Assessing mortality risk and causes in extramammary Paget’s disease: insights from a population-based study

Introduction

Extramammary Paget’s disease (EMPD) is an uncommon cutaneous adenocarcinoma that primarily affects regions rich in apocrine sweat glands, such as the genital and perianal skin (1,2). It shares similar cell morphology and histology with mammary Paget’s disease (PD) of the nipple. The most common anatomic sites for EMPD are the vulva, penis, scrotum, and perianal region (3).

The treatment of EMPD primarily relies on surgical excision, which, while effective, often faces challenges such as high recurrence rates. Recent advancements in pharmacological treatments, particularly topical therapies and immunotherapy, offer promising alternatives for patients with recurrent or inoperable cases (4). In the future, the management of EMPD will place greater emphasis on personalized treatment strategies to enhance therapeutic outcomes and improve patients’ quality of life.

The causes of mortality in Merkel cell carcinoma (5), and other malignancies (6,7) have been comprehensively documented. Due to its rarity, previous studies have seldom examined the factors contributing to mortality in EMPD, particularly non-cancer related aspects. However, with extended survival times and a pursuit of higher quality of life, attention should be paid to deaths caused by non-cancer factors (7,8). Examining the actual factors leading to death in EMPD patients could aid in prioritizing mortality risks during survivorship. We evaluate current, population-based data to identify the causes of death in EMPD survivors. We present this article in accordance with the STROBE reporting checklist (available at https://tcr.amegroups.com/article/view/10.21037/tcr-24-1434/rc).

Methods

Patients and data source

This study adopted a retrospective, observational approach, utilizing data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) 18 registries, spanning the period from 2000 to 2019, which corresponds to roughly 34.6% of the total U.S. population. The SEER*Stat software, along with the associated datasets and detailed tutorials, is freely accessible to the public at the following website: https://seer.cancer.gov/seerstat/.

We enrolled patients diagnosed with EMPD as their initial malignant tumor from January 1, 2000, to December 31, 2019. Patients lacking follow-up duration, staging data, or with unknown vital status were excluded from the study. Additionally, we excluded cases diagnosed solely based on autopsy findings or a death certificate.

Exposures for stratification

We incorporated several variables into our analysis, including disease stage (localized or regional/distant), gender (male or female), age categories (<60, 60–69, or ≥70 years), racial demographics (White, Black, or other), year of diagnosis (2000–2007, or 2008–2015), treatment interventions such as surgery, radiation, and chemotherapy (yes or no), and the primary anatomical locations affected (vulva or labial, skin, penis or scrotum, vagina, or other sites).

Outcome assessments

The primary focus of interest was the overall survival following EMPD diagnosis. Cause of death codes in the SEER database were assigned according to the International Statistical Classification of Diseases and Related Health Problems 10th Edition, 1999 (ICD-10) (9).

Ethical statement

The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013).

Statistical analyses

We employed standardized mortality ratios (SMRs), calculated as the ratio of observed deaths to expected deaths. Expected mortality rates were determined based on age and sex-specific mortality rates within a standard population. The follow-up time commenced from the date of initial diagnosis until the occurrence of death, loss to follow-up (recorded as the date of the last visit), or December 2021, whichever eventuated first. Exact methods were utilized to estimate 95% confidence intervals (CIs) for the SMRs. All SMRs were calculated using SEER*Stat software version 8.3.9.2.

Results

Baseline characteristics

Out of the 1,002 EMPD patients, 437 individuals (43.61%) passed away during the study period. The median follow-up time was 92 months (Q1–Q3, 54–142 months). Female patients accounted for 64.87% (n=650), outnumbering male patients by 1.85 times (n=352, 35.13%). The majority of patients (83.53%, n=837) presented with localized disease, while 16.47% (n=165) had regional or distant disease. White patients comprised the largest ethnic group, constituting 79.34% of the total (n=795). Cancer-directed surgery was administered to the majority of patients (83.93%, n=841). Table 1 displays the fundamental characteristics of EMPD patients alongside the count of deaths observed at different follow-up intervals. Figure 1 illustrates the patient intake and discharge process.

