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Prostate cancer in transgender women
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Urologic Oncology: Seminars and Original Investigations 000 (2018) 1−8
Review Article
Prostate cancer in transgender women D1X XMatthew D. Ingham, D2X XM.D.a,b, D3X XRichard J. Lee, D4X XM.D., Ph.D.c, D5X XDhara MacDermed, D6X XM.D.d, D7X XAria F. Olumi, D8X XM.D.e,* a Division of Urologic Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA c Division of Hematology/Oncology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA d Department of Radiation Oncology, Massachusetts General Hospital Cancer Center at Cooley Dickinson Hospital, Harvard Medical School, Northampton, MA e Division of Urologic Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA b
Received 18 April 2018; received in revised form 4 September 2018; accepted 12 September 2018
Abstract Introduction: As the transgender patient population continues to increase, urologists and other providers who treat genitourinary malignancies will increasingly encounter cases of prostate cancer in transgender women. Little exists in the current literature to help summarize the challenges and opportunities which face this unique patient population. Similarly, little exists to provide guidance on how we may best diagnose, manage, and follow transgender women diagnosed with prostate cancer. We sought to review the available literature in hopes of providing a resource for providers moving forward. Materials and Methods: We collaboratively reviewed the currently available literature, guidelines, and statements of best practice to compile a comprehensive review of this emerging and important topic. Results: Transgender persons face numerous systemic barriers to care with well documented increased risks of suicide and poor health outcomes. Though uncommon, the diagnosis of prostate cancer in transgender women is often associated with significant disease. While many options for management remain in line with standard guidelines, the unique aspects of care in this population—prior/current hormone usage, gender-affirming surgical procedures etc.—must be considered. Surgical, radiation, and hormonal treatments all play a potential role in appropriate treatment. Longitudinal studies are currently lacking and clinical trials are often structured with exclusive language which may lead to further marginalization of this patient population. Conclusion: Transgender persons will almost certainly continue to grow as a population encountered and treated by healthcare professionals. Better training and understanding are needed to ensure all healthcare needs are met as best possible. Prostate cancer represents an area in which great strides may be made to improve both diagnosis and treatment. Urologists, and others who manage urologic cancers, must take the lead to improve the care of transgender persons with genitourinary malignancies. Ó 2018 Published by Elsevier Inc.
Keywords: Transgender; Prostate cancer; Transsexual; Gender identity
1. Introduction As society at large begins to better recognize and understand gender dysphoria and the social and psychological issues surrounding transgender patients, we anticipate that This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. *Corresponding author. Tel. +617-667-4705. E-mail address: [email protected] (A.F. Olumi). https://doi.org/10.1016/j.urolonc.2018.09.011 1078-1439/Ó 2018 Published by Elsevier Inc.
more transgender individuals will feel comfortable in seeking urologic care. Urologists need to be better educated about social, behavioral, physiological, and anatomical issues that face transgender patients. Though estimation is difficult, attempts have been made to quantify the number of transgender persons currently in the United States. The Williams Institute at UCLA estimated 1.4 million persons (0.6% of US adults) identifying as transgender in 2016—a number double that of a prior estimate by the same institute
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in 2011 [1]. The distribution across all 50 states is relatively narrow, ranging from 0.3% in North Dakota to 0.8% in Hawaii [1]. These estimates align with a recent study that found an estimated 0.5% of all US adults identify as transgender [2]. Estimates for other countries around the globe have ranged as high as 1.2% [3]. We aim to review the issues surrounding transgender health and access to care along with the challenges surrounding the diagnosis and management of prostate cancer in transgender females as illustrated by a recent case managed at our institution. 2. Materials and methods We performed a collaborative review of the available literature on the topic of transgender health with a focus on the incidence, diagnosis, and management of prostate cancer in transgender females. A PUBMED search was carried out utilizing the following search terms: transgender, transgender health, transgender health disparity, transsexual, transsexual health, transsexual health disparity, trans hormone, trans surgery, transgender prostate, transgender prostate cancer, transsexual prostate, transsexual prostate cancer, prostate-specific antigen (PSA), PSA screening, and PSA screening trans. Titles and abstracts for all search results were scrutinized by the first author (MDI) and appropriate papers read in full. Papers containing relevant content were then utilized to formulate our collaborative review. Beyond PUBMED, current publications and guidelines from recognized regulatory and societal bodies were also collected to help inform our discussion on contemporary clinical management strategies. 3. Defining transgender Gender refers to a specific set of cultural and social norms that are expected from an individual. Traditionally speaking, this is a label assigned at birth that is based on sex—namely, the presence of phenotypically male or female anatomy. Gender identity, in contrast, refers to the internal perception one has of their own gender—be that male, female, or something outside of this binary distinction—irrespective of any anatomic features [4]. According to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, when one’s gender expression/experience is in conflict with their assigned gender, this is termed gender dysphoria [5]. Colloquially, transgender is the terminology most appropriately used to represent those in whom their assigned gender is incongruent with their gender identity/expression. One who is assigned a male gender at birth but has a female gender identity would be appropriately termed as a transgender female/woman and/or a maleto-female (MTF) transgender person. Conversely, those in whom their assigned gender corresponds to their gender identity/expression are termed cisgender.
