This medical record review assesses the prevalence and types of genital lesions observed in organ transplant recipients.
Key Points
Questions
What types of genital lesions are found in organ transplant recipients and at what frequency?
Findings
In this study of 496 organ transplant recipients, 111 of 120 recipients denied the presence of genital lesions but 53 of 120 were found to have genital lesions on physical examination. High rates of condyloma acuminata and cutaneous genital malignant tumors were found disproportionately in nonwhite organ transplant recipients, and high-risk human papillomavirus subtypes were associated with the development of genital squamous cell carcinoma in transplant recipients.
Meaning
Thorough inspection of genital skin should be part of routine posttransplant examination; nonwhite organ transplant recipients should undergo a targeted program of early detection, prevention, and awareness focused on the risk of genital skin cancer.
Abstract
Importance
Squamous cell carcinoma (SCC) is the most common skin cancer diagnosed in solid organ transplant recipients (OTRs) and confers significant mortality. The development of SCC in the genital region is elevated in nonwhite OTRs. Viral induction, specifically human papillomavirus (HPV), is hypothesized to play a role in the pathophysiology of these lesions.
Objective
To assess the prevalence and types of genital lesions observed in OTRs.
Design, Setting, and Participants
This retrospective review included 496 OTRs who underwent full skin examination from November 1, 2011, to April 28, 2017, at an academic referral center. The review was divided into 2 distinct periods before a change in clinical management that took effect on February 1, 2016 (era 1) and after that change (era 2). Patient awareness of genital lesions was assessed. All lesions clinically suggestive of malignant tumors were biopsied and underwent HPV polymerase chain reaction typing.
Main Outcomes and Measures
Number and types of genital lesions, proportion of malignant tumors positive for HPV, and patients cognizant of genital lesions.
Results
Of the total 496 OTRs, 376 OTRs were evaluated during era 1 (mean [SD] age, 60 years; age range, 32-94 years; 45 [65.2%] male; 164 [43.6%] white) and 120 OTRs were evaluated during era 2 of the study (mean age, 56 years; age range, 22-79 years; 76 [63.3%] male; 30 [25.0%] white). Overall, 111 of the 120 OTRs (92.5%) denied the presence of genital lesions during the history-taking portion of the medical examination. Genital lesions were found in 53 OTRs (44.2%), cutaneous malignant tumors (basal cell carcinoma and SCC in situ) in 6 (5.0%), genital SCC in situ in 3 (4.2%), and condyloma in 29 (24.2%). Eight of the 12 SCC in situ lesions (66.7%) were positive for high-risk HPV. Seven tested positive for HPV-16 and HPV-18, and 1 tested positive for high-risk HPV DNA but could not be further specified.
Conclusions and Relevance
Genital lesions in OTRs are common, but awareness is low. All OTRs should undergo thorough inspection of genital skin as a part of routine posttransplant skin examinations. Patients with darker skin types are disproportionately affected by cutaneous genital malignant tumors and should undergo a targeted program of early detection, prevention, and awareness focused on the risk of genital skin cancer after transplant. High-risk HPV subtypes are associated with genital SCC in OTRs. Additional studies are warranted to identify significant risk factors for HPV infection and to assess the utility of pretransplant HPV vaccination in the prevention of cutaneous genital malignant tumors.
Introduction
Squamous cell carcinoma (SCC) is the most common skin cancer diagnosed in solid organ transplant recipients (OTRs), and SCC-specific mortality is elevated among these patients. The development of SCC in the sun-protected areas of the genital region has been described in OTRs. Viral warts are common in OTRs, and human papillomavirus (HPV) has been hypothesized to play a role in the development of genital SCC. In addition, HPV infection is more frequently associated with tumors that develop in OTRs compared with immunocompetent individuals. The objectives of this study were to describe the prevalence of genital lesions in a diverse, single-center cohort of OTRs and characterize demographic and clinical factors associated with these lesions.
