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Table of Contents
Year : 2022  |  Volume : 40  |  Issue : 2  |  Page : 100-107

Extramammary Paget's disease: A retrospective study in a medical center in Taiwan

1 Department of Dermatology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
2 Department of Dermatology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung; Department of Dermatology, Chang Gung Memorial Hospital, Chiayi, Taiwan

Date of Submission17-Jan-2021
Date of Decision21-Mar-2022
Date of Acceptance28-Mar-2022
Date of Web Publication10-Jun-2022

Correspondence Address:
Dr. Ji-Chen Ho
No. 123, Dapi Road, Niaosong District, Kaohsiung City 83301
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ds.ds_19_22

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Background: Extramammary Paget's disease (EMPD) is a rare malignancy occurring on apocrine sweat gland-bearing skin with occasional association with internal cancers. Its epidemiological characteristics are different between populations in Asian and Western countries. Objectives: The aim of this study was to report the clinical experience of EMPD in a single medical center in Taiwan, compare our results with previous literature, and provide strategies for diagnostic workup. Methods: Medical records and biopsies of 34 Taiwanese patients with EMPD, treated in a single medical center in Kaohsiung, Taiwan, from January 2000 to December 2019, were reviewed. The clinicopathological features, biological behavior, management, and follow-up courses of these patients were analyzed. Results: We found a male predominance in our 34 patients with EMPD, and most patients were diagnosed in their 70s. Only four patients (11.8%) had an associated malignancy while the rest had a primary cutaneous lesion. Most patients (22, 64.7%) underwent wide excision (22, 64.7%), with the rest adopting other various therapeutic modalities. The 5-year overall survival rate was 76.5%, and the statistically significant prognostic factors for survival were lymph node involvement (P < 0.001) and dermal invasion (P = 0.022). Conclusion: In summary, this single-center study described the clinical and histopathologic features of patients with EMPD in Taiwan with a review of literature. We also proposed a complete systemic workup when the diagnosis was made and an extended follow-up period as long as 5 years after the initial treatment.

Keywords: Apocrine sweat gland, extramammary Paget's disease, Paget's disease

How to cite this article:
Yen CH, Lee CH, Ho JC. Extramammary Paget's disease: A retrospective study in a medical center in Taiwan. Dermatol Sin 2022;40:100-7

How to cite this URL:
Yen CH, Lee CH, Ho JC. Extramammary Paget's disease: A retrospective study in a medical center in Taiwan. Dermatol Sin [serial online] 2022 [cited 2022 Dec 3];40:100-7. Available from: https://www.dermsinica.org/text.asp?2022/40/2/100/347096

  Introduction Top

Extramammary Paget's disease (EMPD) was first described by Crocker in 1889,[1] Who reported lesions on penis and scrotum sharing close clinical and histologic resemblance with mammary Paget's disease, which was first reported by James Paget in 1874.[2] EMPD is a rare cutaneous malignancy with an incidence ranging from 0.1 to 2.4 patients per million person-years.[3] It most commonly occurs on apocrine gland-bearing skin, including axilla and genitalia. The age of diagnosis of this disease ranges from 50 to 80 years, peaking at the age of 65 years.[4] The disease is more prevalent among Caucasians, and women seemed to be more commonly affected than men, with a 1:4 male-to-female ratio.[5] In contrast, EMPD was less common in Asian populations, among which a male predominance was often described. In Chinese, Japanese, and Korean patients with EMPD, male-to-female ratios were reported to range from 2.6:1 to 14:1.[6],[7],[8] EMPD presents with various symptoms and signs, and its diagnosis is usually delayed because it could mimic an eczematous lesion refractory to topical corticosteroid with a chronic-relapsing clinical course. The disease is sometimes associated with a visceral or underlying adnexal malignancy. Histologically, EMPD can show invasive features such as dermal invasion and involvement of skin appendages such as eccrine sweat glands and hair follicles. Curative therapeutic strategies included conventional wide local excision and Mohs micrographic surgery (MMS); other adjunctive modalities have been variously attempted such as lymph node dissection, radiotherapy, topical agents such as 5-fluorouracil or imiquimod, and cryotherapy. In general, EMPD runs a favorable prognosis, and several prognostic factors have been sought in previous studies.

