Radiotherapy for extramammary Paget's disease: histopathological findings after radiotherapy

Several reports have suggested the efficacy of radiotherapy for treating extramammary Paget's disease (EMPD); however, these reports comprised only clinical observations, without in-depth histopathological observations. We report our experience of genital EMPD treated by radiotherapy in two elderly women, and the marked efficacy of radiotherapy, confirmed both by clinical observation and by detailed histopathological investigations. Our cases agree with the notion that radiotherapy is useful as an alternative therapy for EMPD, and should be considered particularly in elderly patients who may not tolerate surgery well.     

Depigmented extramammary Paget's disease

BACKGROUND: Depigmented extramammary Paget's disease (EMPD) has been reported in a few cases. Depigmented macules or patches may be the only presenting sign or may coexist with the classical erythematous lesions. OBJECTIVES: To investigate the occurrence rate and clinical presentation of depigmentation in EMPD. METHODS: All pathology-proven cases of EMPD diagnosed in our department during 1990-2003 were retrieved. The clinical photographs were reviewed for evidence of local depigmentation. The pathological diagnosis of EMPD in the whitish lesions was confirmed by positive expression of cytokeratin 7 or carcinoembryonic antigen, and/or the presence of intracytoplasmic mucin. RESULTS: Of 19 cases of EMPD, six (30%) manifested depigmented lesions which were confirmed to be EMPD pathologically. In two patients, the hypopigmentation was associated with erythematous lesions at the initial presentation. In four others, the depigmentation developed later as local recurrence after excision, cryotherapy, photodynamic therapy or radiotherapy. The progressive enlargement of the depigmentation and the appearance of separate new white lesions in these four cases suggested that the localized depigmentation was unlikely to be simple postinflammatory hypopigmentation. CONCLUSIONS: Our study suggests that depigmented EMPD may not be rare. Localized depigmentation in the genital area can be an early sign of EMPD and its local recurrence. In patients with an established diagnosis of EMPD, appearance of new white lesions and continuous enlargement of depigmented patches should not be dismissed as simple treatment-induced postinflammatory hypopigmentation or another type of hypopigmented lesion without biopsy confirmation.     

乳房外Paget病的治疗进展

乳房外Paget病好发于老年人,多发生于肛门及外生殖器周围,由于早期皮损与湿疹、皮炎类似,容易误诊。乳房外Paget病的首选治疗方法为手术治疗,由于皮损边界不清、有多处病灶、肿瘤组织呈跳跃性生长,很难保证切除干净致术后复发率高。其他治疗方法有：放射治疗、化学治疗、光动力疗法、免疫调节剂治疗、分子靶向治疗等。乳房外Paget病预后主要与肿瘤的浸润深度、区域淋巴结转移、淋巴血管转移相关。前哨淋巴结活检对淋巴结清扫有指导意义,选择性淋巴结清扫有助于后续治疗,提高患者生存率。     

反射式共聚焦显微镜在乳房外Paget病的应用进展

乳房外Paget病是一种起源于顶泌汗腺的皮肤恶性肿瘤,老年男性多见,好发于外阴等部位,皮损类似湿疹样表现。该病进展缓慢,临床表现无明显特异性,患者由于症状轻对疾病的重视程度不够,早期易误诊。多数患者愈后较好,病程越长、真皮浸润深度越深、局部淋巴结转移提示预后越差。乳房外Paget病治疗首选外科扩大切除,然而由于术前肉眼判断肿瘤边界不准确导致切缘肿瘤细胞阳性率较高。反射式共聚焦显微镜作为一种良好的实时、在体成像技术,可用于乳房外Paget病的诊断、术前定位,降低手术切缘肿瘤细胞阳性率,减少肿瘤复发,改善预后。     

Extramammary Paget's disease: treatment, prognostic factors and outcome in 76 patients

BACKGROUND: Extramammary Paget's disease (EMPD) is a rare cutaneous carcinoma usually presenting as a genital erythematous lesion in the elderly. Although most EMPD tumours are in situ, invasive EMPD has a poor prognosis. OBJECTIVE: To evaluate the clinical and pathological features of EMPD and determine prognostic factors for survival. METHODS: The medical records of 76 patients with EMPD were retrospectively reviewed. RESULTS: Of the 66 patients who underwent curative surgical excision, five (8%) developed local recurrence, but surgical margin (2 cm) was not correlated with local recurrence. Thirteen of the 76 patients (17%) developed systemic metastases and 10 of these died of disease. On univariate analysis, the presence of nodules in the primary tumour, clinical lymph node swelling, elevated serum carcinoembryonic antigen (CEA) levels, tumour invasion level and lymph node metastasis were significant prognostic factors. On multivariate analysis, invasion level and elevated serum CEA were the only factors that were significantly associated with reduced survival. CONCLUSIONS: Invasion level and lymph node metastasis are important prognostic factors in EMPD. In patients with in situ tumour, local tumour control is the major aim of treatment; however, wide surgical margins are not associated with a lower risk of local recurrence.     