Methods
A retrospective medical record review of electronic medical records from the Drexel Dermatology Center for Transplant Patients was performed to identify documented genital lesions in patients from November 1, 2011, to April 28, 2017. The Drexel Dermatology Center for Transplant Patients is a multidisciplinary medical-surgical dermatology center to which the Drexel University and Hahnemann University Hospital transplant programs refer all OTRs, regardless of race, ethnicity, or skin type, for dermatologic evaluation. The Drexel Dermatology transplant dermatology program tailors patient care to individual patient needs and immunosuppressant regimens and offers all patients total-body skin cancer screening, including genital examination. Consent was waived by the Drexel University Institutional Review Board. All data were deidentified.
The review was divided into 2 distinct periods to evaluate the results of a change in clinical management that took effect on February 1, 2016. At that time, quality improvement measures were initiated to ensure the center’s skin cancer screening model used a standardized full genital examination and thorough history collection. We have labeled the period before this clinical change as era 1 and the period after this clinical change as era 2.
Era 1
The era 1 period was a 4.25-year retrospective review performed from November 1, 2011, to January 31, 2016. During this time, all patients underwent genital examinations. All lesions clinically suggestive of malignant tumors were biopsied, and all histopathologically diagnosed malignant tumors underwent HPV DNA polymerase chain reaction typing, which tested for low-risk HPV-6 and HPV-11 and high-risk HPV-16, HPV-18, HPV-31, and HPV-33.
Era 2
Era 2 was a 15-month period of increased surveillance performed by a single practitioner (C.L.C.) from February 1, 2016, to April 28, 2017. All patients received a standardized full genital examination, including thorough examination of the mons pubis, bilateral inguinal folds, and external genitalia, with deliberate inspection of the scrotum, penis, vulva, perineum, and perianal area. Anal Papanicolaou tests were not performed. Similar to era 1, multiple clinical factors were assessed, including the presence of genital lesions on physical examination, clinical diagnosis, and histopathologic analysis of biopsied lesions. In addition, during era 2, all suspicious lesions with abnormal clinical morphologic features were biopsied, and all histopathologically diagnosed malignant tumors, verruca vulgaris, and condyloma acuminatum underwent HPV DNA polymerase chain reaction typing. Finally, all OTRs were queried during the history-taking portion of the examination about the presence of genital lesions at the time of their medical visit. This information was collected at visits during which full skin examination was required (ie, visits for follow-up issues were not included) and compared with the results of clinical findings on physical examination. Nonparametric χ2 analysis was performed between male and female patients.
Results
Era 1
A total of 376 OTRs were evaluated during era 1 (mean [SD] age, 60 years; age range, 32-94 years; 45 [65.2%] male) (Table 1). Of the 376 OTRs, 164 (43.6%) were white, 27 (7.2%) Asian, 27 (7.2%) Hispanic, and 158 (42.0%) black.
Table 1. Demographics and Clinical Characteristics for Patients in Era 1a.
| Characteristic | Cohort (N = 376) | White (n = 164) | Asian (n = 27) | Hispanic (n = 27) | Black (n = 158) |
|---|---|---|---|---|---|
| Age, mean (range), y | 60 (32-94) | 59 (32-94) | 58 (38-85) | 63 (35-92) | 60 (34-94) |
| Sex | |||||
| Male | 245 (65.2) | 121 (73.8) | 15 (55.6) | 18 (66.7) | 91 (57.6) |
| Female | 131 (34.8) | 43 (26.2) | 12 (44.4) | 9 (33.3) | 67 (42.4) |
| Organ transplant type | |||||
| Kidneys | 267 (71.0) | 99 (60.4) | 21 (77.8) | 18 (66.7) | 129 (81.6) |
| Heart, lung, or heart and lung | 34 (9.0) | 22 (13.4) | 3 (11.1) | 1 (3.7) | 8 (5.1) |
| Liver | 45 (12.0) | 28 (17.1) | 3 (11.1) | 7 (25.9) | 7 (4.4) |
| Multiorganb | 30 (8.0) | 15 (9.1) | 0 | 1 (3.7) | 14 (8.9) |
| Time of immunosuppression, mean (SD), y | 9.0 (6.4) | 8.8 (6.8) | 8.5 (6.8) | 10.9 (8.1) | 7.8 (5.7) |
| Patients with SCC or SCCIS lesions | 50 (13.3) | 42 (25.6) | 2 (7.4) | 1 (3.7) | 3 (1.9) |
| Genital SCC or SCCIS/total SCC or SCCIS lesions | 5/231 (2.2) | 0/223 | 0/2 | 0/1 | 5/5 (100) |
Abbreviations: SCC, squamous cell carcinoma; SCCIS, squamous cell carcinoma in situ.