4. Health disparities and challenges in the transgender population From a general healthcare perspective, the transgender population faces a number of challenges. At the foundation of this lies a pattern of stigma and discrimination encountered by transgender persons within many social determinants of health domains. Studies evaluating the incidence of discrimination in both housing and employment issues have shown significant discrimination against transgender populations [6]. This was most pronounced amongst MTF transgender persons [6]. The effect of this insult to some of the most foundational aspects of health is nicely laid out in the "stigma to sickness slope," as outlined in a recent United Nations Development Programme brief [7]. Namely, institutionalized stigma leads to discrimination and marginalization that, in turn, lead to risky situations/behavior that can result in poor health outcomes [7], evidenced by a nearly 49-fold increased odds of HIV infection in this patient population [8]. Higher rates of anxiety, depression, somatization, and suicide are more common in the MTF transgender population [9]. In a recent study of 6,450 transgender and gender nonconforming individuals, 41% of the respondents reported attempted suicide in the past—a figure 27 times higher than the general population [10]. With such striking challenges faced by transgender persons, one would hope that healthcare delivery systems and providers would serve as a refuge to mitigate the situation. Unfortunately, that is often not the case. A number of barriers to healthcare exist for transgender persons, ranging from financial issues like lack of insurance to systems/ logistic issues like electronic health records and clinic facilities incapable of appropriately accommodating transgender persons [9]. Primary among these, however, is simply lack of access to healthcare providers who are able to competently address the specific health issues faced by transgender persons [9,11]. In a study of transgender patients utilizing the Ontario healthcare system, researchers found that 33.2% of transgender persons reported at least 1 unmet healthcare need in the previous year—triple the 10.7% rate noted in an age-matched cisgender comparison group [12]. Similar to patients’ frustrations with barriers to access, providers also identify a number of issues that they feel prevent them from providing appropriate care to transgender patients. Chief among these were a lack of formal training in medical school/residency on how to manage transgender-specific health issues along with a lack of access to referral networks of appropriately trained physicians and specialists focusing on transgender health [13]. 5. Risks and considerations for long-term hormonal therapy A unique set of potential health concerns exist within the transgender population, namely the effects of gender-
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affirming hormone treatment. Most commonly considered are the impact on cardiovascular risk and malignancy (specifically, breast and prostate cancer in MTF transgender patients). There is a theoretical increased risk of natal organ malignancy in the transgender female because of exposure to exogenous estrogens. However, rates of breast cancer in transgender females align more with cisgender males than with cisgender females [14]. Considerations of natal organ malignancy further encompass prostate cancer, which is discussed in depth below. 6. Prostate cancer in the transgender population 6.1. Case presentation Ms. X is a 60-year-old transgender female who presented for a second opinion to our multidisciplinary genitourinary cancer clinic. Referral was prompted by an abnormal digital rectal exam by her primary care physician wherein a suspicious nodule was appreciated. Subsequent PSA testing revealed a value of 3.3 ng/ml. Ms. X reported a nearly 20-year history of intranasal GnRH agonist to facilitate her MTF transition. She had not undergone genderaffirmation surgery. Also of note, she had multiple urinary obstructive symptoms, including urgency and nocturia (American Urological Association urinary symptom score 18/35). She was seen by a local urologist for performance of a trans-rectal ultrasound-guided 12-core biopsy of the prostate. Pathology was notable for Gleason score 4+5 (grade group 5) adenocarcinoma of the prostate in 2 cores along with Gleason score 4+4 (grade group 4) adenocarcinoma of the prostate in 3 cores. Metastatic work-up with bone scan and CT scan was negative. At that time, Ms. X was interested in radiation therapy and was referred for multidisciplinary consultation by her radiation oncologist. This referral was prompted by a concern that standard radiation therapy may be less likely to succeed without a brachytherapy boost in a case of castration-resistant prostate cancer at initial time of diagnosis, since multicentered clinical studies have shown that combination of external beam radiotherapy with brachytherapy boost leads to superior outcomes in patients with aggressive prostate cancer as compared to those treated with single radiotherapy modalities [15]. We confirmed her exam findings of a suspicious nodule on the right aspect of the prostate consistent with a cT2b prostate cancer. The prostate gland was diffusely atrophied, otherwise. Formal hormone studies were notable for a repeat PSA of 2.3 ng/ml, total testosterone of 19 ng/dl (normal female range 8−60 ng/dl), estrogen of 35 pg/ml (normal premenopausal female range 17−200 pg/ml, postmenopausal female range 7−40 pg/ml), and estradiol of 72 pg/ml (normal premenopausal female range 15−350 pg/ml, postmenopausal female range < 10 pg/ml). A multiparametric MRI of the prostate with a 3 Tesla magnet was performed to better evaluate the prostate and the local
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extent of disease. A 1.2 cm Prostate Imaging—Reporting and Data System (PI-RADs) 5 lesion was noted in the right peripheral zone within a small prostate measuring 12.6 cc. There was also concern for possible extra-prostatic extension with invasion into the right neurovascular bundle. We classified this case as a high-risk, localized, castration-resistant prostate cancer at time of presentation. Our team offered her radical prostatectomy with pelvic lymph node dissection or external beam radiation therapy (likely without concomitant androgen deprivation therapy (ADT) given her castrate level of testosterone) as per accepted National Comprehensive Cancer Network treatment guidelines. Overall, we favored a surgical approach for a number of factors: (1) the unclear benefit of adding ADT (or second-line hormonal therapies) to her radiation, and (2) The inability to offer brachytherapy boost due to her very small gland size. Reviewing 4 previously reported cases, we found that transgender females treated with initial radiation to the prostate had unfavorable outcomes. One patient experienced PSA failure within a month after radiation therapy [18], one had inadequate follow-up to determine the outcome [21], one had a persistently elevated PSA for 2 years after radiation which progressed to a rapidly rising PSA and metastases [25], and the last had an initial PSA response but was then found to have symptomatic bony metastases at 18 months and died within 2 years of radiation treatment [16-19]. Ms. X underwent an uneventful, unilateral nerve-sparing robotic-assisted laparoscopic radical prostatectomy with pelvic node dissection. She had a brisk recovery and an undetectable PSA 3 months postoperatively. At 4 months of follow-up, her voiding symptoms had largely resolved and she only required 1 safety pad per day. Erectile function had yet to return. Final pathology confirmed pT2cN0M0 R0 Gleason score 4+5 (grade group 5) adenocarcinoma of the prostate. 6.2. Sexual function Regarding her sexual health, our patient informed us that she had useful erectile function at presentation. Ms. X lacked erections following surgery, for which she was offered a range of treatment options and further consultation. Sexual health is important to address in all sexually active individuals planning treatment of prostate cancer. Erectile function may be a component of sexual health in patients without gender affirming surgery, such as our patient. Urologists, radiation oncologists, and oncologists should be prepared to address this in a sensitive way by asking the transgender female patient if erectile function is important to her and informing the patient that erectile dysfunction is a significant risk of surgery, radiation therapy, and/or systemic therapy. The patient may provide important feedback as to whether this is an important factor in her medical decision making and whether erectile function should be addressed during follow-up visits.
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6.3. Incidence and role of hormones
have theorized that prostate cancer in transgender females— especially if lower-risk disease at presentation—may actually be driven by estrogenic as opposed to androgenic stimulation [24]. Sharif et al. reported tumoral immunohistochemistry results showing weak androgen receptor staining and strong estrogen receptor staining in their patient who presented with Gleason score 7 prostate cancer [24]. In fact, prostatespecific epigenetic factors have been described which shift the prostatic hormonal milieu away from an androgenic environment to one with increased estrogens (i.e., “androgenic to estrogenic switch”], which can affect prostate cells’ growth potential [28].
