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Nakamura, Y. Extramammary Paget’s Disease. Encyclopedia. Available online: https://encyclopedia.pub/entry/14430 (accessed on 27 July 2024).
Nakamura Y. Extramammary Paget’s Disease. Encyclopedia. Available at: https://encyclopedia.pub/entry/14430. Accessed July 27, 2024.
Nakamura, Yoshiyuki. "Extramammary Paget’s Disease" Encyclopedia, https://encyclopedia.pub/entry/14430 (accessed July 27, 2024).
Nakamura, Y. (2021, September 23). Extramammary Paget’s Disease. In Encyclopedia. https://encyclopedia.pub/entry/14430
Nakamura, Yoshiyuki. "Extramammary Paget’s Disease." Encyclopedia. Web. 23 September, 2021.
Extramammary Paget’s Disease
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This entry is adapted from the peer-reviewed paper 10.3390/curroncol28040260

Extramammary Paget’s disease (EMPD) is a rare neoplasm that usually develops in the apocrine gland-bearing areas of older adults. Clinically, EMPD lesions often exhibit infiltrative erythema with crust and scale, sometimes resembling other skin disorders such as eczema. EMPD can be classified into primary and secondary EMPD manifestations.

Extramammary Paget’s disease diagnosis treatment recent developments

1. Introduction

Extramammary Paget’s disease (EMPD) is a rare neoplasm that usually develops in the apocrine gland-bearing areas of older adults [1][2][3][4]. Clinically, EMPD lesions often exhibit infiltrative erythema with crust and scale, sometimes resembling other skin disorders such as eczema. EMPD can be classified into primary and secondary EMPD manifestations. While primary EMPD arises as intraepithelial neoplasm of the epidermis, secondary EMPD develops from epidermotropic spread of malignant cells or direct extension from an underlying internal neoplasm [5][6]. However, it is sometimes difficult to distinguish primary EMPD and secondary EMPD both clinically and histologically. As the treatment strategy and prognosis for primary and secondary EMPD differ, accurate diagnosis based on detailed histopathological evaluation of multiple immunohistochemical markers is required. Most EMPD cases are diagnosed as carcinoma in situ, which usually shows indolent disease progression. However, once Paget cells invade deeply into the dermis, regional lymph node (LN) metastases and distant metastases frequently develop [7]. Cases with distant metastases have a poor prognosis because conventional chemotherapies, traditionally used for EMPD treatment, show limited efficacy. Recent studies have provided various insights into the mechanism and associated molecules of EMPD development and advancement, which may lead to novel treatment approaches for metastatic EMPD. Here, focusing on recent developments, we review EMPD, including its diagnosis, pathogenesis, and treatment.

2. Epidemiology

EMPD is rare, and a recent study showed that the crude prevalence of EMPD in mainland China was 0.4 per 1,000,000 people in 2016, which is a similar ratio to the age-adjusted prevalence [8]. In 2012, van der Zwan et al. reported that the crude incidence rate and European age standardized incidence rate of invasive EMPD within Europe was 0.7 and 0.6 per 1,000,000 person-years, respectively [9]. The prevalence of EMPD regarding gender differs between Western and Asian populations. In studies of Caucasian populations, EMPD has a female predominance, with male-to-female ratios ranging from 1:2 to 1:7 [1][9][10][11][12]. In contrast, male predominance has been reported in Asian studies [3][13]. A multicenter institution study conducted in Japan revealed that 327 (60.1%) of 544 patients were male [3], and a nationwide population-based study in Taiwan revealed that the male-to-female ratio among EMPD patients was 3.5:1 [13]. EMPD usually develops in older adults, with the mean age at diagnosis being 60–70 years [3][4].

