Topical imiquimod in the treatment of extramammary Paget's disease: A 10 year retrospective analysis in an Asian tertiary centre

Extramammary Paget's disease (EMPD) is a rare intraepithelial adenocarcinoma usually found in apocrine‐rich areas. Although surgery remains standard treatment, topical imiquimod has emerged as a promising drug for the treatment of EMPD in recent years. We present our experience in treating EMPD in Asian skin successfully with topical imiquimod 5% cream, over the past 10 years in our tertiary institution.     

Extramammary Paget disease successfully treated with topical imiquimod 5% and tazarotene

Extramammary Paget disease (EMPD) is an intraepithelial adenocarcinoma usually localized in areas rich in apocrine sweat glands. Surgery remains the treatment of choice for EMPD. However, several nonsurgical treatments have been also described. Around 40 cases of EMPD treated with imiquimod 5% have been published; of these, only six correspond to nonresponses. We describe a recurrent vulvar EMPD with failure to respond to topical imiquimod 5% in monotherapy but a favorable response to its association with tazarotene.     

Extramammary Paget's disease treated with topical imiquimod 5% cream

Extramammary Paget's disease (EMPD) is a rare cutaneous, intraepithelial adenocarcinoma usually found in the apocrine gland bearing areas. It is traditionally treated with surgery but has a high rate of recurrence. Of late, topical imiquimod 5% cream has come into use as another treatment option. We present two cases of EMPD in Asian skin treated successfully with topical imiquimod 5% cream.     

Risk stratification in extramammary Paget disease

Extramammary Paget disease (EMPD) is an uncommon intraepithelial adenocarcinoma that involves body sites with apocrine glands such as the genital, perineal and perianal regions. Risk stratification and treatment planning for EMPD can be challenging. This review presents important prognostic information in EMPD to assist physicians with risk stratification of patients with EMPD. The best‐understood prognostic factors are depth of invasion and involvement of extracutaneous sites. Tumours that invade into the reticular dermis or have a depth of > 1 mm are associated with poorer prognosis. Additionally, tumours spreading outside the skin into lymph nodes or other tissues are higher risk. There is an emerging understanding of the importance of tumour genetics in risk stratification, and we review the data on Ki‐67, cyclin D1, Mucin 5AC and E‐cadherin. There is less evidence supporting the importance of lesion site and patient age in risk stratification. This succinct review will be helpful in clinical practice and in EMPD research.     

Extramammary Paget's disease of the unilateral axilla: a review of seven cases in a 20-year experience

Background Extramammary Paget’s disease (EMPD) is an uncommon malignancy that occurs on apocrine‐rich skin. EMPD of the axillary region is extremely rare and is not well documented. Objectives The aim of the study is to review our experience with axillary EMPD with regard to initial examination, treatment, and long‐term outcome. Methods A retrospective study of inpatient files with the diagnosis of axillary EMPD was made. The data were collected regarding patient demographics, symptoms, surgical treatments, and time to recurrence. Follow‐up information was obtained as well. Results Seven patients with a median age of 67.6 years were diagnosed with axillary EMPD during a 20‐year period from 1989 to 2008. The male‐female ratio was 1 : 1.3. All patients had a unilateral axillary occurrence, with three in the left and four in the right side. Patients typically presented with a chronic erythematous to brownish plaque with or without pruritus. All patients were treated with wide excision with margins up to 2–3 cm. There were no recurrences after surgery during the follow‐up period. Conclusions Extramammary Paget’s disease of the axillary region is a rare finding even in a large medical center. The disease process is generally a prolonged one without remarkable symptoms. The prognosis of axillary EMPD is relatively good, and long‐term follow‐up is recommended.     

Apocrine Carcinoma of the Groin Possibly Associated with Extramammary Paget's Disease

Apocrine carcinoma is a rare malignancy with invasive potential. It presents as painless, slow-growing, firm or cystic, red nodules with focal ulcerations. The tumor is capable of hematogenous dissemination to the liver, lungs, and bone as well as lymphatic spread. In addition, apocrine carcinomas cause intra-epidemial pagetoid spread. We report a case of an apocrine carcinoma related with extensive extramammary Paget''s disease (EMPD). The relationship between apocrine carcinoma and EMPD remains to be understood. Co-existing cases with apocrine carcinoma and EMPD are discussed to better understand the relationship between these two malignant apocrine tumors.     

Treatment of limited extent extramammary Paget's disease with 5 percent imiquimod cream

Extramammary Paget's disease (EMPD) is a rare neoplastic condition of apocrine gland-bearing skin, which may be associated with internal malignancy. Although surgical excision is the generally accepted standard of care for EMPD, treatment with topical imiquimod 5 percent cream has reportedly been efficacious in clearing lesions. We report the case of a 78-year-old woman with biopsy-proven EMPD of the thigh treated successfully with imiquimod application thrice weekly for 16 weeks.     