The diagnosis of prostate cancer in MTF transgender patients is quite rare, with only 10 cases reported in the literature to date [16−25]. Table 1 lists the published case reports. Gooren and Morgentaler reported the largest series to date, studying 2,306 MTF transgender patients treated at the Amsterdam Gender Clinic between 1975 and 2006 [26]. Of these patients, all of whom had received bilateral orchiectomy and supplemental estrogen and testosterone suppression therapy, only 1 was found to have prostate cancer, for an incidence rate of 0.04% [26]. A number of reasons may explain why so few cases of prostate cancer have been identified in this unique patient population. As already discussed, significant issues surrounding marginalization and access exist within this community and may play a role in this low incidence. Specifically, MTF transgender patients may not be getting screened appropriately and/or are lost to follow-up before reaching an age where prostate cancer would be more likely to manifest. Tabaac et al. recently reviewed PSA screening rates in the Behavioral Risk Factor Surveillance System—a telephone survey database administered by the Centers for Disease Control looking at health-related risk behaviors, chronic health conditions, and use of preventive services [27]. Interestingly, they found that while cisgender males were more likely to undergo PSA screening at some point in their lifetime, transgender females were actually more likely to have an up-to-date PSA screen [27]. A biologic theory for the low reported incidence may be related to the protection provided by the low-androgen (or castrate) hormonal milieu [26]. By providing, in essence, long-term ADT, any foci of prostate cancer that develop would be kept in a quiescent state for a long period of time. One may expect, then, that when prostate cancer does become clinically apparent it would have already become castration-resistant and would present with more aggressive disease (as was the case in our patient). Conversely, some
7. Diagnosis and management Prostate cancer screening, in all populations, is a topic of recent debate. Due to the low incidence of prostate cancer identified in the MTF transgender population, we have little evidence on which to base specific screening recommendations. Joint et al. recently published a systematic review of the literature hoping to assess the incidence of reproductive cancers in transgender persons, to include prostate cancer. Unsurprisingly, they conclude that the published literature is too sparse to confidently report a true incidence rate of prostate cancer in this population [29]. Currently, two bodies publish best practices for transgender health issues − the World Professional Association for Transgender Health and the Endocrine Society. Both groups recommend screening in line with the current recommendations for cisgender males [30,31]. A caveat to this paradigm, however, relates to the level at which a PSA result should be viewed with suspicion. As PSA levels in MTF transgender patients on gender-affirming hormone therapy would be suppressed, and based on the results from the Gooren study, a PSA level of 1 ng/ml should be used as an upper threshold of normal [32]. Treatment for prostate cancer in transgender females largely mirrors that of cisgender males. A few special considerations and points of uncertainty do, however, arise.
Table 1 Clinical presentation and management of all currently published case reports of prostate cancer in transgender females. Adapted from Gooren et al.26 Series
Age at diagnosis
PSA at diagnosis
Presenting symptom
Gleason score
Metastatic disease on presentation
Years on gender-affirming hormones
Treatment
Markland [22] 1975 Thurston [19] 1994 van Haarst [25] 1998 Miksad [17] 2006 Dorff [16] 2007 Molokwu [23] 2008 Turo [18] 2013 Ellent [21] 2016
54 64 63 60 78 60 75 65
− 27 > 100 240 177 − 13.5 19
− LUTS Weight loss, bone pain Hematuria Hematuria LUTS LUTS LUTS
− − − 8 9 − 7 9
− Yes Yes Yes Yes − Yes Yes
6 12 10 41 26 41 30 35
Sharif [24] 2017 Deebel [20] 2018 Current report
56 65 60
5 7.5 3.3
Abnormal DRE Elevated PSA Abnormal DRE
7 7 9
No No No
20 20 20
− Radiation ADT Radiation, hormones Radiation, chemotherapy ADT Radiation Orchiectomy, chemotherapy, prostatectomy Prostatectomy Prostatectomy Prostatectomy
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When considering prostatectomy for management of prostate cancer, the treating surgeon must be aware of any gender-affirming surgery and the anatomical implications it may have for performing a successful radical prostatectomy [33]. In gender-affirming surgery, penectomy is typically coupled with creation of a neovagina. Various techniques for neovagina construction exist, all of which result in a neovaginal canal that lies in a potential space developed between the prostate and the rectum. One such technique recently reported on by Papadopulos et al. is the combined vaginoplasty technique wherein a flap of urethral and scrotal tissue is used in combination with the inverted penile skin to facilitate improved vaginal depth and lubrication (Fig. 1) [34]. In this procedure, the preputial skin incisions are first marked out (Fig. 2A) followed by separation of the glans, inner prepuce, and neurovascular bundle from the penile skin (Fig. 2B) [34]. The glans and inner prepuce are sutured into position above the eventual neovaginal canal and are used to recreate the clitoris and clitoral hood (Fig. 2C) [34]. The neovagina is constructed of outer prepuce, penile and scrotal skin, and a spatulated flap of urethral tissue (Fig. 2D) which is then placed into a cavity bluntly developed between the rectum and prostate (Fig. 2E) [34]. Foam supports are placed into the neovagina at the conclusion of the case to help maintain the potential space (Fig. 2F) [34]. An excellent cosmetic result is noted 13 months postop (Fig. 2G) [34]. Prostate biopsy is not contraindicated post −gender-affirming surgery. Transneovaginal ultrasound probe placement allows for prostate visualization and biopsy in a manner quite similar to standard transrectal ultrasound and biopsy. While specific anatomical considerations need to be taken into account, radical prostatectomy after genderaffirming surgery is not contraindicated. Care must be taken during dissection to remain vigilant of the modified anatomy between the prostate, neovagina, and rectum. For those patients in whom gender-affirming surgery has not been undertaken, one must still be aware that the prostate is often exceptionally atrophic ( < 20 g) following years of genderaffirming hormone therapy. Therefore, since anatomical
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prostatic landmarks on very small prostate glands may be less clear, extra care and attention is necessary during radical prostatectomy. For patients considering radiation therapy, most standard therapies can be offered to transgender females. Certainly, in patients who have undergone gender-affirming surgery, the radiation plans must take into account the new anatomic relationships. Modern techniques should allow for appropriate contouring to avoid excessive radiation dose to the neovagina. Patients should be aware of the risk for neovaginal stenosis from any dose that is administered to this structure, with a possible need to increase neovaginal dilation frequency following treatment. When considering brachytherapy (as monotherapy or in a boost fashion) one must consider prostate gland size. As was seen in our patient, brachytherapy seed implantations into very small prostate glands from long-term gender-affirming hormone therapy may be technically challenging and potentially increase the toxicity to adjacent organs. In a retrospective review of cisgender patients with small prostates, those with prostates smaller than 25 cc were deemed to be more technically challenging and patients experienced more edematous reactions, and were less likely to achieve adequate dosimetry distribution to the whole prostate [35]. Our patient’s prostate volume (12.6 cc) was far below the minimum in that study. As noted below, the use of ADT to supplement radiation therapy likely would not confer the same additive benefits as found in cisgender males which may make radiation for higher-risk disease less comparable to surgery in this population. A 10-year follow-up of a randomized trial by the European Organization for Research and Treatment of Cancer (EORTC) showed a dramatic difference in prostate cancer specific mortality in high-risk prostate cancer patients treated with radiation alone (30.4%) compared with radiation and ADT (10.3%) [36]. For Gleason 9 and 10 adenocarcinoma, even in the setting of ADT, recent evidence suggests that external beam radiation would not achieve the same survival rate as surgery, in the absence of a brachytherapy boost [37,38].