A cancer registry-based study conducted in Taiwan consistently showed similar results with a 3.5:1 male-to-female ratio, and the peak incidence in both sexes occurred at the age group above 80 years.[9] However, only gender, age, and location of involvement were recorded without prognosis, therapeutic interventions, and associated malignancies. Back to 1996, Chang et al. reported 22 patients during 14 years and showed that male EMPD patients in Taiwan seemed to have a lower incidence of internal cancers than Caucasians.[7] Recently, Chang et al. reported 63 patients with EMPD in Taipei Veterans General Hospital (2002–2019), which showed a comparable gender ratio in Asians and clinical and pathological risk factors for the patient survival.[10] However, the clinical pictures of EMPD, due to their resemblance to inflammatory dermatoses, usually failed to sound an alarm by most physicians at initial presentation. The tissue mucin stains (including periodic acid–Schiff [PAS] and mucicarmine) and blood carcinoembryonic antigen (CEA) level were not investigated. In this hospital-based study, we aim to investigate the clinical experience of EMPD in a single medical center in Taiwan, describing the epidemiologic data, clinical and histopathological characteristics, managements, and clinical outcomes in Taiwanese patients. The clinical experience is essential for the establishment of a systemic diagnostic workup and management for Taiwanese patients with EMPD.

  Materials and Methods Top

All cases of EMPD diagnosed in a single medical center in Kaohsiung, Taiwan, from January 2000 to December 2019 were retrospectively reviewed, and 34 patients diagnosed with EMPD with histological confirmation were enrolled. This study was approved by the Institutional Review Board of Chang Gung Memorial Hospital (IRB No. 202000699B0). The following data of the patients were recorded and analyzed: demographic features (age upon presentation and sex); clinical presentation (types and location of the lesions, symptoms, presence of palpable lymphadenopathy, presence of an associated malignancy, and elevated serum tumor markers); histopathological findings (special findings such as acanthosis, atrophy, erosion, dermal invasion, eccrine gland involvement, or hair follicle involvement, and positive immunohistochemical staining); management; and follow-up courses (recurrence, metastasis, death, causes of death, and intervals between death and the diagnosis of EMPD). An internal malignancy was considered to be truly associated with EMPD only if the interval between the diagnoses of the two malignancies was <5 years, with the associated malignancy occurring either before or after the diagnosis of EMPD. The tumor sections were examined with routine hematoxylin and eosin (H and E) staining in addition to several other immunohistochemical stains such as CK7, CK20, Alcian blue, mucicarmine, and PAS.

All patients were followed up with physical examination and, if necessary, with further imaging studies. Overall survival (OS) was estimated with Kaplan–Meier curves. Log-rank test was performed to compare the survival distributions of two groups divided according to the presence of an associated malignancy or a histopathological finding such as dermal invasion or adnexal involvement. P < 0.05 was considered statistically significant. All statistical analyses were performed with Statistical Product and Service Solutions version 22.0 (IBM Corp. Armonk, NY, USA).

  Results Top

Most patients with extramammary Paget's disease were men with advanced ages

Among the 34 Taiwanese patients with EMPD, the majority were male (30 men versus 4 women; male-to-female ratio: 7.5:1) [Table 1]. The lesions were all located over urogenital areas, most commonly on scrotum (17 cases, 50.0%) and penis (12 cases, 35.2%); other documented sites included vulva, pubic area, and inguinal area. The mean age of diagnosis was 75 years, and most patients were diagnosed in their 70s (18 cases, 52.9%).
Table 1: Clinical and histopathological features of patients diagnosed with extramammary Paget's disease (n=34)

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The most common clinical presentation is a pruritic plaque in penoscrotal areas, with 11.8% associated with internal malignancies

The lesions of EMPD could be clinically categorized into three types: plaques (26 cases, 76.5%), papulonodules (4 cases, 11.8%), and patches (4 cases, 11.8%). Symptoms such as itching or pain were reported in 21 patients (61.8%) [Figure 1]. Thirty patients (88.2%) had a primary cutaneous lesion, whereas the other four patients (11.8%) had an associated malignancy – two with breast cancers and the rest with a malignancy in the gallbladder and prostate, respectively [Table 2]. The two patients with breast cancers were both diagnosed with EMPD after the diagnosis of breast cancer, with the intervals between the diagnoses of two malignancies as long as 41 and 120 months. The patient with cholangiocarcinoma was diagnosed with EMPD concurrently, although the EMPD was negative for cytokeratin-20 (CK20). The patient with prostate cancer was diagnosed with EMPD before the diagnosis of prostate cancer, with a 1-month interval between the diagnoses of two malignancies; however, the EMPD skin sections were negative for both CK20 and prostate-specific antigen (PSA). Serum tumor markers such as CEA (2/13, 15.4%), PSA (2/12, 16.7%), or carbohydrate antigen 19–9 (2/9, 22.2%) were invariably positive in several patients.
Figure 1: Clinical (a-c) and pathologic (d-i) presentations of our patients with extramammary Paget's disease: (a) plaque, (b) nodule, (c) patch, (d) acanthosis (H and E, ×100), (e) atrophy (H and E, ×100), (f) erosion (H and E, ×100), (g) dermal invasion (H and E, ×200), (h) involvement of eccrine glands (H and E, ×200), and (i) involvement of hair follicles (H and E, ×200).