3. Clinical Presentation

According to Ghazawi et al., the predominant sites of EMPD development are the scrotum and penis in males and the vulva in females [3]; however, perianal, axillar, or umbilicus regions are also sometimes involved. EPMD can be multifocal, and cases of EMPD developed in more than 2 apocrine gland-bearing areas, known as double, triple, or synchronous EMPD, have also been reported [14][15]. Therefore, a thorough physical examination of these regions is important when EMPD is encountered. EMPD skin lesions typically present as a well-circumscribed erythema or erythematous plaques with occasional hyperpigmentation or hypopigmentation. Cases in which the main clinical presentation was hypopigmentation have also been reported, and such cases are difficult to clinically diagnose as EMPD [16]. Crust, scale, or erosion on the erythematous lesions may also be seen, and such lesions may mimic various other skin disorders, such as eczema, psoriasis, and fungal infection. In the later stages, nodules or deep ulcers may occur. Although associated symptoms, such as pruritus and tenderness, may develop, around 10% of EMPD patients are asymptomatic [17][18]. EMPD lesions sometimes show subclinical extension, making it difficult for clinicians to determine the clinical borders between EMPD lesions and the surrounding normal skin [19].
Dermoscopy is a non-invasive tool for diagnosis of skin lesions and has been shown to improve clinical diagnosis of melanocytic lesions [20][21]. Recently, dermoscopic features of EMPD lesions have also been investigated [22][23]. Mun et al. compared dermoscopic features of EMPD lesions and other skin lesions, the gross findings of which may be similar to EMPD, including eczema, fungal infection, and Bowen disease [22]. They found that, among the dermoscopic findings common to other skin lesions, such as milky-red areas, dotted vessels, glomerular vessels, polymorphous vessels, surface scales, and linear irregular vessels, milky red areas were significantly more frequent in EMPD than in eczema, fungal infection, and Bowen disease [22]. In addition, vascular structures were also more common in EMPD than in eczema and fungal infection [22]. In contrast, Payapvipapong et al. suggested that the lava lake structure, defined as a combination of white, branching reticular lines and intermingling white clods resembling a lava lake inside a live volcanic crater, and the cloud-like structureless area, defined as a combination of a white structureless area resembling diffuse layering of stratus clouds and small, round, white clods resembling fluffy cumulus clouds, may be specific dermoscopic findings of EMPD [23].

4. Classification

Primary EMPD is defined by lesions that initially develop as intraepithelial neoplasm of the epidermis. Although primary EMPD typically develops in apocrine gland-bearing areas, it rarely develops in non-apocrine gland-bearing areas such as the face, back, arms and legs [5][6]. Cases of multiple ectopic EMPD have also been reported [24]. Ectopic EMPD appears to be more common among Asian patients [6]. There is no clinical or histological difference between ectopic EMPD and classic (non-ectopic) primary EMPD except for the location [5][6]. Secondary EMPD is defined by primary EMPD-like lesions that develop from the epidermotropic spread of malignant cells or direct extension from an underlying internal neoplasm, such as colorectal carcinoma and urothelial carcinoma [6][25]. Because the treatment strategy and prognosis for primary secondary EMPD differ, accurate diagnosis based on detailed histopathological evaluation is required. Previously, Wilkinson et al. proposed vulvar EMPD classification as either primary or secondary EMPD, with three subtypes for each classification [26]. Primary EMPD is subdivided into intraepithelial cutaneous Paget disease in situ as the usual type, intraepithelial cutaneous Paget disease with invasion, and intraepithelial cutaneous Paget disease as a manifestation of underlying skin-appendage adenocarcinoma [26]. Secondary EMPD is subdivided into Paget disease of anorectal origin, Paget disease of urothelial origin, and Paget disease of other origin [26]. This proposed classification is useful to organize the various types of EMPD and avoid potential confusion (Table 1).
Table 1. Proposed classification of vulvar Paget disease [26].
Primary Vulvar Paget Disease,
a Primary Cutaneous Neoplasm		 Secondary Vulvar Paget Disease
Paget disease as a primary intraepithelial
neoplasm (carcinoma in situ)		 Paget disease secondary to anal or rectal adenocarcinoma
Paget disease as an intraepithelial neoplasm
with invasion		 Paget disease secondary to urothelial neoplasm
Paget disease as a manifestation of an underlying primary
adenocarcinoma of a skin appendage or a subcutaneous
vulvar gland		 Paget disease secondary to adenocarcinoma or
related tumors of other sites