Fig. 1. Combined vaginoplasty technique of gender-affirming surgery (left) as compared to the penile inversion technique (right). Brown/yellow—urethral flap; green—scrotal skin flap; blue—penile skin. Adapted from Papadopulos et al.34
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Fig. 2. A: Preputial skin incisions are marked out. B: Glans, inner prepuce, and neurovascular bundle (BB) are separated from the penile skin (BA). The spatulated urethral flap is also shown (BC). C: Glans and inner prepuce sutured into position to recreate the clitoris and clitoral hood, respectively. D: Creation of the neovagina using scrotal skin (DA), penile skin (DB) and a spatulated flap of urethra (DC). E: Neovagina placement into the cavity developed between prostate and rectum. F: Foam spacers are used to maintain the neovaginal cavity. G: 13 months postop with excellent cosmetic outcome noted. Adapted from Papadopulos et al.34
Use of ADT in conjunction with external beam radiation therapy for localized prostate cancer in transgender females on long-term gender-affirming hormone therapy remains debatable. Despite most reported cases presenting with high-risk and/or metastatic disease, wherein ADT would typically play a large role in cisgender males, transgender females may be less able to benefit from this therapy. With castrate levels of testosterone, transgender female prostate cancer patients often are diagnosed with castration-resistant disease at presentation. Though no data exists to clearly prove as much, use of second-line androgen receptor targeted therapies such as abiraterone or enzalutamide may be the most reasonable hormonal therapy to attempt. Use of abiraterone and ADT in combination with radiotherapy in high-risk localized disease is further supported by the recent STAMPEDE trial suggesting a benefit for this in cisgender males, although majority of cisgender patients are
typically castration-sensitive at the time of prostate cancer diagnosis [39].
8. Future considerations Greater understanding of the biology driving prostate cancer in the transgender female population is needed to better inform decisions on appropriate screening, diagnosis, and management. Longitudinal registry studies are needed to ensure we maximize our ability to extract information from the admittedly small number of cases available to us for study. Another issue of importance pertains to clinical trials in prostate cancer. Eligibility criteria often require that participants are “male”—such that transgender females would likely be excluded from participation. We must, as a medical community, consider more inclusive language
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during trial development to prevent further exclusion of an already marginalized population. 9. Conclusions Transgender persons will almost certainly continue to grow as a population treated by healthcare professionals. We must be sensitive to the specific needs of these patients and ensure that we do not add to the stigma or marginalization that they face. Better training and understanding are needed to ensure all healthcare needs are met as best possible. Though much is currently unknown, prostate cancer represents an area in which great strides may be made to improve both diagnosis and treatment. Urologists, and others who manage urologic cancers, must take the lead to improve the care of transgender persons with genitourinary malignancies. References [1] Flores AR, Herman JL, Gates GJ, Brown TNT. How many adults identify as trangender in the United States? The Williams Institute. 2016. [2] Crissman HP, Berger MB, Graham LF, Dalton VK. Transgender demographics: a household probability sample of US Adults, 2014. Am J Public Health 2017;107:213–5. [3] Winter S, Diamond M, Green J, Karasic D, Reed T, Whittle S, et al. Transgender people: health at the margins of society. Lancet N Am Ed 2016;388:390–400. [4] Schuster MA, Reisner SL, Onorato SE. Beyond bathrooms—meeting the health needs of transgender people. N Engl J Med 2016;375:101–3. [5] American Psychiatric A, American Psychiatric Association DSMTF. Diagnostic and statistical manual of mental disorders: DSM-5. 5th ed. Arlington, VA 2013. [6] Bradford J, Reisner SL, Honnold JA, Xavier J. Experiences of transgender-related discrimination and implications for health: results from the Virginia Transgender Health Initiative Study. Am J Public Health 2013;103:1820–9. [7] Winter S. Lost in transition: transgender people, rights and HIV vulnerability in the Asia-Pacific Region. UNDP; 2012. [8] Baral SD, Poteat T, Stromdahl S, Wirtz AL, Guadamuz TE, Beyrer C. Worldwide burden of HIV in transgender women: a systematic review and meta-analysis. Lancet Infect Dis 2013;13:214–22. [9] Safer JD, Coleman E, Feldman J, Garofalo R, Hembree W, Radix A, et al. Barriers to healthcare for transgender individuals. Curr Opin Endocrinol Diabetes Obesity 2016;23:168–71. [10] Grant JM, Mottet LA, Tanis J, Harrison J, Herman JL, Keisling M. Injustice at every turn: a report of the national transgender discrimination survey 2011. Washington, DC: National Center for Transgender Equality and National Gay and Lesbian Task Force. 2016. [11] Sanchez NF, Sanchez JP, Danoff A. Health care utilization, barriers to care, and hormone usage among male-to-female transgender persons in New York City. Am. J. Public Health 2009;99:713–9. [12] Giblon R, Bauer GR. Health care availability, quality, and unmet need: a comparison of transgender and cisgender residents of Ontario, Canada. BMC Health Services Research. 2017;17:283. [13] Snelgrove JW, Jasudavisius AM, Rowe BW, Head EM, Bauer GR. "Completely out-at-sea" with "two-gender medicine": a qualitative analysis of physician-side barriers to providing healthcare for transgender patients. BMC Health Services Res 2012;12:110.
