Extramammary Paget's disease: Updates in the workup and management

Metastatic disease has a poor 5-year overall survival rate of less than 10% [32]. Currently, there is no standard systemic treatment regimen for such patients [33]. Available combination therapy includes 5-FU and cisplatin (FP therapy), 5-FU, epirubicin, carboplatin, vincristine, and mitomycin C (FECOM therapy), cisplatin, epirubicin, and paclitaxel (PET therapy), or combination S-1 (combination of tegafur, 5-FU, and 5-chloro-2-4-dihydroxypyridine) and docetaxel, S-1 monotherapy, or docetaxel monotherapy [[33], [34], [35], [36]]. Although overall median survival is less than 1 year, patients on FP and FECOM regimens have demonstrated a median progression-free survival of 5.2 months and 6.5 months, respectively [33,36]. Several studies have focused on HER2-PI3K/ERK signaling but not all EMPD cases showed overexpression of HER2. Only 15%–58% of patients exhibited HER2 overexpression on immunohistochemistry and fluorescence in situ hybridization studies in both primary and lymph node metastatic lesions [33,36]. HER2 over-expression was discernible in invasive EMPD cases and was associated with multiple lymph node metastases [36]. Therefore, monoclonal antibodies targeting HER2 which were originally used in breast cancer, such as trastuzumab, may have role in treatment of metastatic EMPD. Some hormone receptors such as the estrogen receptor have also been investigated [37]. EMPD is usually expressed with a low 4% estrogen receptor -positivity rate but has a high 54%–90% androgen receptor-positivity [38]. Androgen receptor expression is more commonly associated with invasive EMPD [38]. Further investigations have been made in androgen blockade agents that are commonly used in advanced prostate cancer. Use of combination of androgen blockade, an antiandrogen (bicalutamide), and a luteinizing hormone-releasing hormone agonist (leuprolide acetate) was reported in one case study [39]. Combination efficacy was only seen for a six-month period and in a single case with wide metastatic EMPD which resulted in reduction of multiple EMPD bony metastases [39]. There have been few studies investigating the expression of programmed death-ligand 1 (PD-L1) to aid in better characterizing the immune landscape for these tumors. Karpathiou et al. [40] investigated the expression of CD3, PD-L1, and CTLA-4 in 22 patients with EMPD, involving the vulva, anus, and inguinal region. None of these cases were found to express PD-L1, but CTLA-4 expression was identified in nine of those cases with most cases showing stromal CD3 and intra-epithelial CD3 expression [40]. Another study by Goto et al. [41] investigated 39 cases to identify PD-L1 and programmed cell death protein 1 staining. Out of 90% of the cohort with genital EMPD, 59% of cases with carcinoma in situ and 41% cases with invasive disease, none of which were found to express PD-L1, respectively [41]. Fujimura et al. [42] in 2016 reported that three of six cases of EMPD expressed PD-L1, even though the data collected from several studies suggest that PD-L1 expression is exceedingly rare suggesting involvement of other immune pathways. Guercio et al. [32] published one case report describing management of metastatic EMPD with combination of ipilimumab and nivolumab, after progressing on cytotoxic chemotherapy. This combination therapy resulted in a partial response lasting 7 months. Such case report represents one of earliest in the literature utilizing combination systemic immunotherapy for metastatic EMPD.

A summary of studies included in this review article is provided in Table 2.

A summary of studies included in this review article.