5. Histopathology

Histopathological examination of EMPD reveals the presence of Paget cells in the epidermis, which are characterized by atypical large cells with abundant, clear, and sometimes eosinophilic cytoplasm in hematoxylin and eosin staining [27]. The cells are present singly or form clusters. In some cases, distinction from Bowen’s disease or melanoma can be difficult without use of immunohistochemical studies [28]. Tumor cells may be pigmented, or there can be colonization of the involved epidermis by non-neoplastic dendritic melanocytes [29]. The epidermis of EMPD often shows acanthosis with hyperkeratosis, parakeratosis, or ulceration [30]
Paget cells, irrespective of whether primary or secondary EMPD, are usually positive for the diastase-periodic acid-Schiff (PAS) reaction, mucicarmine, and zirconyl hematoxylin, indicating the presence of neutral mucopolysaccharides. Immunohistochemical studies are essential for accurate diagnosis of EMPD, especially for differentiating primary EMPD from secondary EMPD. Secondary EMPD frequently develops from colorectal carcinoma and urothelial carcinoma [31]. Primary EMPD is positive for CEA, with a positive rate of 84.2–98.9% [32][33]. However, both colorectal carcinoma and urothelial carcinoma may also show positive staining for CEA [34][35]. The most useful marker for excluding the possibility for secondary EMPD arising from colorectal carcinoma and urothelial carcinoma is gross cystic-disease fluid protein-15 (GCDFP-15), which is usually negative for these lesions, whereas GCDFP-15 is sometimes positive for primary EMPD. However, the positive rate of GCDFP-15 in primary EMPD has been reported to be as little as 30.0–52.6%, and substantial cases of primary EMPD show negative staining of GCDFP-15 [32][36][37]. The combination of CK7 and CK20 staining is also crucial in distinguishing primary EMPD and secondary EMPD [31]. Whereas primary EMPD typically shows CK7+/CK20-, secondary EMPD from colorectal carcinoma typically shows CK7-/CK20+. However, although relatively rare, cases of primary EMPD with positive CK20 staining and cases of secondary EMPD developed from colorectal carcinoma with positive CK7 or negative CK20 staining have also been reported [38][39][40]. Meanwhile, secondary EMPD arising from urothelial carcinoma typically shows CK7+/CK20+ [31][41]. However, cases of secondary EMPD developed from urothelial carcinoma showing negative CK20 staining have also been reported [42], suggesting that the combination of CK7/CK20 staining is not an absolute method to discriminate primary from secondary EMPD. As for other markers, CDX-2, an intestinal cell marker, and uroplakin II and III, urothelial cell markers, could be also useful for the discrimination: both are usually negative for primary EMPD [40][43][44][45]. Collectively, comprehensive evaluation using multiple markers, including CK7/20, GCDFP-15, CDX-2, and uroplakin II and III, is required for accurate discrimination of primary EMPD and secondary EMPD. The microscopic morphology and distribution of tumor cells in melanoma and Bowen disease also sometimes resemble EMPD, and cases of Bowen disease resembling EMPD are known as Pagetoid Bowen disease [46][47]. Whereas melanoma cells are typically positive for S-100, HMB-45, and Melan-A, and atypical keratinocytes of Bowen disease are typically positive for p63, Paget cells in EMPD are usually negative for all of these molecules [47][48][49]. In addition, negative staining of PAS and CEA in melanoma and Bowen disease tumor cells also aid in distinguishing these diseases from EMPD.