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[35] Liu HW, Malkoske K, Sasaki D, Bews J, Demers A, Nugent Z, et al. The dosimetric quality of brachytherapy implants in patients with small prostate volume depends on the experience of the brachytherapy team. Brachytherapy 2010;9:202–7. [36] Bolla M, Van Tienhoven G, Warde P, Dubois JB, Mirimanoff RO, Storme G, et al. External irradiation with or without long-term androgen suppression for prostate cancer with high metastatic risk: 10-year results of an EORTC randomised study. Lancet Oncol 2010;11: 1066–73. [37] Ennis RD, Hu L, Ryemon SN, Lin J, Mazumdar M. Brachytherapybased radiotherapy and radical prostatectomy are associated with
similar survival in high-risk localized prostate cancer. J Clin Oncol: Off J Am Soc Clin Oncol 2018:Jco2017759134. [38] Kishan AU, Cook RR, Ciezki JP, Ross AE, Pomerantz MM, Nguyen PL, et al. Radical prostatectomy, external beam radiotherapy, or external beam radiotherapy with brachytherapy boost and disease progression and mortality in patients with gleason score 9-10 prostate cancer. JAMA 2018;319:896–905. [39] James ND, de Bono JS, Spears MR, Clarke NW, Mason MD, Dearnaley DP, et al. Abiraterone for prostate cancer not previously treated with hormone therapy. N Engl J Med 2017;377:338–51.
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Review Article
Prostate cancer in transgender women D1X XMatthew D. Ingham, D2X XM.D.a,b, D3X XRichard J. Lee, D4X XM.D., Ph.D.c, D5X XDhara MacDermed, D6X XM.D.d, D7X XAria F. Olumi, D8X XM.D.e,* a Division of Urologic Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA c Division of Hematology/Oncology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA d Department of Radiation Oncology, Massachusetts General Hospital Cancer Center at Cooley Dickinson Hospital, Harvard Medical School, Northampton, MA e Division of Urologic Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA b
Received 18 April 2018; received in revised form 4 September 2018; accepted 12 September 2018
Abstract Introduction: As the transgender patient population continues to increase, urologists and other providers who treat genitourinary malignancies will increasingly encounter cases of prostate cancer in transgender women. Little exists in the current literature to help summarize the challenges and opportunities which face this unique patient population. Similarly, little exists to provide guidance on how we may best diagnose, manage, and follow transgender women diagnosed with prostate cancer. We sought to review the available literature in hopes of providing a resource for providers moving forward. Materials and Methods: We collaboratively reviewed the currently available literature, guidelines, and statements of best practice to compile a comprehensive review of this emerging and important topic. Results: Transgender persons face numerous systemic barriers to care with well documented increased risks of suicide and poor health outcomes. Though uncommon, the diagnosis of prostate cancer in transgender women is often associated with significant disease. While many options for management remain in line with standard guidelines, the unique aspects of care in this population—prior/current hormone usage, gender-affirming surgical procedures etc.—must be considered. Surgical, radiation, and hormonal treatments all play a potential role in appropriate treatment. Longitudinal studies are currently lacking and clinical trials are often structured with exclusive language which may lead to further marginalization of this patient population. Conclusion: Transgender persons will almost certainly continue to grow as a population encountered and treated by healthcare professionals. Better training and understanding are needed to ensure all healthcare needs are met as best possible. Prostate cancer represents an area in which great strides may be made to improve both diagnosis and treatment. Urologists, and others who manage urologic cancers, must take the lead to improve the care of transgender persons with genitourinary malignancies. Ó 2018 Published by Elsevier Inc.
Keywords: Transgender; Prostate cancer; Transsexual; Gender identity
1. Introduction As society at large begins to better recognize and understand gender dysphoria and the social and psychological issues surrounding transgender patients, we anticipate that This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. *Corresponding author. Tel. +617-667-4705. E-mail address: [email protected] (A.F. Olumi). https://doi.org/10.1016/j.urolonc.2018.09.011 1078-1439/Ó 2018 Published by Elsevier Inc.
more transgender individuals will feel comfortable in seeking urologic care. Urologists need to be better educated about social, behavioral, physiological, and anatomical issues that face transgender patients. Though estimation is difficult, attempts have been made to quantify the number of transgender persons currently in the United States. The Williams Institute at UCLA estimated 1.4 million persons (0.6% of US adults) identifying as transgender in 2016—a number double that of a prior estimate by the same institute
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in 2011 [1]. The distribution across all 50 states is relatively narrow, ranging from 0.3% in North Dakota to 0.8% in Hawaii [1]. These estimates align with a recent study that found an estimated 0.5% of all US adults identify as transgender [2]. Estimates for other countries around the globe have ranged as high as 1.2% [3]. We aim to review the issues surrounding transgender health and access to care along with the challenges surrounding the diagnosis and management of prostate cancer in transgender females as illustrated by a recent case managed at our institution. 2. Materials and methods We performed a collaborative review of the available literature on the topic of transgender health with a focus on the incidence, diagnosis, and management of prostate cancer in transgender females. A PUBMED search was carried out utilizing the following search terms: transgender, transgender health, transgender health disparity, transsexual, transsexual health, transsexual health disparity, trans hormone, trans surgery, transgender prostate, transgender prostate cancer, transsexual prostate, transsexual prostate cancer, prostate-specific antigen (PSA), PSA screening, and PSA screening trans. Titles and abstracts for all search results were scrutinized by the first author (MDI) and appropriate papers read in full. Papers containing relevant content were then utilized to formulate our collaborative review. Beyond PUBMED, current publications and guidelines from recognized regulatory and societal bodies were also collected to help inform our discussion on contemporary clinical management strategies. 3. Defining transgender Gender refers to a specific set of cultural and social norms that are expected from an individual. Traditionally speaking, this is a label assigned at birth that is based on sex—namely, the presence of phenotypically male or female anatomy. Gender identity, in contrast, refers to the internal perception one has of their own gender—be that male, female, or something outside of this binary distinction—irrespective of any anatomic features [4]. According to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, when one’s gender expression/experience is in conflict with their assigned gender, this is termed gender dysphoria [5]. Colloquially, transgender is the terminology most appropriately used to represent those in whom their assigned gender is incongruent with their gender identity/expression. One who is assigned a male gender at birth but has a female gender identity would be appropriately termed as a transgender female/woman and/or a maleto-female (MTF) transgender person. Conversely, those in whom their assigned gender corresponds to their gender identity/expression are termed cisgender.