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Table 2: The four cases with associated malignancies and their clinical characteristics

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Adnexal and dermal involvements are common histopathological findings

Histopathological features included acanthosis (28 cases, 82.4%), epidermal atrophy (1 case, 2.9%), erosion (25 cases, 73.5%), dermal invasion (8 cases, 23.5%), and involvement of eccrine glands (22 cases, 64.7%) and/or hair follicles (24 cases, 70.6%). Immunohistochemical staining showed that almost all EPMDs were positive for mucin stains: PAS (9/9, 100%) and mucicarmine (16/17, 94.1%); high-molecular-weight (9/10, 90%) and low-molecular-weight (13/13, 100%) cytokeratins and CEA (20/20, 100%) were also invariably positive. CK7 was positive in 23/23 patients (100%), and CK20 was positive in 6/22 (27.3%). Among the CK20+ cases, none had an associated malignancy.

Most patients were treated with conventional wide excision, and extramammary Paget's disease itself seldom directly resulted in mortality

Therapeutic modalities included wide excision (22/34, 64.7%), sentinel lymph node biopsy (SLNB) (2/34, 5.9%), lymph node dissection (2/34, 5.9%), radiation therapy (8/34, 23.5%), systemic chemotherapy (1/34, 2.9%), topical agents (5/34, 14.7%), cryotherapy (2/34, 5.9%), and photodynamic therapy (1/34, 2.9%) [Figure 2]. Among the 22 patients who underwent wide local excision, four received adjuvant radiation therapy.
Figure 2: Therapeutic modalities and clinical follow-up data for the outcome of patients with extramammary Paget's disease (n = 34).

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During a 5-year follow-up period, 22 patients (64.7%) were alive without recurrence. Two patients were alive with recurrent disease (5.9%), and both of them did not receive radiation therapy; one received surgical excision with an unknown surgical margin and the other with a 1-cm margin, with recurrence diseases taking place 34 and 84 months after the operation, respectively. Seven patients died due to medical problems unrelated to EMPD (20.6%), the causes of death including pneumonia, spontaneous intracranial hemorrhage, heart failure, acute coronary disease, and renal failure. One patient died of recurrent EMPD with extensive metastatic disease (1/34, 2.9%). Two (5.9%) patients were lost to follow-up. In total, three patients suffered from recurrent disease, two of whom had local recurrence and one had recurrence in liver and distant lymph nodes. Among the three patients with a recurrent disease, the average time from treatment to recurrence was 83.3 months.

Among the two patients with elevated serum CEA levels, neither of them had an associated internal malignancy, and both patients eventually died of conditions unrelated to EMPD. One of them demonstrated no dermal invasion or lymph node disease and was treated with simply radiotherapy without surgery. He died because of pneumonia 1 month after the diagnosis of EMPD. The other patient showed extensive dermal invasion histologically, and inguinal lymphadenopathy was palpated clinically. A concurrent vulvar adenocarcinoma was diagnosed. She was treated with wide excision of the tumor with regional radiotherapy for the lymph node disease. She died of end-stage renal disease 30 months after the diagnosis of EMPD.

Distant metastasis occurred in two patients: one with metastasis at initial presentation and the other one with metastasis 24 months after wide excision with a 1.5-cm margin and lymph node dissection (which showed no lymph node metastasis). These two patients were both in their 70s at presentation and had adnexal involvement and dermal invasion histologically. Neither of them showed elevated serum CEA levels. The patient with distant metastasis at initial presentation was treated with systemic chemotherapy with tegafur and uracil and died 2 months after the diagnosis. The other patient with local disease was treated with wide excision and lymph node dissection first, and after 24 months, distant metastasis at multiple sites ensued, followed by the patient's death 2 months later.

