EMPD

Introduction

Extramammary Paget's Disease (EMPD) is a rare and slowly progressing malignancy of the external genitalia, accounting for 6.5% of all Paget's disease cases. Unlike Paget's disease, EMPD typically arises in areas rich in apocrine glands outside the mammary gland, primarily located in the genital area. However, cases have also been reported in the perianal region, axilla, or umbilical area. EMPD often progresses slowly and is often diagnosed as in situ cancer. However, due to frequent microscopic spread and occasional satellite lesions, in situ EMPD usually requires extensive local excision for treatment.

Lesions of EMPD typically present as well-defined erythematous patches or scaly plaques, which may also exhibit crusting, scaling, or ulceration. The non-specific nature of EMPD lesions can lead to misdiagnosis as other skin conditions such as eczema, psoriasis, or fungal infections. Nodules or deep ulcers may develop in later stages. Although symptoms such as itching and tenderness may occur, approximately 10% of EMPD patients remain asymptomatic.

The incidence rate of EMPD is estimated to be 0.1-2.4 cases per million people per year. In Caucasians, females have a higher incidence rate, approximately 2-7 times that of males, while in Asian populations, males have a 1.5-3.5 times higher incidence rate compared to females. In Taiwan, records show only 34 cases from January 2000 to December 2019. EMPD typically occurs in the elderly population, with an average age of diagnosis between 60-70 years.

Pathology

Recent advances in related basic and translational medicine have elucidated factors and molecular mechanisms that promote metastasis. Genetic analysis studies have identified somatic mutations in multiple genes in EMPD, including TP53, ERBB, NRAS, BRAF, PIK3CA, and AKT1. Driver mutations such as ERBB2, ERBB3, KMT2C, TP53, PIK3CA, NUP93, AFDN, and CUX1 have been identified in EMPD cases through exome analysis. Copy number alteration (CNA) analysis showed a correlation between frequent deletions of CDKN2A and amplifications of ERBB2 with high recurrence rates in patients.

Overexpression of HER2 has been observed in EMPD lesions, suggesting the involvement of the downstream RAS/RAF-MEK-ERK and PI3K-AKT-mTOR signaling pathways in the pathogenesis of EMPD. Studies have indicated that HER2 overexpression is consistent in both in situ tumors and lymph node metastases, indicating potential efficacy of HER2-targeted therapy for both in situ and metastatic lesions.

Treatment

Wide local excision (WLE) has long been considered the standard treatment for EMPD. Due to the multifocal nature of Paget cells and their discontinuous subclinical spread, most previous reports suggest a margin of 2 to 5 cm of normal skin during WLE. In another study, among 66 patients who underwent radical surgical excision, 5 cases experienced local recurrence, but the surgical margin (≤2 cm or >2 cm) was not associated with local recurrence. These results indicate that a 1 to 2 cm surgical margin is sufficient for WLE in the treatment of EMPD. While WLE remains the preferred treatment method, Mohs micrographic surgery (MMS) has gained popularity since the late 1990s for its effectiveness in reducing recurrence rates. MMS allows physicians to excise lesion tissue during surgery, examine the margins for residual tumor cells under a microscope after frozen section, and repeat the procedure until no tumor cells remain.

A review article published in JAMA Oncology compared three surgical approaches: WLE, margin control, and MMS indicated lower recurrence rates with MMS. According to statistics, the recurrence rates for WLE and margin control were 37% and 18.7%, respectively, while the recurrence rate for MMS was 11.2%.

For patients who are unable to undergo surgery due to reasons such as patient preference, poor general condition, or coexisting conditions, several alternative non-surgical treatments can be considered, such as radiation therapy, topical Imiquimod cream, and photodynamic therapy (PDT). Radiation therapy can be used for lesions that cannot be surgically excised or as adjuvant therapy for post-surgical recurrence. Several cases have shown the effectiveness of radiation therapy for in situ EMPD, with retrospective analysis suggesting a 5-year local non-worsening rate of up to 82%. The topical immune response modifier Imiquimod has been successfully used in a few EMPD cases and seems to be beneficial for superficial lesions. Imiquimod can be considered as an alternative to surgery, a pre- or post-operative adjunct, or part of a combination therapy with other treatment modalities. Although limited case reports have been published to date, results with Imiquimod treatment appear promising.

Photodynamic therapy (PDT) is a non-invasive treatment that utilizes light-activated drugs (e.g., aminolevulinic acid) selectively absorbed by tumor cells. The relevant area is then exposed to light of appropriate wavelengths, generating toxic free radicals that disrupt tumor cells. While some cases show a certain anti-tumor effect of PDT, its overall efficacy in curing EMPD remains limited and may be challenging as a curative therapy. It may be more suitable as a palliative treatment to alleviate symptoms of EMPD.

Treatment of Invasion and Metastasis

Once EMPD invades the dermis and becomes invasive EMPD, the tumor cells acquire a high potential for metastasis. This can lead to lymph node metastasis even in patients with microinvasion of the dermis, with over one-third of these patients subsequently developing distant metastases. To date, various chemotherapy regimens such as low-dose 5-FU/Cisplatin (FP), FECOM (5-FU, Epirubicin, Carboplatin, Vincristine, Mitomycin-C), docetaxel, TS-1 (tegafur, gimeracil, and oteracil potassium), and PET (Cisplatin, Epirubicin, and paclitaxel) have been employed to treat metastatic EMPD. However, although more than half of the patients initially respond to these regimens, few are able to overcome tumor recurrence. Additionally, overall survival (OS) starts to decline 10 months after initiating chemotherapy, with patients having distant metastases exhibiting a poor prognosis, a median OS of 1.5 years, and a 5-year survival rate of 7%.

Therefore, exploring new therapeutic strategies to prevent and treat metastatic EMPD is imperative. As previously mentioned in the gene expression analysis of HER2, overexpression of HER2 is common in EMPD lesions and may play a significant role in the disease's onset and progression. Currently, several advanced cases of HER2-positive EMPD have been treated with anti-HER2 antibodies such as trastuzumab, either alone or in combination with other chemotherapeutic agents (e.g., paclitaxel or carboplatin). Most of these cases have demonstrated a progression-free survival (PFS) exceeding 12 months, indicating that anti-HER2 antibodies represent a promising therapeutic option for advanced EMPD. However, related studies are still in their early stages.

Outlook