Introduction

Extramammary Paget’s disease (EMPD) is a rare intraepithelial neoplasm that typically presents in the sixth to eighth decades of life with a female predominance in the United States (US).1, 2, 3 Primary EMPD is characterized by a cutaneous adenocarcinoma, which often arises in regions rich in apocrine sweat glands, particularly the perineum, vulva, penis, scrotum, and surrounding truncal skin.1, 4, 5 These cutaneous lesions are often banal-appearing, resembling eczematous dermatoses or fungal infections, and typically raise suspicion when found to be unresponsive to topical steroids or antifungal creams.6, 7 Importantly, EMPD is often asymptomatic and slow-growing but can present with nonspecific symptoms of pruritus, pain, and burning in the afflicted regions.7 Owing to the rarity of EMPD and its clinical appearance, patients almost invariably experience delays in diagnosis, which can range from the order of months to years.8, 9 In addition, palpable inguinal lymph nodes at presentation are often a sign of regionally advanced disease, with pathologic confirmation in up to 80% at the time of surgery.10

Skin biopsy and dermatopathology are critical for the diagnosis and prognosis of EMPD.3 The characteristic histologic findings in EMPD include atypical epithelioid cells with round, pale vacuolated cytoplasm on H&E staining within the epithelium termed Paget cells.8 Although no formal histopathological staging criteria currently exist for EMPD, tumor thickness, dermal and lymphatic invasion, and regional and distant lymph nodal involvement have been proposed as possible staging criteria.11, 12 Furthermore, dermal invasion and lymphovascular invasion are predictive of node-positive disease and cancer-specific mortality.10, 11, 12, 13, 14

Nonsurgical management options for localized EMPD include topical treatment (i.e. 5-FU, imiquimod), photodynamic therapy, and laser ablation, while systemic (paclitaxel, trastuzumab) or radiation therapies are options for both localized to advanced EMPD.15, 16, 17 Wide local excision (WLE) remains standard of care for the surgical management of EMPD. Given the limited data for this rare disease, optimal margins of excision are poorly defined, with a recognition that the goal of clear microscopic margins is critical. Secondary to asymmetric spread of these tumors, mapping with punch biopsy can help ensure negative surgical margins.18, 19 Mohs micrographic surgery may be an option for individuals with smaller lesions, while patients with invasive disease and other negative prognostic pathologic markers may require more extensive resection and reconstruction with lymph node dissection.20, 21 Limited data exists for the surgical management of EMPD with nodal involvement, although, one study reports a 5-fold increase in mortality with two or more positive lymph nodes.20 Updated clinical guidelines published in 2022 recommended against the routine use of sentinel lymph node biopsy for detection, however, in the absence of randomized clinical trials, insufficient evidence exists for the role of these therapies in both surgical and non-surgical candidates.3

The Surveillance, Epidemiology, and End Results (SEER) program includes one of the largest cohorts of patients with EMPD in the US. Published analyses of the database have provided results on the impact of primary skin location, demographic factors, oncologic stage, and treatment options on survival outcomes for men and women with EMPD.2, 22, 23 Given the rarity of these cancers, and the scarcity of current guidelines for treatment recommendations, further investigation is required to understand the updated epidemiology of EMPD, the contemporary utilization of treatment modalities, and their impact on all-cause mortality. We sought to use more contemporary and expansive SEER data to examine EMPD incidence, patient characteristics, treatment utilization, and survival outcomes across sexes and other subgroup populations in the US from 2004 through 2020.