Data are expressed as number (percentage) of patients unless otherwise indicated.
Kidney combined with any of the following: pancreas, liver, lung, or heart.
Malignant Lesions
There were 5 cutaneous genital SCC in situ (SCCIS) lesions diagnosed in 3 black patients. No genital skin cancers were found in white, Asian, or Hispanic patients during this period. The overall rate of cutaneous genital malignant tumors in the era 1 cohort was 0.80%. Among the black OTR population, 3 (1.9%) were diagnosed with genital SCCIS during this period.
Condyloma Acuminata Lesions
In the era 1 cohort, 5 OTRs (1.2%) were diagnosed with condyloma acuminata. Four of these patients (80.0%) were male, and 3 (60.0%) were black. Four condyloma acuminatum lesions were biopsied in the 5 patients. The mean size of the biopsied lesions was 4.6 mm, with a range of 2 to 8 mm. Condyloma acuminata were observed throughout the genital region but were most commonly identified in inguinal folds (n = 2), penis (n = 2), and mons pubis (n = 1). One biopsied specimen was tested for HPV subtypes. This lesion was negative for low-risk HPV-6 and HPV-11 and high-risk HPV-16, HPV-18, HPV-31, and HPV-33 strains.
Era 2
A total of 120 OTRs were evaluated during era 2 of the study (mean age, 56 years; age range, 22-79 years; 76 male [63.3%]) (Table 2). Of the 120 OTRs in era 2, 30 were white (25.0%), 12 Asian (10.0%), 13 Hispanic (10.8%), and 65 black (54.2%). A total of 111 OTRs (92.5%) denied the presence of genital lesions during the history-taking portion of the medical examination. Fifty-three (44.2%) were found to have at least one genital lesion on physical examination (Figure).
Table 2. Demographics and Clinical Characteristics for Patients in Era 2a.
| Characteristic | Cohort (N = 120) | White (n = 30) | Asian (n = 12) | Hispanic (n = 13) | Black (n = 65) |
|---|---|---|---|---|---|
| Age, mean (range), y | 56 (22-79) | 56 (22-77) | 59 (38-74) | 50 (28-68) | 57 (24-79) |
| Sex | |||||
| Male | 76 (63.3) | 23 (76.7) | 8 (67) | 9 (69.2) | 37 (56.9) |
| Female | 44 (37) | 7 (23.3) | 4 (33) | 4 (30.8) | 29 (44.6) |
| Organ transplant type | 6/7 | ||||
| Kidney(s) | 98 (81.7) | 22 (73.3) | 9 (75) | 8 (61.5) | 59 (90.8) |
| Heart, lung, or heart and lung | 9 (7.5) | 5 (16.7) | 1 (8) | 0 | 3 (5) |
| Liver | 12 (10.0) | 3 (10.0) | 2 (17) | 5 (38.5) | 2 (3.1) |
| Multiorganb | 1 (0.8) | 0 | 0 | 0 | 1 (1.5) |
| Time of immunosuppression, mean, y | 6.2 (5.5) | 6.3 (6.2) | 6.0 (4.6) | 5.6 (5.5) | 5.6 (5.4) |
| Patients with SCC or SCCIS lesions | 18 (15.0) | 9 (30.0) | 3 (25) | 2 (15.4) | 4 (6.2) |
| Genital SCC or SCCIS/total SCC or SCCIS lesions | 7/37 (18.9) | 0/26 | 1/3 (33) | 1/2 (50.0) | 5/6 (83.3) |
Abbreviations: SCC, squamous cell carcinoma; SCCIS, squamous cell carcinoma in situ.