6. Pathogenesis

Some previous studies involving genomic analyses in EMPD lesions reported somatic mutations in various genes, including TP53, ERBB, NRAS, BRAF, PIK3CA, and AKT1 genes [50][51]. Ishida et al. conducted genetic analyses of 87 EMPD lesions and their exome analysis identified ERBB2, ERBB3, KMT2C, TP53, PIK3CA, NUP93, AFDN, and CUX1 as likely driver mutations [52]. Their copy-number alteration analysis showed regions spanning CDKN2A as recurrently deleted and ERBB2 as recurrently amplified and that greater copy-number alteration load correlated with high frequency of recurrence [52]. Frequent gene alternations in ERBB2, RAS, RAF, AKT1, and PIK3C in EMPD lesions detected in previous studies suggested that HER2, which is encoded by ERBB2, and its downstream signaling, including RAS/RAF-MEK-ERK pathway and PI3K-AKT-mTOR pathway, may play important roles in the pathogenesis of EMPD in many cases. Takeichi et al. also analyzed genomic alteration in 48 patients with EMPD and identified FOXA1 mutations, a GAS6–FOXA1 fusion gene, and somatic hotspot mutations in the FOXA1 promoter region in 11 of the 48 patients [53]. They also revealed that FOXA1 expression was strongly expressed in Paget cells in all of the EMPD samples and was associated with estrogen receptor (ER) expression [53]. Given that FOXA1 assists the transcriptional activity of the ER and may be involved cooperatively in the tumorigenesis of breast cancer, the FOXA1-ER axis may also play crucial roles in EMPD development and progression in some cases [54].
As for molecular expression in EMPD lesions, multiple studies have demonstrated HER2 overexpression in EMPD lesions, which was associated with amplified ERBB2 [55][56]. These HER2-positive EMPD cases conferred a more aggressive biology [57]. In addition, Tanaka et al. demonstrated that around 90% of patients with EMPD showed no difference in HER2 overexpression and ERBB2 gene amplification between primary lesions and lymph node (LN) metastasis, indicating that targeting therapies for HER2 may be effective for the treatment of both primary and metastatic lesions [58]. Lin et al. used microarray analysis and identified that expressions of ERBB4, PRLR, TCF3, PIK3R3, SULT1A1, and TCF7L1 were significantly overexpressed in EMPD lesions [59]. Immunohistochemical studies also confirmed the overexpression of PRLR, a prolactin (PRL) transmembrane receptor, interacting with PRL to activate downstream signaling in breast cancer [59][60]. Therefore, targeting therapies for the PRL-PRLR axis might be an effective EMPD therapy. Although most EMPD cases exhibit low expression of estrogen receptor (ER), EPMD shows a high androgen receptor (AR)-positive rate at 54–90%, and AR expression was stronger in invasive EMPD than in situ EMPD [61][62][63], indicating that AR signaling may be involved in the EMPD progression and that blockade of AR signaling might be another effective therapy for EMPD. Chang et al. immunohistochemically evaluated expression of CXCR4 and CXCR7 in 92 EMPD lesions [64]. CXCR4 and CXCR7 share the same chemokine ligand, CXCL12, and have been reported to play important roles in tumor growth, angiogenesis, and metastases in various cancer, such as lung and breast cancer [64]. They demonstrated that high expression of CXCR4 and CXCR7 were both correlated with regional LN metastases and presence of lymphovascular invasion, and high expression of CXCR7 also correlated with the depth of invasion. Therefore, both CXCR4 and CXCR7 can be used as biomarkers for prediction of the aggressiveness of EMPD, and therapies targeting CXCR4 and CXCR7 may be helpful to prevent EMPD progression [64].
There have been multiple studies regarding the immune environment in EMPD. Regulatory T cells (Tregs), which show FoxP3 expression; suppress the activation of other immune cells, including effector T cells; and play a crucial role in immune evasion in various malignant tumors. A previous study demonstrated that the number of CD4+ cells and CD8+ cells as well as the CD8+/FoxP3+ ratio were significantly decreased in the epidermis of vulvar EMPD compared with healthy controls, whereas the stromal compartment was highly infiltrated by various immune cells, including T cells and myeloid cells, suggesting immunocompromised environment in the epidermis of EMPD lesions [65]. The authors speculate that the immune cells may be unable to penetrate the epidermis to clear Paget cells [65]. Press et al. analyzed FoxP3+ cells at the dermal–epidermal junction in vulvar EMPD and found that both nonrecurrent and recurrent cases with positive surgical margin had more FoxP3+ cells than those with negative surgical margin, suggesting that increased Tregs may be