Methods

Patient Selection & Characteristics

Information was extracted on male and female EMPD patients reported to the 22 SEER registries (including Illinois and Massachusetts) from 2004 to 2020.24 Available data was deidentified and this study was deemed exempt by the institutional review board. EMPD diagnoses were found according to the International Classification of Diseases for Oncology (ICD-O) code 8542/3. Eligible cases were categorized by region of interest based on primary labeled site coding (Supplemental Table 1). Non-anogenital skin sites included external ear, lips, torso, upper limbs, trunk, lower limbs, and overlapping sites not otherwise specified. In addition, information on age at diagnosis, sex, race, ethnicity, tumor stage, cancer-related treatments, and survival was obtained. Although the SEER 22 registries (including Illinois and Massachusetts) contain data from 2000 to 2020, only cases diagnosed in and after 2004 applied the Combined Summary Stage variable. This classified cases as localized (no evidence of nearby or distant spread), regional (spread only to nearby nodes or tissues), distant (spread beyond local nodes or tissues), or unknown/unstaged (insufficient information). Age was reported as a categorical variable in 3 tiers: <65 years old, 65-74 years old, and ≥75 years old. Treatment information, including surgery, radiation, and systemic therapy was determined according to multiple site-specific coding variables. Categories of treatment were then reported as listed: no cancer-directed treatment; surgery only; surgery with radiation and/or systemic therapy; and radiation and/or systemic therapy without surgery. Type of surgical treatment was further defined. Patients with available treatment data were additionally dichotomized by time to treatment: <3 months or ≥3 months.

Incidence Trend Calculation

Information on EMPD incidence rates was obtained from the 22 SEER registries (including Illinois and Massachusetts) to examine trends in incidence from 2000 to 2020. Rates were reported by cases per 100,000 with 95% confidence intervals (CI) and age-adjusted to the 2000 United States Standard Population (19 age groups - Census P25-1130).25 Incidence rates were reported among the entire population and according to sex, race, EMPD site, and EMPD stage. Changes in incidence rates over time were reported as an annual percentage change (APC) with 95% CI, which was calculated using the weighted least squares method. P-values were reported with p<0.05 indicating the APC to be significantly different from 0. The APC statistic could not be calculated for subgroups with too few cases. Incidence rates for EMPD stage were reported from 2004 to 2020, however, the 2000-2020 APC statistic could not be calculated since the Combined Summary Stage variable was not available for cases from 2000-2003.

Survival Analyses

Survival information was obtained from the 22 SEER registries from 2004-2020, excluding Illinois and Massachusetts and other cases with unavailable survival data. Kaplan-Meier overall survival (OS) curves were constructed for all patients with EMPD according to sex, race, site, stage, treatment type, and time to treatment. One-, Five-, and Ten-year survival estimates (SE) were calculated accompanied by log-rank tests for comparisons among subgroups. Patients classified as White, Black, or Asian/PI were included while the remaining were excluded given low case size (American Indian/Alaska Native [n=3]; Unknown [n=48]). In addition, the Other Genitourinary (n=13) site category and Unknown/Unstaged (n=304) classification were excluded from their respective comparisons. univariable and multivariable Cox regression models were constructed to examine factors associated with OS, including sex, race, age (categorical), EMPD site, EMPD stage, treatment type, and time to treatment (categorical). Results were reported as hazard ratios (HR) with corresponding 95% CIs. American Indian/Alaska Native race, Unknown race, Other Genitourinary site, missing time to treatment, and Unknown/Unstaged cases were excluded from the final analysis. All variables in the multivariable model were tested for proportional hazard assumptions, and all models were tested for the presence of interactions between each covariate. All statistical analyses were performed using SEER*Stat software v.8.4.3 (National Cancer Institute, Bethesda, MD) and Stata v15.1 (StataCorp, College Station, TX).

Results

Patient & Disease-related Characteristics

In the SEER 22 registries, 3608 patients diagnosed with EMPD from 2004 through 2020 were identified: 2429 (67.3%) female and 1179 (32.7%) male. Table 1 summarizes the patient and disease-related characteristics of the cohort. Approximately 46% of patients in the entire cohort were aged 75 years or older, with a greater proportion of female versus male patients <65 years old when diagnosed with EMPD (25.0% vs. 17.7%). With regard to race, the cohort majority was white (82.7%), followed by Asian/PI (13.9%) and Black (1.4%). A larger percentage of Asian/PI patients were male, relative to female (19.4% vs. 11.2%). Visualized in Fig. 1, the vulva (82.3%) was the most common anatomical site for EMPD among female patients, followed by non-anogenital skin (12.8%) and perianal or rectum (3.8%). A more even distribution among anatomic sites is observed among men with EMPD sites, with the greatest proportion of cases located in general non-anogenital skin sites (49.5%), followed by penis and scrotum (45.5%), and perianal or rectum (4.7%).