Data are expressed as number (percentage) of patients unless otherwise indicated.
Kidney combined with any of the following: pancreas, liver, lung, or heart.
Figure. Distribution of Genital Lesions During the 15-Month Increased Surveillance Period.
aSix additional patients had multiple genital lesions with at least 1 clinically diagnosed condyloma acuminatum; however, these patients were classified by their biopsied lesion.
bThree patients with condyloma acuminatum also had biopsy specimens with a different histologic lesion, including a basal cell carcinoma, a labial lentigo, and a seborrheic keratosis (1 condyloma acuminatum also demonstrated moderate dysplasia on the biopsy specimen).
Malignant Lesions
Seven genital SCCISs and 1 penile basal cell carcinoma (BCC) were diagnosed in 6 OTRs. Five genital SCCISs were diagnosed in 3 black OTRs and 1 lesion each in 1 Asian and 1 Hispanic OTR. The single BCC was found on the penile shaft of a black OTR. Similar to era 1, no cutaneous genital malignant tumors were diagnosed in white transplant recipients during this period. The mean lesional size was 5.7 mm, with a range of 3 to 10 mm. The penis (n = 2) and vulva (n = 2) were the most common locations, but lesions were seen throughout the genital region. Cutaneous genital malignant tumors were found in 6 patients (5.0%) and genital SCCISs in 5 (4.2%). When divided by race, genital skin cancer occurred in 4 black (6.2%), 1 Hispanic (7.7%), and 1 Asian (8.3%) OTRs. No perianal cutaneous malignant tumors were diagnosed in any cohort.
Condyloma Acuminata Lesions
In this cohort, 29 OTRs (24.2%) were diagnosed with condyloma acuminata. Of these patients, 24 (82.8%) were male and 23 (79.3%) were nonwhite. Fifty-three condyloma acuminatum lesions were biopsied in 24 patients. The mean size of the biopsied lesions was 4.5 mm, with a range of 1 to 15 mm. Condylomata were observed throughout the genital region but were most commonly identified in inguinal folds (n = 15), penis (n = 12), and scrotum (n = 11). Thirteen specimens (24.5%) tested positive for HPV. Ten lesions were positive for low-risk HPV-6 and HPV-11 and 3 were positive for high-risk HPV-16 and HPV-18 strains. One lesion demonstrated moderate dysplasia but tested negative for HPV. Five of 6 patients with genital malignant tumors (83.3%) developed their skin cancer on a background of condyloma acuminata.
Other Lesions
Five patients were diagnosed with seborrheic keratoses, 2 with intertrigo, 2 with verrucous vulgaris, 2 with pruritus scroti, 1 with eczematous dermatitis, 1 with lentigo, and 1 each with epidermolytic acanthoma, nevus, scabies, perianal dermatitis, fibroepithelial polyps, and inverse psoriasis.
Eras 1 and 2: HPV Testing for Genital Malignant Tumors
During the entire study period (November 1, 2011, to April 28, 2017), 8 patients were diagnosed with 12 SCCIS lesions and 1 patient with solitary BCC (Table 3). Eight of 12 SCCISs (66.7%) tested positive for high-risk HPV. Seven tested positive for HPV-16 and HPV-18, and 1 lesion was positive for high-risk HPV DNA but could not be further specified. Three patients were diagnosed with multiple lesions, and 2 of these patients had multiple SCCIS lesions that tested positive for high-risk HPV. The penile BCC tested negative for HPV DNA.
Table 3. HPV Typing in Genital Malignant Tumors in Eras 1 and 2.