associated with more extensive EMPD cases, and these Tregs might promote survival and subclinical spread of Paget cells along the epidermis [66]. Macrophage are other immune cells that significantly regulate immune response to tumor. Fujimura et al. reported that large numbers of CD163+ M2 macrophages and metalloproteinase (MMP)-9+ cells were detected in invasive but not in situ EMPD lesions, suggesting that an increased number of MMP-9+ cells may be associated with CD163+ M2 macrophages and may be involved in the progression of invasive EMPD [67]. Given that aminobisphosphonate has been reported to decrease pro-MMP-9 and may abrogate the induction of CD163+ M2 macrophages in the tumor microenvironment, bisphosphonates might be effective for the prevention of not only bone metastasis but also disease progression in patients with invasive EMPD [68][69]. Receptor activator of nuclear factor κB ligand (RANKL) and its receptor RANK have multiple divergent effects in immunity; they not only activate T-cell priming but also promote Treg generation, which may induce tolerance against tumor antigens [70][71]. Kambayashi et al. demonstrated that expressions of RANKL and MMP-7, which cleaves RANKL to release a soluble form of RANKL (sRANKL), in EMPD lesions were higher than in non-lesional skin [72]. In contrast, RANK was mainly expressed by CD163+ Arg1+ CD206+ M2 macrophages, suggesting that the sRANKL released from Paget cells may stimulate these M2 macrophages via RANK [72]. It has also been reported that most of the CD163+ M2 macrophages expressed CCL17 in EMPD lesions [73]. CCL17 attracts CCR4-expressing cells, which are mainly T cells, and CCR4 is highly expressed in effector Tregs, characterized by high expression of FoxP3 [74]. Consistently, Foxp3+ cells have been shown to surround CD163+ M2 macrophages, indicating that M2 macrophages stimulated by RANKL/RANK signaling might recruit effector Tregs into the tumor microenvironment of EMPD [73]. Therefore, denosumab, which is an anti-RANKL antibody and is currently approved for use to treat bone metastases, could be a potential treatment for advanced EMPD lesions.
Recent clinical trials have revealed that immune checkpoint inhibitors, including anti-PD-1/PD-L1 antibodies and anti-CTLA4 antibodies, improved survival of patients with various malignancies, such as melanoma and renal cell carcinoma [75][76][77]. PD-L1/PD-L2 expression is known to correlate with the anti-tumor response of anti-PD-1/PD-L1 antibodies [78][79][80]. However, Karpathiou et al. conducted immunohistochemical studies of 41 patients with EMPD and showed that PD-L1 was not expressed by any tumor cells or the associated lymphocytes, although dense T-cell infiltration was observed [81]. Pourmaleki et al. also demonstrated very focal expression of PD-L1 and no expression of PD-L2 in EMPD lesions [82]. They revealed high expression of B7 family members B7-H13 and B7-H14 in EMPD lesions, indicating that targeting therapies for these molecules might be effective for EMPD treatment [82]. In contrast, Mazuo et al. demonstrated that PD-L1 was expressed in tumor cells in 3 of 21 (14%) EMPD cases and in tumor-infiltrating immune cells in 15 of 21 (71%) EMPD cases [83]. They also showed that PD-1 was expressed in the tumor-infiltrating immune cells in all cases, although the density of PD-1 and PD-L1 in the tumor did not correlate with any clinical data, including overall survival (OS), disease-specific survival, and time to metastasis [83]. Recently, Kawaguchi et al. also revealed that PD-L1 and PL-L2 were expressed in tumor cells in 13 of 47 (27.7%) EMPD cases and 21 of 47 (44.7%) EMPD cases, respectively [84]. In this study, both PD-L1 and PD-L2 expression, as well as low CD8+ tumor-infiltrating T-cell (TIL) numbers, were associated with shorter postoperative recurrence-free survival, suggesting that the expression of PD-L1/PD-L2 in tumor cells may be a factor for worse prognosis [84]. The discrepancy of PD-L1 and PD-L2 expression between each study may be explained by the different cut-off values provided, differences in used antibody clones, and difference of the ratio of invasive cases [83][84]. It has been reported that the status of high microsatellite instability (MSI-H) is another predictor for better anti-tumor response from anti-PD-1 antibodies [85]. Although germline mutations in mismatch repair genes, such as MLH1 and MSH2, which may be associated with microsatellite instability, were found in some EMPD patients, previous studies have reported that MSI-H status was not observed in most EMPD cases [86][87]. 

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Yoshiyuki Nakamura
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