Disease stage at diagnosis was relatively similar between male and female patients, with localized disease representing 71.5% of the total cohort, followed by regional (9.2%) and distant disease (1.9%). When excluding patients with insufficient data needed for staging purposes, the new disease staging proportions in the total cohort are as follows: 86.4% localized, 11.3% regional, and 2.3% distant. Up to 23.8% of the total cohort did not receive any cancer-directed treatment, while 65.7% received surgery alone, 2.0% radiation and/or systemic therapy, and 6.9% with a combination of surgery plus radiation and/or systemic therapy. According to site-specific coding, local excision/destruction was the most common modality utilized in 44% of surgical cases. There was a discrepancy in surgical modality between sexes: partial or radical surgery was categorized in 20.3% of male EMPD cases versus 61.8% of female cases. Of patients with documented treatment, 32.4% of the total cohort did not receive any therapies until 3 or more months after diagnosis. The median time from diagnosis to treatment was 4 months (min-max: 3-20) for the group that experienced delayed treatment.

EMPD Incidence Trends: 2000 to 2020

Table 2 summarizes the age-adjusted incidence rates (per 100,000 persons per year) and APCs according to the total and subgroup populations of patients with EMPD. Among the total population, from 2000-2020, the calculated incidence rate was 0.23 with an APC of +1.22% (p<0.01). Stratified by male patients, the rate was 0.17 with an APC of +1.27 (p=0.02), compared to 0.27 with an APC of +1.23% (p<0.01) in female patients. Incidence was highest among Asian/PI patients with a rate of 0.44, although this has remained stable over time. However, the incidence has significantly risen among female Asian/PI patients with a rate of 0.41 and APC of +1.33% (p=0.04). Furthermore, the incidence among White patients has risen significantly across both male and female patients with rates of 0.16 (APC +1.95%; p<0.01) and 0.28 (APC +0.98%; p=0.01), respectively. In male patients, the incidence of EMPD in non-anogenital skin sites is greatest with a rate of 0.09 and an APC of +2.02% (p=0.01). There has been no change in the rate of EMPD affecting the penis and scrotum or the perianal and rectal regions in males. In female patients, the incidence of EMPD affecting the vulva is highest at 0.22 with an APC of +1.12% (p<0.01).

Overall Survival from 2004 to 2020

The total cohort in the survival analyses included 1934 patients with available data from 22 SEER registries (excluding Illinois and Massachusetts) from 2004 through 2020. Table 3 summarizes the 1-, 5-, and 10-year survival estimates according to sex along with the log-rank p-values per subgroup comparison. Fig. 1 demonstrates the Kaplan-Meier OS curves according to sex and EMPD stage. Male EMPD patients had notably worse survival estimates than female patients at both the 5-year (73.8% vs. 81.3%) and 10-year (53.4% vs. 63.0%) periods (p<0.001). In Fig. 2, there was a consistent difference between sexes according to disease stage as well. Supplementary Table 2 lists the survival estimates according to race, EMPD site, EMPD stage, treatment time, and time to treatment, which is further visualized in Supplemental Figure 1. OS across White, Black, and Asian/PI race groups was not significantly different. The 5-year survival estimates according to EMPD stage are as follows: 82.3% localized; 67.6% regional; and 20.3% distant (p<0.001). Patients treated with surgery alone demonstrated the greatest 5- (82.3%) and 10-year (62.3%) OS rates compared to patients forgoing cancer-directed treatment (5-year SE: 68.1%; 10-year SE: 49.7%; p<0.001). Per disease site, vulvar EMPD demonstrated the highest 5- (81.9%) and 10-year (63.2%) OS rates, followed by penis & scrotum (5-year SE: 79.1%; 10-year SE: 58.6%), and then perianal/rectum (5-year SE: 71.9%; 10-year SE: 54.4%) and non-anogenital skin (5-year SE: 72.4%; 10-year SE: 53.7%; p<0.001). When stratified by sex (Fig. 3), there was no significant difference in site-specific survival rates among female patients (p=0.759), however, among male patients, OS was greatest for EMPD of the penis and scrotum and lowest when found in the perianal and rectal region (Table 3; p<0.001).