| Patient No./Race/Sex | Fitzpatrick Skin Typea | Organ | Time From Transplant to Diagnosis, y | Location | HPV Typingb |
|---|---|---|---|---|---|
| 1/Black/M | V | Kidney | 8 | Ventral penile shaft | High-risk HPV |
| 8 | Coronal sulcus | Negative | |||
| 4 | Penile shaft | High-risk HPV-16 and HPV-18 | |||
| 2/Black/M | VI | Kidney | 13 | Penile shaft | High-risk HPV-16 and HPV-18 |
| 3/Black/M | VI | Heart and lung | 2 | L inguinal fold | Negative |
| 4/Black/F | VI | Kidney | 6 | R inguinal fold | High-risk HPV-16 and HPV-18 |
| 6 | R labia majora | High-risk HPV-16 and HPV-18 | |||
| 5/Black/M | VI | Kidney (3 times) | 20 | L scrotum | High-risk HPV-16 and HPV-18 |
| 6/Asian/F | IV | Kidney | 3 | R groin | High-risk HPV-16 and HPV-18 |
| 7/Hispanic/F | IV | Kidney | 1 | L labia majora | Negative, Bowenoid |
| 8/Black/M | V | Kidney | 12 | Penile shaft | High-risk HPV-16 and HPV-18 |
| 12 | Penile shaft | Negative | |||
| 9/Black/Mc | V | Kidney | 3 | Penile shaft | Negative |
Abbreviation: HPV, human papillomavirus.
Fitzpatrick skin type is a self-identified classification based on a patient's ability to burn with sun exposure. It is classified on a scale of I to IV, with I being the most likely to burn and IV the least.
Human papillomavirus typing tests whether HPV DNA is present in a lesion and identifies which viral subtype is present. High-risk HPV indicates HPV DNA present in lesion, but the specific subtype is not identified (may be 16, 18, 31, or 33); high-risk HPV-16 and HPV-18, HPV DNA present in the lesion, and the specific subtype is identified; negative, no HPV DNA present in the lesion; and bowenoid, no HPV DNA present in the lesion and lesion identified as a Bowenoid papulosis.
Marks the only patient with basal cell carcinoma. All other patients presented with squamous cell carcinoma in situ.
Era 2: Sex Differences
A total of 38 of 76 male OTRs (50.0%) had genital lesions. Only 15 of 44 female OTRs (34.1%) had genital lesions. Six of the 9 patients (66.7%) diagnosed with genital malignant tumors were male.
Discussion
To our knowledge, this study is unique in its focus on genital lesions in OTRs and the diagnostic rates of disease before and after implementation of a quality improvement initiative within a combined medical-surgical transplant dermatology center. Although the cohort is relatively small, our findings have significant implications in the prevention, screening, and management of cutaneous genital malignant tumors in the organ transplant population.
We diagnosed 5 cutaneous genital malignant tumors in 376 OTRs in era 1, with a prevalence of 0.80%, and 8 genital skin cancers (7 SCCISs, 1 BCC) in 120 OTRs in era 2, with a prevalence of 5.0%. Modifying our clinical practice to a standardized screening model increased our detection rate of genital malignant tumors 6.25-fold: from 3 patients of 376 patients during era 1 (rate of 0.8%) to 6 of 120 patients during era 2 (rate of 5.0%). Similarly, we observed a 21.86-fold increase in our detection rate of condyloma acuminata lesions: 5 of 376 in era 1 vs 29 of 120 in era 2.
We diagnosed 5 genital condyloma acuminatum lesions in era 1, with a prevalence of 1.2%, and 29 condyloma acuminatum lesions in era 2, with a prevalence of 24.2%. The demographics and clinical characteristics of patients in each era were otherwise comparable. This marked increase in detection rate suggests that the prevalence of genital cutaneous lesions in OTRs may be significantly higher than previously reported and indicates that thorough, standardized, routine genital examination is integral in the dermatologic management of this high-risk population.
Overall, genital lesions were common in the transplant population. A total of 44.2% of OTRs in the era 2 cohort had genital lesions on physical examination, and 37 (69.8%) of these patients required a biopsy. The most frequent histopathologic diagnosis we observed was condyloma acuminatum (24.2%) followed by malignant tumor (5.0%) and seborrheic keratosis (5.0%). High-risk HPV subtypes were found in association with condyloma acuminatum (5.7%) but to a greater degree with genital SCCIS (66.7%) (Table 3). In addition, 3 patients had multiple SCCIS lesions, and 83.3% of patients with malignant tumors developed lesions in a background of condylomata. Viral warts have been reported to affect 75% to 90% of patients 5 years after transplant, and HPV viruses have been detected in 90% of SCCs in a cohort of transplant recipients. Transplant increases the risk of SCC by inducing keratinocyte proliferation, and high-risk HPV-16, HPV-18, HPV-31, and HPV-33 are most often linked to genital SCC lesions.