Malassezia‐derived aryl hydrocarbon receptor ligands enhance the CCL20/Th17/soluble CD163 pathogenic axis in extra‐mammary Paget's disease

Malassezia yeast play a role in the pathogenesis of chronic dermatitis, especially in apocrine areas, by polarizing the local immunologic background to a Th2/Th17 state through aryl hydrocarbon receptor (AhR)‐dependent pathways. Extra‐mammary Paget's disease (EMPD) is an adenocarcinoma of apocrine origin, and except for cases associated with Malassezia yeast and their metabolites, the lesions typically develop in areas not exposed to environmental material. The purpose of this study was to investigate (a) the immunomodulatory effects of Malassezia metabolites on normal human keratinocytes (NHKCs), focusing on interleukin (IL)‐17 and related cytokines/chemokines (IL‐23, IL‐36γ, CCL20), (b) the expression of these factors in lesion‐affected skin in EMPD and (c) the activation of tumor‐associated macrophages (TAMs) by these factors. Malassezia metabolites augmented the expression of cytochrome P450, family 1, subfamily A, polypeptide 1 (CYP1A1), CCL20 and IL‐36γ mRNA in NHKCs in vitro. In lesion‐affected skin of patients with EMPD, epidermal keratinocytes expressed CYP1A1 and CCL20. In addition, Paget cells expressed CCL20 and IL‐23. IL‐17–producing cells were distributed adjacent to Paget cells. Compared to healthy donors, patients with EMPD exhibited significantly increased serum levels of soluble (s)CD163, CXCL5, CXCL10 and CCL20. In addition, serum levels of sCD163 decreased significantly following tumor resection. Our study demonstrates a possible mechanism for the development of EMPD involving AhR‐mediated signalling by epidermal keratinocytes and RANKL‐induced recruitment of Th17 cells and TAMs.     

Successful treatment of three cases of primary extramammary Paget’s disease of the vulva with Imiquimod – proposal of a therapeutic schedule

Background/aim Extramammary Paget‘s disease (EMPD) is an intraepidermal adenocarcinoma of apocrine gland‐bearing skin. Although surgery remains the mainstay of treatment, loss of tissue function and high recurrence rates have been reported. Recently, topical Imiquimod has been shown as a safe and effective treatment option for extramammary Paget‘s disease. Methods Three patients diagnosed of EMPD of the vulva were treated with a daily application of 5% Imiquimod cream for three weeks, followed by an every other day application for an additional three weeks. Results Complete clinical and histological remission of the disease was achieved in the three patients. Mild irritation and tenderness were observed as the only side effects. Conclusion Based on our results, we consider that Imiquimod cream is a safe and effective therapeutic option for the treatment of vulvar EMPD. These promising results warrant further studies to determine the real efficacy and safety of Imiquimod 5% cream for the treatment of this uncommon disease.     

Differential expression of mucin core proteins and keratins in apocrine carcinoma, extramammary Paget's disease and apocrine nevus

Background:  Apocrine carcinomas are rare, the immunohistochemical characterizations that are incomplete. The purpose of this study was to determine the immunohistochemical characteristics of mucin core proteins and keratins in apocrine carcinoma, extramammary Paget's disease (EMPD) and apocrine nevus.
Methods:  We report four cases of apocrine carcinomas along with immunohistochemical analyses: (i) an axillary apocrine carcinoma with an apocrine nevus, (ii) an inguinal apocrine carcinoma, (iii) a vulvar apocrine carcinoma with EMPD and (iv) an axillary apocrine carcinoma with EMPD and an apocrine nevus.
Results:  The tumor cells of apocrine carcinomas, EMPD and apocrine nevi displayed a positive reaction to MUC-1 and CK7 and a negative reaction to CK20. Apocrine carcinomas had high molecular weight (HMW) cytokeratin(+)/CK5(+)/CK14(−)/MUC5AC(−), EMPD with underlying apocrine carcinoma had HMW cytokeratin(−)/CK5(−)/CK14(−)/MUCA5AC(−) and the apocrine nevi had HMW cytokeratin(+)/CK5(+)/CK14(+)/MUCA5AC(+).
Conclusion:  The immunohistochemical findings suggest that apocrine carcinomas, apocrine nevi and EMPD with underlying apocrine carcinomas are quite different, even though they are all derived from apocrine glands.     