Usefulness of docetaxel as first‐line chemotherapy for metastatic extramammary Paget's disease

In invasive extramammary Paget's disease (EMPD), distant metastases may develop and the condition may become fatal; however, no standardized treatment has been established. Although based on only a few cases, several chemotherapy regimens were reported to be promising. We conducted a multicenter, retrospective study to evaluate the efficacy of docetaxel for metastatic EMPD. We retrospectively collected data on 18 metastatic EMPD patients treated using docetaxel from 1998 to 2012 in 12 institutes in Japan. The following clinical data were collected: tumor response, time to progression, overall survival and adverse effects. Of those, three patients treated combined with S‐1, one patient treated with weekly schedule and one patient treated combined with radiotherapy were excluded from the further analysis. All 13 patients received monthly docetaxel as the first‐line treatment. The average number of treatment cycles was 9.1. Among the 12 patients with a confirmed response, seven (58%) showed a partial response, three (25%) stable disease and two (17%) progressive disease. The disease control rate (partial response + stable disease) was as high as 83%. The time to progression and median overall survival were 7.1 and 16.6 months, respectively. The 1‐year overall survival rate determined by the Kaplan–Meier method was 75.0%. All adverse effects were manageable and no treatment‐related deaths were observed. The high disease control rate and overall survival shown by this study suggest that first‐line use of docetaxel may be a promising treatment for metastatic EMPD. A prospective clinical trial is required to confirm our results.     

Spontaneous apparent clinical resolution with histologic persistence of a case of extramammary Paget's disease: response to topical 5-fluorouracil

An 86-year-old woman presented with a 3-year history of an erythematous axillary lesion, which was histologically confirmed to be extramammary Paget's disease (EMPD) confined to the epidermis and adnexa. Surprisingly, spontaneous clinical regression occurred in the lesion, but Paget's cells persisted within the epidermis and adnexa on histologic examination. One year of intermittent topical chemotherapy with 5-fluorouracil resulted in ulcers that were interpreted as EMPD and completely excised. Histologic examination showed a complete absence of Paget's cells. To our knowledge, only one previous report investigated apparent spontaneous clinical resolution with histologic persistence of EMPD. We emphasize that topical 5-fluorouracil cannot be considered a safe treatment modality for EMPD, but it may be useful in certain cases in which the extent of the lesions, or the general condition of the patient, advise against surgery or radiotherapy.     

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.     

Ectopic extramammary Paget's disease affecting the upper abdomen

Summary We present 57-year-old man in whom ectopic extramammary Paget's disease (EMPD) affected the upper abdomen. Although the clinical appearance was suggestive of Bowen's disease or superficial basal cell epithelioma (BCE), the biopsy specimen showed EMPD histologically. Only 12 cases of ectopic EMPD have been reported (including this case). In our 20 year experience of 129 EMPD, this is the first ectopic case. Thus, the frequency of ectopic EMPD is 0–78% (one of 129) in our study. The male/female ratio in the reported 12 cases is 2 : 1. nearly the same as EMPD in general (2:1:1, in our 129 cases). The mean age of the 12 patients is 65.8 years, which is not significantly different from ordinary EMPD (66–;4 years, in our 129 cases). Comparing ectopic EMPD to ordinary EMPD, clinically and histologically. we could find no difference. As they appear to be the same disease, ectopic and ordinary EMPD may share similar origins and mechanisms of occurrence. We support the hypothesis that Paget's cells originate from the remaining pluripotential germinative cells which are able to differentiate into many kinds of secreting glands.     

Outcomes of lymph node dissection in the treatment of extramammary Paget’s disease: A single-institution study

Extramammary Paget’s disease (EMPD) often invades the dermis and metastasizes to the lymph nodes. Patients with EMPD associated with lymph node metastases have poor prognosis; to date, effective treatment has not yet been established. Lymph node dissection, aiming to control the local disease, is a standard form of management for EMPD patients with lymph node metastases (LNM). We investigated the clinical and pathological features, treatment strategies and prognostic factors of patients with metastatic EMPD who underwent lymph node dissection. We retrospectively evaluated 38 cases of extramammary Paget’s disease with lymph node metastasis over 10 years. All patients underwent wide resection of the primary lesion and lymph node dissection. Univariate analysis revealed the number of metastatic nodes and lymphadenopathy as prognostic factors. In multivariate analysis, the number of metastatic lymph nodes retained statistical significance (hazard ratio, 35.3; 95% confidence interval, 3.23–387.0; P = 0.003). The 5-year survival rate was 100% and 19.1% in patients with two or less LNM and with three or more LNM, respectively. In patients with three or more LNM, the 5-year survival rate after adjuvant radiation therapy was better than that after surgery alone (75% vs 0%). In conclusion, patients with two or less LNM can be expected to have long-term survival with lymph node dissection only, while patients with three or more LNM may require adjuvant radiation therapy to improve prognosis. These results suggest that lymph node dissection may be a strategy to treat EMPD with regional LNM.     

