was used to block AR signaling, and dutasteride (a 5--reductase-inhibitor) was used to inhibit testosterone conversion to dihydrotestosterone.3, 5 Subsequent radiation confounds assessment of continued antiandrogen response.
While AR expression is common in prostate cancer, expression of ER/PR is not.3, 5, 7 Although estrogen may initiate prostate cancer in rodents,7 the lack of ER/PR expression and the PSA response to antiandrogen treatment despite estrogen supplementation suggests that estrogen did not promote her cancer. Increased AR levels are common after testosterone depletion, suggesting enhanced AR sensitivity.5, 7
To our knowledge, this case represents the longest reported duration of a castrate state preceding prostate cancer diagnosis. The PSA response to antiandrogen treatment is consistent with a role of the AR pathway in her cancer progression. Although the presence of microscopic lesions before estrogen initiation at 19 years of age cannot be excluded, animal studies suggest that androgen depletion inhibits progression to macroscopic cancer.8 It is possible that her residual androgens promoted carcinogenesis.5 The prolonged androgen depletion and estrogen exposure in this patient prior to diagnosis raises questions about the role of castrate levels of testosterone and estrogen in prostate cancer carcinogenesis.
Author Contributions: Drs Miksad and Bubley had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Miksad, Bubley, and Sanda.
Acquisition of data: Miksad, Bubley, Church, Cooper, Rofsky, Kaplan, and Sanda.
Analysis and interpretation of data: Miksad, Bubley, and Sanda.
Drafting of the manuscript: Miksad.
Critical revision of the manuscript for important intellectual content: Miksad, Bubley, Church, Cooper, Rofsky, Kaplan, and Sanda.
Financial Disclosures: Dr Rofsky reports that he has received research support from General Electric Healthcare Technologies and Medrad, Inc, and is on the Advisory Board of Berlex Laboratories. All other authors report no conflicts of interest or financial disclosures.
Funding/Support: Dr Bubley receives funding from the National Cancer Institute and the Hershey Family Foundation for Prostate Cancer Research. Dr Sanda receives research funding from the National Cancer Institute.
Role of the Sponsors: The funding organizations had no role in the design and conduct of the study; the collection, management, analysis, and interpretation of the data; or the preparation, review, or approval of the manuscript.
Previous Presentation: Portions of this work were presented as a poster at the American Society of Clinical Oncology (ASCO) Prostate Cancer Symposium in San Francisco, Calif, on February 26, 2006. The abstract for this poster was included in the 2006 ASCO Annual Meeting Proceedings: Miksad R, Bubley G, Church P, Cooper A, Rofsky N, Kaplan I, Sanda M. Analysis of hormonal receptor status in tissue from prostate cancer that developed 26 years after bilateral orchiectomy and following 41 years of estrogen therapy.
Acknowledgment: Written consent was provided by the patient for the use of her tissue and clinical data in scientific research, and for publication of this case report in JAMA.
Rebecca A. Miksad, MD
Rebecca_Miksad{at}post.harvard.edu
Glenn Bubley, MD
Division of Hematology and Oncology
Paul Church, MD;
Martin Sanda, MD
Division of Urology
Neil Rofsky, MD
Department of Radiology
Irving Kaplan, MD
Department of Radiation Oncology
Beth Israel Deaconess Medical Center
Boston, Mass
Amiel Cooper, MD
Department of Pathology
Faulkner Hospital
Boston, Mass
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Letters Section Editor: Robert M. Golub, MD, Senior Editor.
JAMA. 2006;296:2316-2317.
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