Dermal invasion and lymph node involvement are significantly associated with poor prognosis

The 5-year OS rate was 76.5%. Patients with dermal invasion (n = 9) had a 5-year OS of 57.1%, whereas those without (n = 25) had a 5-year OS of 90.0% (P = 0.022, log-rank test) [Figure 3]. Those with lymph node involvement of the tumor (n = 3) had a 5-year OS of 0%, whereas those without (n = 31) had a 5-year OS of 83.3% (P < 0.001, log-rank test). On the other hand, patients with either adnexal involvement (n = 6, 5-year OS: 83.3%) or an associated malignancy (n = 4, 5-year OS: 75.0%) showed slightly decreased 5-year OSs compared to the groups without those features (n = 28, 5-year OS: 75.0%, and n = 30, 5-year OS: 76.7%, respectively) but failed to reach statistical significance (P = 0.637 and 0.898, respectively).
Figure 3: Kaplan–Meier survival curves. Overall survival rates according to (a) associated malignancy, (b) adnexal involvement, (c) dermal invasion, and (d) lymph node involvement (n = 34).

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  Discussion Top

In this single-center retrospective study, we found a male predominance in 34 Taiwanese patients with EMPD, 4 out of which had an associated malignancy. Our study showed a male predominance with the male-to-female ratio as high as 7.5:1, which is consistent with previous reports in Eastern Asian countries including Taiwan. Although the pathogenesis of EMPD remains unclear, there are several possible explanations for the discrepancy of epidemiologic characteristics between Caucasian and Asian populations. First, differences exist in concepts of health and cultural attitudes between Asian and Western countries. For example, it is speculated that Asian women with advanced age are generally conservative and are too shy about seeking medical treatment for genital lesions. This could further result in underestimation of the incidence of EMPD in Asian populations.[9] Second, some races might be associated with certain common genotypes, and their related gene expressions, such as overexpressions of Sp1, p53, MAPK, p-AKT, p-Stat3, Stat5a, p-ATF2, NGF, and BDNF, can contribute to the pathogenesis of EMPD.[11],[12],[13],[14],[15]

Four out of 34 patients (11.8%) with EMPD in our study had an associated malignancy. EMPD has two forms: primary and secondary. Primary EMPD arises from the epidermis or apocrine sweat glands without an association with an underlying malignancy, while secondary EMPD is thought to be associated with one. An associated underlying internal malignancy has been reported in 7%–40% of patients with EMPD. Commonly underlying internal malignancies include gastrointestinal, urinary tract, and genital cancers, and they are more commonly associated with EMPD in Western than in Asian patients.[3],[6],[16] Regional and temporal correlations between EMPD and associated malignancies support the development of associated cancers, but it remains difficult to establish the true association with EMPD from the coincidental occurrence of two distant cancers. Hence, criteria to distinguish associated malignancies from coincidental occurrences were proposed by Lee et al.: A truly associated malignancy should be diagnosed within 5 years of the time of EMPD diagnosis; it should be anatomically associated with the location of EMPD; and the tumor cells of EMPD should be positive for CK20.[8] Among the four patients with an associated malignancy in our study, one patient with breast cancer was diagnosed 10 years prior to the diagnosis of EMPD, and another patient was found to have an underlying cholangiocarcinoma concurrent with the diagnosis of EMPD. The relatively long interval between breast cancer and EMPD and the exceptional association between cholangiocarcinoma and EMPD rendered the true association of these underlying malignancies with EMPD suspicious. Only one case report was found to describe a Japanese patient with EMPD having an associated bile duct cancer (poorly differentiated carcinoma).[17] In addition, none of these four patients with an associated malignancy was positive for CK20 in the tumor cells of EMPD. Hence, the true association between an underlying malignancy and EMPD might be even weaker in our series, which was consistent with previous literature stating that an associated malignancy is more commonly found in Western patients with EMPD compared to Asian populations.[16] However, although an associated internal malignancy might not be as common in Asian patients with EMPD as in Western counterparts, we still recommend appropriate diagnostic workup for screening of any internal cancer in Asian patients with EMPD, such as computer tomography or sonography of the chest/abdomen/pelvis, colonoscopy, cystoscopy,  Pap smear More Details, and mammography.