Cystic fibrosis transmembrane conductance regulator is helpful in the distinction of extra-mammary Paget's disease from squamous cell carcinoma in situ (Bowen's disease)

Cystic fibrosis transmembrane conductance regulator (CFTR) represents a cAMP-dependent channel found in normal apocrine glands. The classification and histogenesis of extra-mammary Paget's disease (EMPD) remains controversial, but it is generally accepted that primary EMPD exhibits apocrine differentiation. Therefore, we examined the utility of CFTR in the differential diagnosis of EMPD and squamous cell carcinoma in situ (SCCIS). Twenty-five cases of SCCIS and 14 cases of EMPD were evaluated for immunohistochemical expression of CFTR. Expression was scored as 0 (<5% of cells positive), 1+ (5-75% of cells positive) or 2+ (>75% cells positive). Twenty-three of 25 cases of SCCIS showed no reactivity for CFTR, and the remaining 2 cases showed 1+ staining. Thirteen of 14 cases of EMPD showed 2+ staining, while 1 case showed 1+ staining. We recognize that the pathological appearance along with clinical history and site of occurrence are sufficient to distinguish EMPD and SCCIS in most instances. However, distinction between the two can become more challenging when the location and histopathology are not characteristic. We conclude that when an immunohistochemical panel is diagnostically necessary, the expression of CFTR favors a diagnosis of EMPD over SCCIS.     

乳房外Paget病中汗腺病理及免疫组化分析

目的：分析乳房外Paget病(EMPD)中汗腺上皮组织CK7和CEA的表达及临床意义。方法：应用免疫组化SP法对15例EMPD皮损和周边正常皮肤CK7和CEA的表达进行检测。结果：15例中有8例在汗腺腺体及导管部见CK7和CEA呈阳性，其中仅5例发现汗腺上皮细胞呈异常改变。结论：免疫组化方法在诊断和鉴别诊断EMPD中汗腺上皮细胞的不典型增生具有一定价值。     

Extramammary Paget disease of the penis as a manifestation of recurrent transitional cell carcinoma

Extramammary Paget disease (EMPD) mainly affects elderly women in areas with apocrine glands. Only 10 cases have been reported to involve the penis in patients with underlying transitional cell carcinoma of the bladder. Herein we report a patient with EMPD of the penis after radical cystectomy.     

Extramammary Paget’s disease with intracytoplasmic lumen formation

Extramammary Paget’s disease (EMPD) is regarded as a malignancy most likely derived from or differentiated into apocrine sweat duct and gland. The tumor cells in EMPD usually have abundant pale cytoplasm and large pleomorphic nuclei. We present a case with EMPD where the tumor included many signet ring cells, cells with intracytoplasmic lumen formation and glandular formation. This case is interesting in that the tumor included many cells with intracytoplasmic lumen formation. Signet ring cells and glandular formation support the traditional speculation that EMPD is derived from apocrine sweat gland and intracytoplasmic lumen formation may mimic the intrafollicular apocrine duct.     

Matrilysin-1 (MMP-7) and MMP-19 are expressed by Paget's cells in extramammary Paget's disease

BACKGROUND: Extramammary Paget's disease (EMPD) is a rare malignant neoplasm of apocrine gland bearing skin characterized by intraepidermal proliferation of adenocarcinoma cells. Tumor growth depends on the ability of tumor cells to migrate by proteolysis and on angiogenesis. The matrix metalloproteinase (MMP) enzymes have been implicated in both of these processes in other types of skin cancer. METHODS: The expression of MMP-1, MMP-2, MMP-3, MMP-7, MMP-9, MMP-13, and MMP-19 was analyzed by immuno- histochemistry and/or in situ hybridization in 27 EMPD and five mammary PD (MMPD) specimens. The distribution of laminin-5 (LN-5) and tenascin-C, two extracellular matrix proteins associated with tumor invasion, was studied by immunohistochemistry. RESULTS: MMP-7 (matrilysin-1) and MMP-19 were the most frequently expressed MMPs in Paget's cells. Overexpression of MMP-2, MMP-9, or MMP-13, which is seen in many cancers, was not evident in EMPD. LN-5 and tenascin-C positivity did not correlate with the level of invasion. MMP-7, MMP-13, and MMP-19 were detected abundantly in MMPD, while MMP-9 was absent. CONCLUSIONS: MMP expression did not generally associate with the level of invasion of EMPD. In three samples positive for MMP-7 and four samples positive for MMP-19, an underlying carcinoma was detected, suggesting the importance of these two MMPs as predictors of secondary EMPD or the putative origin of Paget's cells from the dermal adenocarcinoma cells of apocrine duct origin.     