4. Health disparities and challenges in the transgender population From a general healthcare perspective, the transgender population faces a number of challenges. At the foundation of this lies a pattern of stigma and discrimination encountered by transgender persons within many social determinants of health domains. Studies evaluating the incidence of discrimination in both housing and employment issues have shown significant discrimination against transgender populations [6]. This was most pronounced amongst MTF transgender persons [6]. The effect of this insult to some of the most foundational aspects of health is nicely laid out in the "stigma to sickness slope," as outlined in a recent United Nations Development Programme brief [7]. Namely, institutionalized stigma leads to discrimination and marginalization that, in turn, lead to risky situations/behavior that can result in poor health outcomes [7], evidenced by a nearly 49-fold increased odds of HIV infection in this patient population [8]. Higher rates of anxiety, depression, somatization, and suicide are more common in the MTF transgender population [9]. In a recent study of 6,450 transgender and gender nonconforming individuals, 41% of the respondents reported attempted suicide in the past—a figure 27 times higher than the general population [10]. With such striking challenges faced by transgender persons, one would hope that healthcare delivery systems and providers would serve as a refuge to mitigate the situation. Unfortunately, that is often not the case. A number of barriers to healthcare exist for transgender persons, ranging from financial issues like lack of insurance to systems/ logistic issues like electronic health records and clinic facilities incapable of appropriately accommodating transgender persons [9]. Primary among these, however, is simply lack of access to healthcare providers who are able to competently address the specific health issues faced by transgender persons [9,11]. In a study of transgender patients utilizing the Ontario healthcare system, researchers found that 33.2% of transgender persons reported at least 1 unmet healthcare need in the previous year—triple the 10.7% rate noted in an age-matched cisgender comparison group [12]. Similar to patients’ frustrations with barriers to access, providers also identify a number of issues that they feel prevent them from providing appropriate care to transgender patients. Chief among these were a lack of formal training in medical school/residency on how to manage transgender-specific health issues along with a lack of access to referral networks of appropriately trained physicians and specialists focusing on transgender health [13]. 5. Risks and considerations for long-term hormonal therapy A unique set of potential health concerns exist within the transgender population, namely the effects of gender-
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affirming hormone treatment. Most commonly considered are the impact on cardiovascular risk and malignancy (specifically, breast and prostate cancer in MTF transgender patients). There is a theoretical increased risk of natal organ malignancy in the transgender female because of exposure to exogenous estrogens. However, rates of breast cancer in transgender females align more with cisgender males than with cisgender females [14]. Considerations of natal organ malignancy further encompass prostate cancer, which is discussed in depth below. 6. Prostate cancer in the transgender population 6.1. Case presentation Ms. X is a 60-year-old transgender female who presented for a second opinion to our multidisciplinary genitourinary cancer clinic. Referral was prompted by an abnormal digital rectal exam by her primary care physician wherein a suspicious nodule was appreciated. Subsequent PSA testing revealed a value of 3.3 ng/ml. Ms. X reported a nearly 20-year history of intranasal GnRH agonist to facilitate her MTF transition. She had not undergone genderaffirmation surgery. Also of note, she had multiple urinary obstructive symptoms, including urgency and nocturia (American Urological Association urinary symptom score 18/35). She was seen by a local urologist for performance of a trans-rectal ultrasound-guided 12-core biopsy of the prostate. Pathology was notable for Gleason score 4+5 (grade group 5) adenocarcinoma of the prostate in 2 cores along with Gleason score 4+4 (grade group 4) adenocarcinoma of the prostate in 3 cores. Metastatic work-up with bone scan and CT scan was negative. At that time, Ms. X was interested in radiation therapy and was referred for multidisciplinary consultation by her radiation oncologist. This referral was prompted by a concern that standard radiation therapy may be less likely to succeed without a brachytherapy boost in a case of castration-resistant prostate cancer at initial time of diagnosis, since multicentered clinical studies have shown that combination of external beam radiotherapy with brachytherapy boost leads to superior outcomes in patients with aggressive prostate cancer as compared to those treated with single radiotherapy modalities [15]. We confirmed her exam findings of a suspicious nodule on the right aspect of the prostate consistent with a cT2b prostate cancer. The prostate gland was diffusely atrophied, otherwise. Formal hormone studies were notable for a repeat PSA of 2.3 ng/ml, total testosterone of 19 ng/dl (normal female range 8−60 ng/dl), estrogen of 35 pg/ml (normal premenopausal female range 17−200 pg/ml, postmenopausal female range 7−40 pg/ml), and estradiol of 72 pg/ml (normal premenopausal female range 15−350 pg/ml, postmenopausal female range < 10 pg/ml). A multiparametric MRI of the prostate with a 3 Tesla magnet was performed to better evaluate the prostate and the local
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extent of disease. A 1.2 cm Prostate Imaging—Reporting and Data System (PI-RADs) 5 lesion was noted in the right peripheral zone within a small prostate measuring 12.6 cc. There was also concern for possible extra-prostatic extension with invasion into the right neurovascular bundle. We classified this case as a high-risk, localized, castration-resistant prostate cancer at time of presentation. Our team offered her radical prostatectomy with pelvic lymph node dissection or external beam radiation therapy (likely without concomitant androgen deprivation therapy (ADT) given her castrate level of testosterone) as per accepted National Comprehensive Cancer Network treatment guidelines. Overall, we favored a surgical approach for a number of factors: (1) the unclear benefit of adding ADT (or second-line hormonal therapies) to her radiation, and (2) The inability to offer brachytherapy boost due to her very small gland size. Reviewing 4 previously reported cases, we found that transgender females treated with initial radiation to the prostate had unfavorable outcomes. One patient experienced PSA failure within a month after radiation therapy [18], one had inadequate follow-up to determine the outcome [21], one had a persistently elevated PSA for 2 years after radiation which progressed to a rapidly rising PSA and metastases [25], and the last had an initial PSA response but was then found to have symptomatic bony metastases at 18 months and died within 2 years of radiation treatment [16-19]. Ms. X underwent an uneventful, unilateral nerve-sparing robotic-assisted laparoscopic radical prostatectomy with pelvic node dissection. She had a brisk recovery and an undetectable PSA 3 months postoperatively. At 4 months of follow-up, her voiding symptoms had largely resolved and she only required 1 safety pad per day. Erectile function had yet to return. Final pathology confirmed pT2cN0M0 R0 Gleason score 4+5 (grade group 5) adenocarcinoma of the prostate. 6.2. Sexual function Regarding her sexual health, our patient informed us that she had useful erectile function at presentation. Ms. X lacked erections following surgery, for which she was offered a range of treatment options and further consultation. Sexual health is important to address in all sexually active individuals planning treatment of prostate cancer. Erectile function may be a component of sexual health in patients without gender affirming surgery, such as our patient. Urologists, radiation oncologists, and oncologists should be prepared to address this in a sensitive way by asking the transgender female patient if erectile function is important to her and informing the patient that erectile dysfunction is a significant risk of surgery, radiation therapy, and/or systemic therapy. The patient may provide important feedback as to whether this is an important factor in her medical decision making and whether erectile function should be addressed during follow-up visits.