Figure 1 Flow chart of participant selection. SEER, Surveillance Epidemiology and End Result.

Factors leading to death in patients with localized EMPD

Among the localized EMPD patient cohort, there were 24 (7.06%), 131 (38.53%), 126 (37.06%), and 59 (17.35%) deaths within <1, 1–<5, 5–<10, and ≥10 years, respectively. Notably, the majority of deaths among patients with localized disease occurred within the 1–<5 or 5–<10 years periods (see Table 1). In the localized EMPD patient subset, all malignant cancers constituted 29.71% (n=101) of all deaths, with this proportion decreasing as survival time extended (refer to Table 2). Cardiovascular and cerebrovascular diseases emerged as the predominant non-cancer causes of death, accounting for 29.71% of all cause deaths (n=101), and this proportion increased with prolonged survival time (see Table 2). For all causes of death, apart from the 5–<10 years interval, the SMR for EMPD patients closely paralleled that of the general population (SMR =0.74, 95% CI: 0.47–1.1 for <1 y; SMR =1.04, 95% CI: 0.87–1.24 for 1–<5 y; SMR =1.26, 95% CI: 1.05–1.50 for 5–<10 y; SMR =1.03, 95% CI: 0.79–1.33 for ≥10 y). Patients of different genders and ages have similar risks of all-cause death (Tables S1,S2).

Factors leading to death in patients with regional/distant EMPD

Among the 97 patients who passed away during their follow-up, 55 (56.70%) succumbed to all malignant tumors, while 42 (43.30%) perished due to non-cancer related causes (see Table 3). Notably, cardiovascular disease emerged as the primary non-cancer cause of death, accounting for 16 cases (16.5% of all deaths). Throughout the entire follow-up period, the overall mortality rate exceeded that of the general population (SMR, 1.91; 95% CI: 1.55–2.33) (refer to Table 3). The highest SMR was observed within the first year of diagnosis (SMR, 3.32; 95% CI: 2.00–5.18), with risk gradually diminishing over time (SMR =2.07 for 1–<5 years; SMR =1.57 for 5–<10 years; SMR =1.49 for ≥10 years). Interestingly, there was no notable discrepancy in all-cause mortality between patients surviving beyond 10 years and the standard population (SMR, 1.49; 95% CI: 0.87–2.38). Among patients who survived for more than five years, the mortality rate due to digestive system cancers was higher compared to the general population, while there was no significant difference for urinary and respiratory system cancers (SMR =6.78 for 5–<10 years; SMR =5.01 for ≥10 years).

Compared to patients aged 60–70 and above 70 years, patients under 60 years of age had a lower SMR of all-cause mortality (Tables S1,S2) (SMR =1.61; 95% CI: 0.44–4.12 for <60 years; SMR =2.11; 95% CI: 1.29–3.26 for 60–69 years; SMR =1.88; 95% CI: 1.47–2.36 for ≥70 years).

Discussion

EMPD, a rare form of skin cancer, has an estimated annual incidence ranging from 0.1 to 2.4 cases per million individuals (10,11). In this study, we compared SMRs between EMPD and standard population. This study provided important epidemiological information about EMPD patients, especially detailed analysis of the risk of patient death and causes of death. Through these findings, the long-term impact of EMPD and potential strategies for managing patients can be better understood. We stratified our results by patient characteristics and stage. The relationship between gender and EMPD exhibits variability across different studies and populations (12-14). In our study, the number of female patients was 1.85 times higher than that of male patients. This differs from the findings in Asian populations, which may be due to differences in the populations included (12).