Table 4 reports the results of the univariable and multivariable Cox proportional hazards regression models assessing predictors of all-cause mortality. On univariable analysis, male sex (HR 1.43; p<0.001), old age (65-74: HR 2.10, p<0.001; 75+: HR 5.78, p<0.001), advanced stage (regional: HR 1.62, p<0.001; distant: HR 9.43, p<0.001), and delayed treatment (HR 1.53; p<0.001) were associated with worsened OS, while vulvar EMPD (HR 0.70; p<0.001) and surgical treatment alone (HR 0.51; p<0.001) were associated with improved OS. On multivariable analysis, male sex and vulvar EMPD were no longer associated with a significant impact on OS. However, old age (65-74: HR 2.35, p<0.001; 75+: HR 5.92, p<0.001) and advanced stage (regional: HR 1.80, p<0.001; distant: HR 12.45, p<0.001) remained significantly associated with worsened survival. Furthermore, EMPD of the penis/scrotum was associated with a 29% decline in mortality (HR 0.71; p=0.033), while surgery alone was associated with a 27% decline (HR 0.73; p=0.043). In addition, the combination of surgery plus radiation and/or systemic therapy (HR 1.59; p=0.039) along with delay in treatment (HR 1.29; p=0.047) worsened OS.

Survival in Localized EMPD

Supplementary Figure 2 demonstrates the Kaplan-Meier survival estimates in patients with localized EMPD according to race, age, treatment type, and time to treatment. Supplementary Table 3 further reports the percent survival at 1-, 5-, and 10-years. Per site, localized vulvar disease demonstrated the highest 5- (86.0%) and 10-year (65.7%) OS rates, followed by penis & scrotum (5-year SE: 83.5%; 10-year SE: 62.0%), and then perianal/rectum (5-year SE: 74.8%; 10-year SE: 61.0%) and non-anogenital skin (5-year SE: 74.1%; 10-year SE: 55.1%; p<0.001). Patients treated with surgery alone demonstrated the greatest 5- (85.1%) and 10-year (65.8%) OS rates compared to patients forgoing cancer-directed treatment (5-year SE: 68.1%; 10-year SE: 45.2%; p<0.001). A delay in treatment also resulted in worse 5- and 10-year survival rates among patients with localized disease. Supplemental Table 4 reports the results of the univariable and multivariable Cox proportional hazards regression models assessing predictors of survival in patients with localized disease. From multivariable analysis, older age (75+ years: HR 5.45; p<0.001) and 3+ month delay to treatment (HR 1.34; p=0.041) were the only factors associated with increased risk of all-cause mortality.

Discussion

This study examined patient and disease-related characteristics, incidence trends, and survival rates of male and female EMPD cases from 2004-2020 as reported by 22 registries in the SEER program. This analysis of registry-collected patients with EMPD contextualizes the impact of sex, site, stage, and treatment on survival outcomes. The updated 10-year SE for the entire study population was 59.7%, in comparison to 60.2% as previously reported from 1973-2009.22 Notably, these results demonstrate that although over 80% of patients present with localized disease, delays in treatment are associated with significantly worse overall survival and may represent an important barrier to adequate care for a rare cancer.

In addition, it is important to highlight the stage-specific survival rates in comparison to recent studies. Localized disease represented 86.5% of this more contemporary cohort, in contrast to the 73% included by Herrel et al. from SEER registries reported from 1973-2009.(Herrel et al. 2015) This may reflect improvement in diagnosis at earlier stages, however, OS was not different between studies as listed above. The largest and most recent study to report on cancer-specific survival is from Hatta et al. who analyzed outcomes in primary EMPD patients from 2015-2019 at 19 different Japanese centers.(Hatta et al. 2024) Of the 643 EMPD patients treated, 86.0% would be classified as localized, 10.3% regional, and 3.7% distant spread, which closely aligns with our reported distribution for the US.(Hatta et al. 2024) Furthermore, 5-year cancer-specific survival rates were found to be 65.7-98.7% for localized, 49.5-68.4% for regional, and 16.1% for distant disease, which remain in line with our findings.