Treatment modalities include wide local excision, MMS, topical immunotherapy, photodynamic therapy, radiation therapy, topical chemotherapy, and systemic chemotherapy. Exceptional cases with HER2-amplified metastatic EMPD have been successfully managed with ado-trastuzumab emtansine therapy.[18] In our study, 22 patients received surgery for their EMPD lesions, and all of them received wide local excision with various sizes of surgical margins ranging from 1 to 5 cm, with an average of 2.07 cm. Regardless of approach, wide local excision results in a high rate of recurrence (20%–60%),[19] possibly because of clinically ill-defined margins, microscopic extension of tumor cells, and multifocal disease. Recommendation for surgical margin sizes varies, ranging from 1 to 5 cm.[20] Hatta et al. demonstrated that surgical margin was not correlated with local recurrence.[21] Intraoperative frozen section examination and further widened excisions performed on the margin-positive side until a negative margin is yielded may be used to ensure a clear margin.[22] MMS results in a significantly lower recurrence rate (11%) compared to local wide excision (31%).[8],[23] However, MMS for large EMPD lesions can be technically challenging and time consuming. EMPD with dermal invasion or deeper is known to bear the potential for lymphovascular invasion and thus lymph node or distant metastasis.[24] The use of SLNB has been supported to evaluate the prognosis of invasive EMPD.

Radiation therapy can serve as both primary and adjuvant treatments with response rates as high as 62%–100% and is considered safe and effective as it contributes to prolonged survival with good tumor control.[20],[25] In our study, none of the patients receiving wide excision followed by radiation therapy developed tumor recurrence. Hence, adjuvant radiation therapy can be considered after wide local excision for EMPD if MMS is not considered due to unmet technical demands and time limit for operation. The literature described that patients who received radiotherapy alone had a mean disease-specific survival of approximately 12 years (143.4 months).[25] Hence, patients who are considered poor candidates for surgery may consider radiation therapy as the primary therapeutic modality with curative intent.

Patients with EMPD generally have a good prognosis with a 5-year OS rate ranging from 75% to 95%.[20] Our study demonstrated that dermal invasion and lymph node disease are significantly associated with decreased overall 5-year survival rates, whereas an associated underlying malignancy and adnexal involvement are not consistent with previous literature.[20],[26] The presence of nodules in the primary tumor, more extensive dermal invasion (reticular dermis or depth of ≥1 mm), and elevated serum CEA levels have been reported to be important prognostic factors in EMPD, while the tumor size or the longest diameter of skin lesions was not.[21],[27] Additional factors that may be associated with a poor prognosis include advanced age (above 75 years) at diagnosis, primary site in the perianal area, distant or regional metastasis, and radiotherapy.[28] It is postulated that little subcutaneous fat in the perianal area greatly increases the risk of metastasis, and hence, EMPD at this site is associated with poorer survival.

Currently, validated guidelines for the follow-up protocol in patients with EMPD are lacking. Literature provided various lengths of follow-up periods, and exceptional cases with recurrence more than 15 years after initial treatment have been reported.[29] Hence, long-term surveillance for patients with EMPD is warranted, and any suspicious lesions appearing after the initial treatment should be biopsied. At least biannual evaluation for 3 years followed by annual evaluation for 10 years has been suggested by Kanitakis.[30] Those with invasive disease or distant metastasis should be followed even more frequently than those with noninvasive disease. Several serum biomarkers reflecting the clinical course of EMPD have been identified, such as a combination of serum CEA and cytokeratin 19 fragment (CYFRA 21–1) and cell-free DNA, which might be of additional value for the long-term follow-up of EMPD aside from regular physical examination and skin biopsy.[31],[32] Herein, we provided a recommended treatment algorithm for EMPD [Figure 4].
Figure 4: A recommended treatment algorithm for extramammary Paget's disease. Chest X-ray, positron emission tomography/computed tomography, Mohs micrographic surgery, photodynamic therapy, radiation therapy, and sentinel lymph node biopsy.

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  Conclusions Top

In summary, this single-center study provides the clinical and histopathologic features of EMPD in Taiwan and the treatment experience with a 5-year follow-up period. Taiwanese patients with EMPD share some common epidemiologic features with many other Asian populations. Dermal invasion and lymph node disease are significantly associated with decreased survival and hence portend a poor prognosis. Besides skin biopsy for the primary skin lesion, we recommend a complete systemic workup for screening of an underlying malignancy and lymph node examinations. Long-term surveillance of patients with EMPD is warranted, and we recommend a follow-up period for at least 5 years after the initial treatment.

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Conflicts of interest

Prof. Chih-Hung Lee, an editorial board member at Dermatologica Sinica, had no role in the peer review process of or decision to publish this article. The other authors decalared no conflicts of interest in writing this paper.

  References Top

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  [Figure 1], [Figure 2], [Figure 3], [Figure 4]

  [Table 1], [Table 2]


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