Recurrence of Quadruple Extramammary Paget’s Disease after 12 Years: A Case Report and Literature Review

Introduction

Extramammary Paget’s disease (EMPD) is a rare skin cancer that typically develops in the genital, perianal, axillary, and umbilical regions. It is often multicentric and occurs at multiple sites in up to 5% of all cases [1]. Quadruple EMPD is a four-site EMPD whose frequency has not been thoroughly investigated, and is infrequently described in the literature. Here, we report a case of heterochronous quadruple EMPD and review the clinical features of seven reported cases of quadruple EMPD, including ours. The CARE Checklist has been completed by the authors for this case report, attached as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000538675).

Case Report

An 69-year-old man with a history of kidney failure was admitted to our hospital. Two years prior to admission, an erythematous lesion appeared on his genitals; he was diagnosed with EMPD via skin biopsy. Computed tomography (CT) did not reveal any signs of lymph node or visceral metastases. After the mapping biopsy, total excision and split-thickness skin grafting were performed, and the margins were negative (shown in Fig. 1). Six years later, the patient underwent total prostatectomy for prostate cancer. He completed follow-up for 9 years after the total resection. Twelve years after total resection, an erythematous lesion appeared on the resection margin in the lower abdomen (shown in Fig. 2a), and the serum carcinoembryonic antigen (CEA) was 0.9 ng/mL (cut-off <5.0 ng/mL). Similar lesions were observed in the umbilical fossa, the scar in the umbilical region, and both axillae (shown in Fig. 2b–d). Histological examination revealed that all lesions were EMPD and in situ. Immunohistochemically, the tumour cells were positive for CEA, gross cystic disease fluid protein −15, cytokeratin (CK) 7, and periodic acid-Schiff staining and negative for CK20, which was the same result as that of total excision performed 12 years ago (shown in Fig. 3). No other lesions were detected on CT.

Discussion

Quadruple EMPD is an extremely rare skin cancer, and only six cases have been previously reported. Here, quadruple EMPD did not include Paget’s disease of the breast but presented as discontinuous lesions occurring simultaneously that were heterochronous at four sites. Given that EMPD spreads laterally and discontinuously, it is difficult to determine whether it is multicentric in origin. In this study, we counted lesions from the anal, perineal, and genital areas as single lesions because they were anatomically adjacent. We reviewed six cases of quadruple EMPD, including our case, with respect to race, sex, age, site, recurrence, time to recurrence, and depth (Table 1) [2‒6].

All 6 patients were elderly Japanese males. This observation is unsurprising as EMPD is more frequent in Japanese males, with a 2:1 male-to-female ratio, whereas it is more common in females in Caucasian populations [7]. A study of 20 cases of multiple EMPD reported that it was more common in Asian men, but quadruple EMPD was found only in elderly Japanese male patients [8].

In all cases, the lesions were located in the apocrine region, which is a common site of EMPD in the genital and axillary areas. Tsutsui et al. [9] reported a rare case of EMPD in which 13 lesions were completely unrelated to the apocrine region, and were also observed in the breast. The latter case led to the recognition of the possibility of EMPD originating in eccrine glands or pluripotent germinative cells rather than apocrine glands. We did not include this case in our review because of the different site and origin. There were only two cases of recurrence. In case 4, recurrence occurred in the glands 16 months after total resection, found on the penis near the initial tumour [5]. Our patient had solitary genital EMPD at the initial diagnosis, but 139 months later when the patient was aged 81 years, in situ recurrences occurred in the resection margins in the lower abdomen. Although this is the only known case of heterochronous quadruple EMPD, we cannot rule out the possibility that the patient was not adequately examined or that occult EMPD already existed at the first visit [10]. Shaco-Levy et al. [11] reported that the time to recurrence in 18 cases of recurrent vulvar EMPD ranged from 13 to 131 months. Considering this time range, our patient had a fairly late recurrence.

Serum CEA levels have been reported to be elevated in metastatic EMPD, but not in EMPD in situ [12]. In this review, the CEA level was elevated in only 1 patient, who had a large mass measuring 17 cm [5]. The fact that CEA is usually not elevated in quadruple EMPD supports the idea that it arises multicentrally rather than skin metastases from any one lesion. In all cases, lesions were limited to the epidermis. In particular, Iijima et al. [5] reported a large mass measuring 17 cm, and pathological examination showed a thickening of the epidermis to 6 mm while the basement membrane was preserved in periodic acid-Schiff staining. Therefore, quadruple EMPD is less likely to cause metastasis and is presumed to have a favourable prognosis. These characteristics of quadruple EMPD have also been reported for multiple EMPD [13].

Imiquimod is a topical agent that has shown efficacy against intraepidermal malignancies and verrucae by activating local immunity via toll-like receptor 7 [14]. Thus, the therapeutic effects of imiquimod can be expected in EMPD in situ. The main treatment for EMPD is wide excision; however, quadruple EMPD requires excision of many sites, and the predilection sites of EMPD are susceptible to postoperative infection and engraftment failure [15]. Given that quadruple EMPD is likely to remain intraepidermal, it may be a good indication for imiquimod treatment. Furthermore, as EMPD in situ is less likely to affect the prognosis in elderly patients who cannot tolerate surgery, imiquimod may be useful.

Despite numerous reports in the recent years, EMPD pathogenesis remains unclear. We hope that further studies will explore and elucidate the underlying mechanisms of EMPD pathology based on racial differences and multiple lesions, and that more reports on quadruple EMPD will be published in literature in the future.

Acknowledgments

We would like to thank Editage (www.editage.com) for English language editing.

Statement of Ethics

Ethical approval is not required for this study in accordance with local or national guidelines. Written informed consent was obtained from the patient for publication of this case report and any accompanying images.

Conflict of Interest Statement

The authors have no conflicts of interest to declare.

Funding Sources

The authors did not receive any financial support for the present study.

Author Contributions

Akihiro Ishiguro and Nobuyuki Iwashita: the conception, design, and the acquisition, analysis, interpretation of data, drafting the work, final approval of the version to be published, and agreement to be 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. Michihiro Abe, Tomohiro Takeo, Daisuke Watanabe, and Akina Ogawa: the conception, design, revising it critically, final approval of the version to be published, and agreement to be 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.

Data Availability Statement

All data generated or analysed during this study are included in this article. Further enquiries can be directed to the corresponding author.

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