In males, HPV has been associated with 22.4% of verrucous and 66.3% of basaloid or warty SCC, with HPV-16 and HPV-18 accounting for 65% of these malignant tumors, and occurs 35% more frequently in association with tumors that arise in OTRs. Among female kidney transplant recipients, 20% have a change in HPV status from negative before transplant to positive after transplant. Whether the increase in HPV after transplant is related to higher susceptibility, higher risk of persistent infection, or reactivation of latent HPV infection is unknown. Irrespective, the high rate of HPV, particularly in genital SCC lesions, in the cohort supports the need for investigation into the utility of pretransplant HPV vaccination and its effect on the development of posttransplant SCC.
We diagnosed 1 case of penile BCC in a black kidney transplant recipient. The presence of BCC in sun-protected areas is uncommon, with fewer than 25 cases of genital BCC being described in the literature and cases of genital BCC in the black population even less commonly described. Basal cell carcinomas that arise in sun-protected areas are associated with a prior history of nonmelanoma skin cancer, immunosuppression, radiation, or other predisposing factors. The patient’s lesion was discovered on a background of biopsy-proven condylomata, and, although posited, the association between HPV infection and genital BCC has not been clearly established. Laboratories in the United States routinely screen for only 4 of the many oncogenic HPV strains; thus, we cannot exclude the association of HPV infection in the development of the penile BCC or the genital SCCIS that did not demonstrate HPV DNA positivity.
There were several other notable findings in this study. First, a larger proportion of male OTRs (38 of 76 [50.0%]) when compared with female OTRs (15 [34.1%]) was found to have genital lesions. Second, of the 9 patients diagnosed with genital malignant tumors, 6 (66.7%) were male. The reasons for this sex discrepancy are unclear, but most female OTRs in this study reported undergoing routine gynecologic evaluation, whereas male OTRs did not have their genitalia examined on a regular basis by a physician or via self-examination; therefore, this difference may in part be related to sex differences in health care. This sex variance also suggests that dermatologists who follow up transplant recipients should not only closely inspect the genital skin of all such patients but also recognize their role as potentially the sole health care practitioner for the screening of male OTRs for the signs and symptoms of genital skin disease.
We also observed several racial disparities between white and nonwhite transplant recipients with respect to the burden of genital lesions. The nonwhite transplant cohort demonstrated higher rates of condyloma acuminatum than the white cohort, and all genital malignant tumors were diagnosed in nonwhite OTRs. Overall, cutaneous SCC (genital and nongenital) developed 14 times more frequently in the white transplant population; however, none were found in the genital region, even during the increased surveillance period. Furthermore, although all black, Asian, and Hispanic OTRs developed genital SCCIS at similar rates, genital lesions comprised 100% of all diagnosed cutaneous SCC lesions in black OTRs compared with 50.0% of all diagnosed SCC in Hispanic and Asian OTRs in era 2. It remains unclear whether nonwhite OTRs have higher rates of HPV-associated SCCIS because of a higher incidence of pretransplant HPV infection, which is intensified in the setting of immunosuppression, thereby leading to malignant tumors, or if nonwhite individuals are uniquely susceptible to oncogenic HPV strains, leading to accelerated posttransplant carcinogenesis.
Regardless, the potential effect of underdiagnosis on mortality from genital SCC should not be underestimated in the immunocompromised transplant population, particularly in black OTRs. Among immunocompetent patients, mortality rates of invasive penile SCC are significantly greater in the black population. Although white populations experience 1 death for every 5.18 lesions, the mortality rate in the black population has been reported to be 1.5 times higher, with 1 death for every 3.44 lesions. Lack of screening and poor patient education are thought to be important contributors to poor medical outcomes and have been implicated as significant factors in the increased mortality from genital SCC in the nonwhite population. Similarly, we found a strikingly low awareness of the presence of genital lesions by the entire OTR cohort but noted this deficit irrespective of race/ethnicity. A total of 92.5% of patients denied having lesions, but nearly half had at least one lesion in the genital area. Thus, screening transplant recipients by history alone is insufficient, and close inspection of the genitalia is critical.