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6.3. Incidence and role of hormones
have theorized that prostate cancer in transgender females— especially if lower-risk disease at presentation—may actually be driven by estrogenic as opposed to androgenic stimulation [24]. Sharif et al. reported tumoral immunohistochemistry results showing weak androgen receptor staining and strong estrogen receptor staining in their patient who presented with Gleason score 7 prostate cancer [24]. In fact, prostatespecific epigenetic factors have been described which shift the prostatic hormonal milieu away from an androgenic environment to one with increased estrogens (i.e., “androgenic to estrogenic switch”], which can affect prostate cells’ growth potential [28].
The diagnosis of prostate cancer in MTF transgender patients is quite rare, with only 10 cases reported in the literature to date [16−25]. Table 1 lists the published case reports. Gooren and Morgentaler reported the largest series to date, studying 2,306 MTF transgender patients treated at the Amsterdam Gender Clinic between 1975 and 2006 [26]. Of these patients, all of whom had received bilateral orchiectomy and supplemental estrogen and testosterone suppression therapy, only 1 was found to have prostate cancer, for an incidence rate of 0.04% [26]. A number of reasons may explain why so few cases of prostate cancer have been identified in this unique patient population. As already discussed, significant issues surrounding marginalization and access exist within this community and may play a role in this low incidence. Specifically, MTF transgender patients may not be getting screened appropriately and/or are lost to follow-up before reaching an age where prostate cancer would be more likely to manifest. Tabaac et al. recently reviewed PSA screening rates in the Behavioral Risk Factor Surveillance System—a telephone survey database administered by the Centers for Disease Control looking at health-related risk behaviors, chronic health conditions, and use of preventive services [27]. Interestingly, they found that while cisgender males were more likely to undergo PSA screening at some point in their lifetime, transgender females were actually more likely to have an up-to-date PSA screen [27]. A biologic theory for the low reported incidence may be related to the protection provided by the low-androgen (or castrate) hormonal milieu [26]. By providing, in essence, long-term ADT, any foci of prostate cancer that develop would be kept in a quiescent state for a long period of time. One may expect, then, that when prostate cancer does become clinically apparent it would have already become castration-resistant and would present with more aggressive disease (as was the case in our patient). Conversely, some
7. Diagnosis and management Prostate cancer screening, in all populations, is a topic of recent debate. Due to the low incidence of prostate cancer identified in the MTF transgender population, we have little evidence on which to base specific screening recommendations. Joint et al. recently published a systematic review of the literature hoping to assess the incidence of reproductive cancers in transgender persons, to include prostate cancer. Unsurprisingly, they conclude that the published literature is too sparse to confidently report a true incidence rate of prostate cancer in this population [29]. Currently, two bodies publish best practices for transgender health issues − the World Professional Association for Transgender Health and the Endocrine Society. Both groups recommend screening in line with the current recommendations for cisgender males [30,31]. A caveat to this paradigm, however, relates to the level at which a PSA result should be viewed with suspicion. As PSA levels in MTF transgender patients on gender-affirming hormone therapy would be suppressed, and based on the results from the Gooren study, a PSA level of 1 ng/ml should be used as an upper threshold of normal [32]. Treatment for prostate cancer in transgender females largely mirrors that of cisgender males. A few special considerations and points of uncertainty do, however, arise.
Table 1 Clinical presentation and management of all currently published case reports of prostate cancer in transgender females. Adapted from Gooren et al.26 Series
Age at diagnosis
PSA at diagnosis
Presenting symptom
Gleason score
Metastatic disease on presentation
Years on gender-affirming hormones
Treatment
Markland [22] 1975 Thurston [19] 1994 van Haarst [25] 1998 Miksad [17] 2006 Dorff [16] 2007 Molokwu [23] 2008 Turo [18] 2013 Ellent [21] 2016
54 64 63 60 78 60 75 65
− 27 > 100 240 177 − 13.5 19
− LUTS Weight loss, bone pain Hematuria Hematuria LUTS LUTS LUTS
− − − 8 9 − 7 9
− Yes Yes Yes Yes − Yes Yes
6 12 10 41 26 41 30 35
Sharif [24] 2017 Deebel [20] 2018 Current report
56 65 60
5 7.5 3.3
Abnormal DRE Elevated PSA Abnormal DRE
7 7 9
No No No
20 20 20
− Radiation ADT Radiation, hormones Radiation, chemotherapy ADT Radiation Orchiectomy, chemotherapy, prostatectomy Prostatectomy Prostatectomy Prostatectomy
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When considering prostatectomy for management of prostate cancer, the treating surgeon must be aware of any gender-affirming surgery and the anatomical implications it may have for performing a successful radical prostatectomy [33]. In gender-affirming surgery, penectomy is typically coupled with creation of a neovagina. Various techniques for neovagina construction exist, all of which result in a neovaginal canal that lies in a potential space developed between the prostate and the rectum. One such technique recently reported on by Papadopulos et al. is the combined vaginoplasty technique wherein a flap of urethral and scrotal tissue is used in combination with the inverted penile skin to facilitate improved vaginal depth and lubrication (Fig. 1) [34]. In this procedure, the preputial skin incisions are first marked out (Fig. 2A) followed by separation of the glans, inner prepuce, and neurovascular bundle from the penile skin (Fig. 2B) [34]. The glans and inner prepuce are sutured into position above the eventual neovaginal canal and are used to recreate the clitoris and clitoral hood (Fig. 2C) [34]. The neovagina is constructed of outer prepuce, penile and scrotal skin, and a spatulated flap of urethral tissue (Fig. 2D) which is then placed into a cavity bluntly developed between the rectum and prostate (Fig. 2E) [34]. Foam supports are placed into the neovagina at the conclusion of the case to help maintain the potential space (Fig. 2F) [34]. An excellent cosmetic result is noted 13 months postop (Fig. 2G) [34]. Prostate biopsy is not contraindicated post −gender-affirming surgery. Transneovaginal ultrasound probe placement allows for prostate visualization and biopsy in a manner quite similar to standard transrectal ultrasound and biopsy. While specific anatomical considerations need to be taken into account, radical prostatectomy after genderaffirming surgery is not contraindicated. Care must be taken during dissection to remain vigilant of the modified anatomy between the prostate, neovagina, and rectum. For those patients in whom gender-affirming surgery has not been undertaken, one must still be aware that the prostate is often exceptionally atrophic ( < 20 g) following years of genderaffirming hormone therapy. Therefore, since anatomical
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prostatic landmarks on very small prostate glands may be less clear, extra care and attention is necessary during radical prostatectomy. For patients considering radiation therapy, most standard therapies can be offered to transgender females. Certainly, in patients who have undergone gender-affirming surgery, the radiation plans must take into account the new anatomic relationships. Modern techniques should allow for appropriate contouring to avoid excessive radiation dose to the neovagina. Patients should be aware of the risk for neovaginal stenosis from any dose that is administered to this structure, with a possible need to increase neovaginal dilation frequency following treatment. When considering brachytherapy (as monotherapy or in a boost fashion) one must consider prostate gland size. As was seen in our patient, brachytherapy seed implantations into very small prostate glands from long-term gender-affirming hormone therapy may be technically challenging and potentially increase the toxicity to adjacent organs. In a retrospective review of cisgender patients with small prostates, those with prostates smaller than 25 cc were deemed to be more technically challenging and patients experienced more edematous reactions, and were less likely to achieve adequate dosimetry distribution to the whole prostate [35]. Our patient’s prostate volume (12.6 cc) was far below the minimum in that study. As noted below, the use of ADT to supplement radiation therapy likely would not confer the same additive benefits as found in cisgender males which may make radiation for higher-risk disease less comparable to surgery in this population. A 10-year follow-up of a randomized trial by the European Organization for Research and Treatment of Cancer (EORTC) showed a dramatic difference in prostate cancer specific mortality in high-risk prostate cancer patients treated with radiation alone (30.4%) compared with radiation and ADT (10.3%) [36]. For Gleason 9 and 10 adenocarcinoma, even in the setting of ADT, recent evidence suggests that external beam radiation would not achieve the same survival rate as surgery, in the absence of a brachytherapy boost [37,38].