Modern EMPD Treatment Practices

The percentage of patients with EMPD who forgo any cancer-directed treatment has declined in this analysis compared to historical series. Herrel et al. showed that 40% of male patients did not receive any treatment for EMPD from 1973 through 2009, whereas that proportion declined to one-quarter from 2004 to 2020.22 An increase can be seen in patients receiving localized surgical treatment with rates increasing by up to 15%. There is now an improved understanding of the prognostic impact of tumor depth of invasion on survival, which may explain the increased role of surgical evaluation and treatment.12, 13, 14, 26, 27 In addition, surgical treatment alone was associated with a 27% decreased risk of mortality when referred to no cancer-directed therapy, which supports the survival benefit of complete, early resection.

In multiple series, complete resection is associated with prolonged OS and may delay time to recurrence or metastasis.9, 28, 29, 30 In an early analysis of patients with perianal EMPD, Marchesa et al. showed that a wide local excision (>1 cm margin), with repeat resection for recurrence, improved 8-year actuarial survival (40% vs. 0% [excision with <1 cm margin]).28 In addition, in a retrospective review from 1971 to 1998, the extent of resection (local vs. hemivulvectomy) was not related to time of recurrence, however, 56% of patients had documented microscopically positive margins, which were significantly correlated with recurrence rates.29 Furthermore, it should be noted that 94% of patients had gross complete resection of disease according to the primary surgeon, which indicates intraoperative difficulty in accurately assessing complete disease excision.29 In a comprehensive review from Leong & Chung, 11 series that were included reported on the positive surgical margin and recurrence rates of wide local excision across EMPD patients.30 Among patients with negative margins on pathology, the composite rate of recurrence was 15%, whereas it rose to 48% in patients with positive margins.30 In total, margin positivity rate is 33.7% across all EMPD cases, which although represents a decline, indicates the difficulty in achieving early, local control.30

Preoperative mapping biopsies when planning resection can also help lower the risk of positive margins. In a single-site retrospective study from Hatta et al., 66 patients underwent curative surgical excision with mapping biopsy performed in 68%.26 All patients had grossly negative margins, and only 5 (8%) developed local recurrence.26 Although mapping biopsy was not correlated with the rate of recurrence, both the positive margin and recurrence rate were notably lower than prior reports, which may indicate the importance of such a technique. Furthermore, Jung et al. provided their experience with wide local excision in 19 male patients with EMPD, of which 12 underwent preoperative mapping biopsy.19 Although the positive margin rate was 50%, none of the 12 patients developed recurrence, however mapping biopsy was not correlated with resection margin or local recurrence.19 Preoperative mapping biopsy appears to carry the greatest benefit among patients with ill-defined EMPD borders or when planning extensive resection with grafting and reconstruction where healthy tissue needs to be optimized.18

One factor that may serve as a barrier to complete surgical control is delay in treatment. Importantly, our study demonstrated that among patients with documented cancer-directed treatment, 32% experienced a delay of 3 or more months from the time of diagnosis. This factor was associated with a 29% increase in the risk of all-cause mortality across all patients and a 34% increase in risk for localized EMPD patients on subgroup analysis. It should be noted that since there is no substratification of localized disease we cannot distinguish between higher volume or more complex local lesions versus smaller volume less complex disease. The former may require referral to a tertiary center thus contributing to a delay in treatment, whereas smaller volume, less complex disease could be excised in the community, which may explain the survival difference observed. Given the rarity and insidious clinical presentation of EMPD, there is often a delay in diagnosis, which can contribute to more advanced disease staging.8, 9, 31 However, in a report of 25 scrotal EMPD cases, time from symptom onset to diagnosis was not associated with an increased rate of dermal invasion.32 Although EMPD may often take months to years to ultimately diagnose, availability of treatment centers with prior experience may additionally explain this barrier.15 Delayed or lengthy referral processes given the relative paucity of centers with specialists experienced in the treatment of EMPD may contribute to this delay observed in one-third of patients. These findings highlight the need for improved awareness of EMPD across specialties, research into improved (and possibly molecular) diagnostic tools, along with the need for early referral and complete treatment.