In localized EMPD patient cohort, non-cancer causes of deaths were 2.37-fold more frequent (70.29% vs. 29.71%). In patients with stage regional/distant disease, 56.70% (n=55) of patients died from all malignant cancers. The extent of tumor infiltration and thickness are acknowledged as critical prognostic indicators for EMPD patients (12). Tumors limited to the epidermis typically suggest a more favorable prognosis, whereas deeper infiltration signifies a poorer prognosis due to heightened metastatic risks. Some investigations have shown notable prognostic disparities between cases where EMPD is confined to the papillary dermis and those infiltrating into the reticular dermis or deeper tissue layers. This is consistent with our research results.

The research conducted by van der Linden et al. concludes that patients with cutaneous noninvasive vulvar Paget’s disease (VPD) do not have an increased risk of developing breast, intestinal, or urological malignancies (15). In our research, we found that among patients with localized EMPD, the SMR for all causes of death did not significantly differ from that of the general population, except for a higher SMR observed in the 5–<10 years range. This further supports their findings. Van der Linden and colleagues still recommend conducting relevant tumor screenings for newly diagnosed EMPD patients, while routine screening for these associated malignancies during subsequent follow-ups may not be necessary.

The studies by van der Linden et al. (16) and Preti et al. (17) found that non-invasive and micro-invasive VPD, despite having a high recurrence rate, is associated with very low mortality. However, the prognosis for invasive VPD is significantly worse, which is consistent with our findings. Our results emphasize the importance of personalized follow-up strategies that take into account factors such as age and disease stage to improve long-term outcomes and quality of life.

As anticipated, the vast majority of our patients underwent cancer-direct surgery, deemed the standard treatment for EMPD patients, although it is constrained by high local recurrence rates in many cases (18,19). Recent advancements in surgical treatment have introduced preoperative biopsies and clock mapping to optimize excision margins and reduce recurrence rates (20,21). Additionally, the use of Mohs micrographic surgery has further enhanced the effectiveness and personalization of surgical treatment (22). Radiation therapy was utilized sparingly, primarily in cases of advanced-stage disease. This aligns with existing literature findings. When surgical intervention is either contraindicated or impractical, radiation therapy with curative intent may be considered. In cases of persistent or recurrent EMPD, post-operative adjuvant radiation therapy might be contemplated (23,24).

In recent years, imiquimod has shown considerable promise in treating non-invasive and even micro-invasive cases (25,26). Although our study primarily focused on mortality causes, it is noteworthy that imiquimod provides a non-surgical treatment option that may alleviate the overall burden on patients and enhance their quality of life. Future research should continue to explore the long-term survival effects of imiquimod in this patient population.

Naturally, our study comes with certain limitations. Firstly, being a retrospective analysis with a large dataset, there is an inherent risk of selection bias that cannot be completely avoided. To address potential bias, we applied rigorous screening criteria and employed SMR to account for variations in age, gender, and race, rather than solely relying on mortality rates relying solely on mortality rates to minimize potential confounding effects. Secondly, the SEER database does not provide comprehensive details regarding treatment approaches, concurrent medical conditions, recurrence-free survival data and information on metastatic organs. Thirdly, there is a possibility of misclassification of causes of death and rare histological types within the SEER database. Nonetheless, previous research has indicated that this variable is generally reliable (27). Lastly, the majority of our study population comprises individuals of Caucasian descent, thus the generalizability of our findings to other racial groups remains uncertain and warrants further investigation.

Conclusions

In conclusion, our study offers the most up-to-date and comprehensive analysis of mortality causes among EMPD patients. Non-cancer related fatalities represent over 70% of cases in localized stage and 40% in regional/distant stage. While cancer-specific mortality risk surpasses that of the general population, overall mortality risk for localized stage patients remains unchanged. Therefore, it is crucial to not only focus on anticancer treatments but also address other potential risk factors.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tcr.amegroups.com/article/view/10.21037/tcr-24-1434/rc

Peer Review File: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-24-1434/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-24-1434/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013).

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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