Fig. 1. Combined vaginoplasty technique of gender-affirming surgery (left) as compared to the penile inversion technique (right). Brown/yellow—urethral flap; green—scrotal skin flap; blue—penile skin. Adapted from Papadopulos et al.34
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Fig. 2. A: Preputial skin incisions are marked out. B: Glans, inner prepuce, and neurovascular bundle (BB) are separated from the penile skin (BA). The spatulated urethral flap is also shown (BC). C: Glans and inner prepuce sutured into position to recreate the clitoris and clitoral hood, respectively. D: Creation of the neovagina using scrotal skin (DA), penile skin (DB) and a spatulated flap of urethra (DC). E: Neovagina placement into the cavity developed between prostate and rectum. F: Foam spacers are used to maintain the neovaginal cavity. G: 13 months postop with excellent cosmetic outcome noted. Adapted from Papadopulos et al.34
Use of ADT in conjunction with external beam radiation therapy for localized prostate cancer in transgender females on long-term gender-affirming hormone therapy remains debatable. Despite most reported cases presenting with high-risk and/or metastatic disease, wherein ADT would typically play a large role in cisgender males, transgender females may be less able to benefit from this therapy. With castrate levels of testosterone, transgender female prostate cancer patients often are diagnosed with castration-resistant disease at presentation. Though no data exists to clearly prove as much, use of second-line androgen receptor targeted therapies such as abiraterone or enzalutamide may be the most reasonable hormonal therapy to attempt. Use of abiraterone and ADT in combination with radiotherapy in high-risk localized disease is further supported by the recent STAMPEDE trial suggesting a benefit for this in cisgender males, although majority of cisgender patients are
typically castration-sensitive at the time of prostate cancer diagnosis [39].
8. Future considerations Greater understanding of the biology driving prostate cancer in the transgender female population is needed to better inform decisions on appropriate screening, diagnosis, and management. Longitudinal registry studies are needed to ensure we maximize our ability to extract information from the admittedly small number of cases available to us for study. Another issue of importance pertains to clinical trials in prostate cancer. Eligibility criteria often require that participants are “male”—such that transgender females would likely be excluded from participation. We must, as a medical community, consider more inclusive language
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during trial development to prevent further exclusion of an already marginalized population. 9. Conclusions Transgender persons will almost certainly continue to grow as a population treated by healthcare professionals. We must be sensitive to the specific needs of these patients and ensure that we do not add to the stigma or marginalization that they face. Better training and understanding are needed to ensure all healthcare needs are met as best possible. Though much is currently unknown, prostate cancer represents an area in which great strides may be made to improve both diagnosis and treatment. Urologists, and others who manage urologic cancers, must take the lead to improve the care of transgender persons with genitourinary malignancies. References [1] Flores AR, Herman JL, Gates GJ, Brown TNT. How many adults identify as trangender in the United States? The Williams Institute. 2016. [2] Crissman HP, Berger MB, Graham LF, Dalton VK. Transgender demographics: a household probability sample of US Adults, 2014. Am J Public Health 2017;107:213–5. [3] Winter S, Diamond M, Green J, Karasic D, Reed T, Whittle S, et al. Transgender people: health at the margins of society. Lancet N Am Ed 2016;388:390–400. [4] Schuster MA, Reisner SL, Onorato SE. Beyond bathrooms—meeting the health needs of transgender people. N Engl J Med 2016;375:101–3. [5] American Psychiatric A, American Psychiatric Association DSMTF. Diagnostic and statistical manual of mental disorders: DSM-5. 5th ed. Arlington, VA 2013. [6] Bradford J, Reisner SL, Honnold JA, Xavier J. Experiences of transgender-related discrimination and implications for health: results from the Virginia Transgender Health Initiative Study. Am J Public Health 2013;103:1820–9. [7] Winter S. Lost in transition: transgender people, rights and HIV vulnerability in the Asia-Pacific Region. UNDP; 2012. [8] Baral SD, Poteat T, Stromdahl S, Wirtz AL, Guadamuz TE, Beyrer C. Worldwide burden of HIV in transgender women: a systematic review and meta-analysis. Lancet Infect Dis 2013;13:214–22. [9] Safer JD, Coleman E, Feldman J, Garofalo R, Hembree W, Radix A, et al. Barriers to healthcare for transgender individuals. Curr Opin Endocrinol Diabetes Obesity 2016;23:168–71. [10] Grant JM, Mottet LA, Tanis J, Harrison J, Herman JL, Keisling M. Injustice at every turn: a report of the national transgender discrimination survey 2011. Washington, DC: National Center for Transgender Equality and National Gay and Lesbian Task Force. 2016. [11] Sanchez NF, Sanchez JP, Danoff A. Health care utilization, barriers to care, and hormone usage among male-to-female transgender persons in New York City. Am. J. Public Health 2009;99:713–9. [12] Giblon R, Bauer GR. Health care availability, quality, and unmet need: a comparison of transgender and cisgender residents of Ontario, Canada. BMC Health Services Research. 2017;17:283. [13] Snelgrove JW, Jasudavisius AM, Rowe BW, Head EM, Bauer GR. "Completely out-at-sea" with "two-gender medicine": a qualitative analysis of physician-side barriers to providing healthcare for transgender patients. BMC Health Services Res 2012;12:110.
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