The clinical morphologic features of the SCCISs diagnosed in the cohort varied from small, benign-appearing, verrucous papules to large, irregular, dyspigmented plaques. The penile BCC appeared as a hyperpigmented flat-topped papule, mimicking condyloma acuminatum. In addition, several lesions were found in sites that were difficult to visualize, such as the lateral scrotum and the genitalia close to the perineum. This variability in clinical presentation of nonmelanoma skin cancer in the genital area not only emphasizes the importance of thorough inspection of the genitalia but also indicates that practitioners should have a high index of suspicion for genital skin cancer in OTRs and perform biopsies on all concerning lesions. The median time to diagnosis of genital malignant tumors in the cohort was 6 years, which falls within the 3- to 8-year window that has been estimated as the mean time to development of skin cancer in OTRs. These data, coupled with the higher prevalence rate of 5.0% during the period of increased surveillance, suggest that consideration should be given to the inclusion of screening for genital malignant tumors in the development of skin cancer screening guidelines for the organ transplant population. Moreover, we suggest that genital malignant tumors may disproportionately affect nonwhite OTRs and that minority patients with darker skin types should not have screening delayed after transplant but rather undergo a targeted program of early detection, prevention, and awareness.
Because, to our knowledge, this is the first study to date to report increased rates of cutaneous genital malignant tumors in nonwhite OTRs, the implications of overdiagnosis on overall morbidity and mortality are not yet fully understood. The approach toward early-stage genital skin cancer may benefit from observations made from prostate cancer screening in the general population. Most men who are diagnosed with prostate cancer harbor low- to intermediate-risk disease, and in efforts to avoid overtreatment, active surveillance has become increasingly common. Recent investigations report that 40% of men diagnosed with low-risk disease eventually require definitive treatment after a median time of 63.4 months receiving active surveillance. In addition, analogous to prostate-specific antigen, cutaneous genital examination may serve to stratify transplant recipients at risk for developing invasive cutaneous carcinomas of the genital region and ensure they receive appropriate monitoring. Another alternative model is for posttransplant genital examination to be performed on lesion-specific, symptomatic, patient-directed concerns. However, consideration must be given to well-established evidence that, in the immunocompetent nonwhite population, skin cancer is diagnosed at more advanced stages and associated with overall worse outcomes. These disparities are attributed to issues of low patient and practitioner awareness and health care access by minority persons, with the former validated among the cohort of high-risk transplant recipients. Additional studies that evaluate long-term patient outcomes from genital carcinoma in situ are necessary to fully extrapolate the risks and benefits of early detection and treatment in the organ transplant population.
Limitations
Limitations of this study include its single-center design and small cohort size. We acknowledge the possibility of interpractitioner variability in genital examination during era 1, which could lead to a potential underdiagnosis of SCC. This was eliminated in era 2 of the study, resulting in increased diagnosis of SCC. In addition, our analysis of the association between HPV and SCC was limited by DNA testing for only 4 high-risk HPV subtypes of the numerous associated with malignant tumors.
Conclusions
Genital lesions are common in the transplant population and include high rates of condylomata and skin cancer. Nonwhite OTRs, in particular black OTRs, are disproportionately affected. High-risk HPV subtypes are closely associated with genital SCC in transplant recipients. Patient awareness of the presence of genital lesions is alarmingly low. Querying OTRs regarding the presence or absence of genital lesions should not be used as a proxy for genital examination. All OTRs should undergo thorough inspection of genital skin as a part of routine posttransplant total-body skin examinations. Transplant recipients with darker skin types, particularly nonwhite males, should not have their dermatologic screening delayed after transplant. We suggest that a targeted program of early detection, prevention, and awareness focused on the risk for genital skin cancer is warranted.