Sex-Specific Differences in EMPD

Female patients displayed a much higher prevalence of anogenital EMPD (86.1%) with the vast majority arising from the vulvar region. This is consistent with prior reported rates (>80%) of genital EMPD, whereas, male patients are often split between penoscrotal versus non-anogenital skin locations.2, 3 Male patients displayed poorer SE across all stages when compared with female patients, however, sex was not predictive of all-cause mortality on multivariable regression. This is in contrast to Yao et al., who showed male sex was associated with a 42% increased risk of all-cause mortality using SEER data from 1973-2013, with the only difference being adjustment for delayed time to treatment.2

An explanation for the sex-specific difference in survival may also be attributed to the surgical treatments offered. In an extensive review of all English-language studies conducted in the US from 1946-2018, Rastogi et al. examined all the initial surgical treatments performed for anogenital EMPD according to sex (302 female vs. 77 male).33 Men were far more likely to be offered Mohs micrographic surgery (40.3% vs 1.9%), despite having a significantly greater extent of disease (21.1% vs. 1.7%) than women, which could have been an important contraindication to such a procedure.33 The current study further supports this finding provided the discrepancy in partial and radical surgical treatment between male and female sexes. Although the SEER appendix lacks specificity to describe exact surgical procedures, there is a 40% absolute difference in partial/radical surgery performed across sexes, which strongly suggests female patients are treated with more extensive resections.

An additional observation was how the anatomic site did not affect survival estimates among female patients. This is in contrast to male patients, where perianal or rectal EMPD has long been reported as a poor prognostic factor.2, 3, 22 This could be explained by the lower prevalence of perianal or rectal EMPD among female patients, which may have underpowered the analysis, however, it should be noted that 10-year survival for vulvar EMPD was 2.2% lower.

Is EMPD Incidence on the Rise?

This study additionally demonstrated an APC increase of 1.22%. Since 1973, disease incidence has risen, reaching a peak APC of 3.2%.22 From 2000-2020, although EMPD remains rare with an overall age-adjusted incidence of 2.3 per 1,000,000 persons, this represents a 1.4- to 6-fold increase when compared to prior SEER-based reports.22, 34 This likely reflects improved awareness of the clinical presentation of EMPD, along with increased referrals to specialized cancer centers for management, thus inclusion in SEER registry collection. In addition, incidence is less than two-fold between Asian to white patients, whereas it was previously reported to be 4-times higher.22 This may indicate improved identification along with understanding that EMPD does not have such a strong Asian population predominance as previously thought.

From a global perspective, both European and Chinese population claims-based studies have shown approximately equivalent incidence rates as those calculated in US SEER-based studies.35, 36 However, European countries demonstrated a 1:1 ratio of male versus female cases, whereas Asian countries have shown a male predisposition.4, 27, 35, 36, 37 The current study’s reported incidence of EMPD by sex is a 1.6:1 ratio between female to male patients, which is shifting from the female predisposition.2, 23, 38 It is unclear what is driving this change, with one theory being improved understanding of sex-specific differences as reported by international studies. The true incidence and prevalence of EMPD are widely debated, however, as the SEER program continues to expand registries from which data is collected, this will provide greater insight into the actual number of annual cases in addition to common predisposing patient factors.

Limitations

Histopathologic confirmation and review are unavailable, however, standards have improved over the past 20 years. In addition, prognostic pathologic features, including depth of invasion, maximum tumor or patch width, and surgical margin rate cannot be readily obtained from the SEER database. The 22 registries reporting to SEER from 2000 to 2020 now include information on radiation and systemic therapy, which adds further context to the overall utilization and influence on survival outcomes. However, information on the exact type of medical and radiation therapies is lacking.

Conclusions

The present study is the largest and most contemporary SEER-based study to evaluate patient and disease characteristics, trends in incidence, and survival outcomes among patients diagnosed with EMPD from 2004 through 2020. Diagnoses and surgical treatment have risen, however, one-third experience treatment delays, negatively impacting survival. Early, complete excision remains standard of care with diagnostic and treatment delays representing important barriers.

Ethics Statement

None

Funding

Nothing to declare

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Declaration of Competing Interests

No conflicts of interest

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