Adenocarcinoma of the mammary-like glands of the vulva:

An unusual case of primary adenocarcinoma of the vulva is described. It combined features of the three different types of adenocarcinoma of the skin of the vulva which are currently recognized, i.e. sweat gland carcinoma, adenocarcinoma derived from supernumerary mammary glands, and extramammary Pagel's disease (EMPD). Central in this tumor was a recently recognized type of cutaneous gland which appeared special for the anogenital region and was distinguished because it combined morphological features of eccrine, apocrine and mammary glands. As it most resembles mammary glands, it is named "mammary-like gland". On the basis of the case presented and of a critical review of the literature, it was concluded that, with the exception of a few sweat gland carcinomas similar to those elsewhere in the skin, adenocarcinomas of the skin of the vulva form a single category of neoplasms with a variable expression of features reminiscent of eccrine, apocrine and mammary gland carcinomas. The data strongly suggested a common derivation from the mammary-like gland or, in cases of EMPD, its related germinative cells in the epidermis.     

Modified weekly regimen of cisplatin,epirubicin and paclitaxel induced a durable response in two cases of metastatic extramammary Paget's disease

Metastatic extramammary Paget's disease (EMPD) is a rare cancer with no standardized treatment. We report two cases of metastatic EMPD treated with a modified weekly PET (cisplatin, epirubicin and paclitaxel) regimen given biweekly (i.e. 2 weeks on/2 weeks off) that had durable responses. Case 1 was a 74‐year‐old man with EMPD metastatic to lymph nodes, lung, and bone who presented with a hemorrhagic tumor on the scrotum. We tried the PET regimen weekly, but adjusted the interval to biweekly after two doses because of hematological side‐effects. After five doses, he showed a partial response (PR) on imaging, including the bone lesions. The lesions have remained the same size for 1 year. Case 2 was a 65‐year‐old man with EMPD metastatic to a right inguinal lymph node who presented with an erosive tumor on the scrotum. He was started on weekly docetaxel. However, the lymph node grew and iliac lymph node metastasis developed. Therefore, we tried the PET regimen with a 2 weeks on/2 weeks off schedule. After five doses, he showed a PR. In both cases, all adverse effects were manageable and this modified regimen could be administrated on an outpatient basis. With no current validated chemotherapy regimen, clinicians may consider a modified weekly PET regimen in future treatment of metastatic EMPD.     

Extramammary Paget disease with underlying hidradenoma papilliferum: guilt by association?

Extramammary Paget disease (EMPD) is a heterogenous entity representing either an intraepidermal adenocarcinoma in situ with apocrine differentiation or an expression of underlying malignancy of the skin or of the intestinal or genitourinary tract. The coexistence of EMPD with a benign underlying hidradenoma papilliferumn (HP) is, however, exceptional. We present the case of a 79-year-old woman with diffuse and patchy gray-white lesions involving her left vulva as well as an underlying 0.7-cm asymptomatic firm nodule. Histologically, the epidermis and dermis showed features characteristic of EMPD and HP, respectively. Malignant transformation in HP giving rise to EMPD in the overlying epithelium has been reported. In our case, however, failure to demonstrate continuity between the two lesions together with the lack of cytologic atypia, mitoses, and necrosis in the HP lends additional support to the possibility that the HP is "innocent" and that its association with EMPD is thus coincidental. A common histogenetic derivation of these two lesions from the mammary-like glands or from related germinative cells in the epidermis is suggested to explain this rare presentation.     

Extramammary Paget''s disease:

We examined 32 cases (38 lesions) of extramammary Paget's disease (EMPD) in relation to comparative studies on intraductal carcinoma of the breast (ductal carcinoma in situ, DCIS) and apocrine adenocarcinoma (AAC). Lesions included scrotum (18 lesions), vulva (8), axilla (6), groin (3), penis (2) and chest wall (1), and the distribution was compatible with that of apocrine or supernumerary mammary glands. Histologically, extra-mammary Paget's and DCIS cells exhibited a large amount of a pale-stained cytoplasm. The cytoplasm of AAC cells frequently contained granules, was eosinophilic and differed from that of Paget's or DCIS cells. Immunohistochemical studies revealed positive reactions for polyclonal and monoclonal antibodies to carcinoembryonic antigen in all EMPD and most DCIS, but not in AAC. Recent studies have shown that extramammary Paget's cells exhibit characteristics of glandular epithelial cells and that most cases of EMPD are not accompanied by an underlying carcinoma. The results obtained in this study, coupled with data on the frequency of the supernumerary breasts, lead to the speculation that extramammary Paget's cells originate from ectopic mammary glands or from pluripotential germinative cells in the epidermis, capable of differentiating toward the mammary glands.