References
- 1.Garrett GL, Lowenstein SE, Singer JP, He SY, Arron ST. Trends of skin cancer mortality after transplantation in the United States: 1987 to 2013. J Am Acad Dermatol. 2016;75(1):106-112. [DOI] [PubMed] [Google Scholar]
- 2.Chung CL, Nadhan KS, Shaver CM, et al. Comparison of posttransplant dermatologic diseases by race. JAMA Dermatol. 2017;153(6):552-558. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Pritchett EN, Doyle A, Shaver CM, et al. Nonmelanoma skin cancer in nonwhite organ transplant recipients. JAMA Dermatol. 2016;152(12):1348-1353. [DOI] [PubMed] [Google Scholar]
- 4.Arron ST, Jennings L, Nindl I, et al. ; Viral Working Group of the International Transplant Skin Cancer Collaborative (ITSCC) & Skin Care in Organ Transplant Patients, Europe (SCOPE) . Viral oncogenesis and its role in nonmelanoma skin cancer. Br J Dermatol. 2011;164(6):1201-1213. [DOI] [PubMed] [Google Scholar]
- 5.Cervical Cancer Rates by Race and Ethnicity. Centers for Disease Control and Prevention website. https://www.cdc.gov/cancer/cervical/statistics/race.htm. Updated June 16, 2016. Retrieved March 5, 2017.
- 6.Harwood CA, Proby CM. Human papillomaviruses and non-melanoma skin cancer. Curr Opin Infect Dis. 2002;15(2):101-114. [DOI] [PubMed] [Google Scholar]
- 7.Connolly K, Manders P, Earls P, Epstein RJ. Papillomavirus-associated squamous skin cancers following transplant immunosuppression: one Notch closer to control. Cancer Treat Rev. 2014;40(2):205-214. [DOI] [PubMed] [Google Scholar]
- 8.de Jong-Tieben LM, Berkhout RJ, ter Schegget J, et al. The prevalence of human papillomavirus DNA in benign keratotic skin lesions of renal transplant recipients with and without a history of skin cancer is equally high: a clinical study to assess risk factors for keratotic skin lesions and skin cancer. Transplantation. 2000;69(1):44-49. [PubMed] [Google Scholar]
- 9.Stratton KL, Culkin DJ. A contemporary review of HPV and penile cancer. Oncology (Williston Park). 2016;30(3):245-249. [PubMed] [Google Scholar]
- 10.Bleeker MC, Heideman DA, Snijders PJ, Horenblas S, Dillner J, Meijer CJ. Penile cancer: epidemiology, pathogenesis and prevention. World J Urol. 2009;27(2):141-150. [DOI] [PubMed] [Google Scholar]
- 11.Hinten F, Hilbrands LB, Meeuwis KAP, et al. Reactivation of latent HPV infections after renal transplantation. Am J Transplant. 2017;17(6):1563-1573. [DOI] [PubMed] [Google Scholar]
- 12.Greenbaum SS, Krull EA, Simmons EB. Basal cell carcinoma at the base of the penis in a black patient. J Am Acad Dermatol. 1989;20(2, pt 2):317-319. [DOI] [PubMed] [Google Scholar]
- 13.Roewe RJ, Uhlman MA, Bockholt NA, Gupta A. Basal cell carcinoma of the penis: a case report and review of the literature. Case Rep Urol. 2014;2014:173076. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Hernandez BY, Barnholtz-Sloan J, German RR, et al. Burden of invasive squamous cell carcinoma of the penis in the United States, 1998-2003. Cancer. 2008;113(10)(suppl):2883-2891. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Whalen MJ, Pak JS, Lascano D, et al. Oncologic outcomes of definitive treatments for low- and intermediate-risk prostate cancer after a period of active surveillance [published online October 16, 2017]. Clin Genitourin Cancer. 2017;S1558-7673(17)30313-0. doi: 10.1016/j.clgc.2017.10.007 [DOI] [PubMed] [Google Scholar]
- 16.Battie C, Gohara M, Verschoore M, Roberts W. Skin cancer in skin of color: an update on current facts, trends, and misconceptions. J Drugs Dermatol. 2013;12(2):194-198. [PubMed] [Google Scholar]