Differential expression of two new members of the p53 family, p63 and p73, in extramammary Paget's disease

Background.  The proteins p53, p63 and p73 are known to be overexpressed and to play important roles in the pathogenesis of many tumours, but the expression of p63 and p73 has not previously been investigated in extramammary Paget's disease (EMPD).
Aim.  To investigate the potential contribution of p53, p63 and p73 in the pathogenesis of EMPD.
Methods.  In total, 35 paraffin wax-embedded tissue samples from patients with EMPD were examined using immunohistochemical staining for p53, p63 and p73.
Results.  All of the 35 EMPD specimens, including all 6 invasive EMPD and 2 metastatic lymph-node specimens, showed nuclear overexpression of both p53 and p73. The expression levels (percentage of positive cells) of p53 and p73 (90.66 ± 12.53% and 80.20 ± 13.07%) in EMPD were significantly higher than those of normal skin. There was a significant correlation between the expression levels of p53 and p73 in EMPD. In 29 of 35 EMPD specimens, there was no nuclear expression of p63, and weak or moderate staining was found in only 6 specimens. The expression level of p63 in EMPD was significantly less than that in normal skin.
Conclusions.  Our study shows that the concordant overexpression of p53 and p73 and the decreased expression of p63 may play a pivotal role in the pathogenesis of EMPD. The decreased expression of p63 may play a more important role in the pathogenesis of EMPD than the overexpression of p53 and p73.     

Enfermedad de Paget extramamaria

Background and objectiveExtramammary Paget disease (EMPD) has seldom been studied in Mediterranean populations. We aimed to review the characteristics of our patients with EMPD, the presence of a neoplasm in continuity, and the long-term course of the disease.Patients and methodsRetrospective observational study of 27 patients diagnosed with EMPD between 1990 and 2015. All clinical and pathology findings related to clinical course and outcomes were retrieved for analysis.ResultsTwenty patients were women and 7 were men. Ages ranged from 42 to 88 years (median, 76 years). Lesions were in the following locations: vulva (16 cases), pubis–groin (5), perianal region (4), and axilla (2). Time from onset to diagnosis ranged from 1 to 60 months (median, 12 months) and maximum lesion diameter from 20 to 140 mm (median, 55 mm). In 3 cases (11.1%) EMPD was a secondary condition. None of the lesions developed on a previous cutaneous adnexal adenocarcinoma. Ten of the 24 primary EMPDs (41.7%) invaded the dermis. Eight of the 27 patients (29.6%) experienced local recurrence after the initial surgical treatment.Three patients (11.1%) died as a consequence of metastasis from the EMPD.ConclusionsThe presence of an underlying cutaneous adnexal adenocarcinoma is uncommon, but it is not unusual to find an extracutaneous adenocarcinoma in continuity. Although EMPD is a slow-growing tumor, dermal invasion is frequent and metastasis is not uncommon. Local recurrence is common even after excision with wide margins and may be delated, so long term follow-up is essential.     

Perineal extramammary Paget disease responsive to topical imiquimod

Extramammary Paget disease (EMPD) is a rare neoplasm that arises in skin rich in apocrine glands, such as the axillae and anogenital region and usually affects the elderly. In most cases, EMPD is an apocrine carcinoma in situ, but it can be associated with internal malignancy spreading to overlying skin. Surgical excision with margin control is the generally accepted standard of care. A 74‐year‐old woman presented with a 1 year history of a pruritic eczematous eruption in perineum which on biopsy was diagnosed as EMPD. Because of the location and extent of the tumor, any surgical approach would have been problematic. Imiquimod 5% cream applied three times weekly for 16 weeks induced complete resolution. Topical imiquimod appears to be a promising treatment option for EMPD, especially when surgery is a challenge, but only a few cases have been reported.     

5-Aminolevulinic acid-based photodynamic therapy for the treatment of two patients with extramammary Paget's disease

Photodynamic therapy (PDT), which employs a combination of a tumor-localizing photosensitizer and visible light, has been used in the treatment of extramammary Paget's disease (EMPD). Two patients with EMPD were treated with PDT using 5-aminolevulinic acid (ALA). Histologically, in both cases, Paget's cells were present within the epidermis. Case 1 was a 92-year-old male who underwent total extirpation for treatment of EMPD. Two topical ALA-PDT treatments were applied to parts of the lesions at a total dose of 200J/cm2. Case 2 was a 73-year-old female, whose lesions in the right labia majora were treated with 3 topical ALA-PDT sessions at a total dose of 300 J/cm2. Clinical findings after the irradiation showed improvement in both patients, and elimination of tumor cells in the epidermis was confirmed histologically. Case 1 had no recurrence in the irradiation field at three months after PDT. Case 2 had a recurrence only in the periphery parts of the lesions at two months after PDT, but the periphery lesions remitted with two more PDT treatments. Topical ALA-PDT is an effective treatment for EMPD with tumor cells within the epidermis. It is noninvasive and achieves a cosmetically excellent outcome, especially in elderly patients and those in poor general condition.     

Extramammary Paget's disease resistant to surgery and imiquimod monotherapy but responsive to imiquimod combination topical chemotherapy with 5-fluorouracil and retinoic acid: a case report

Extramammary Paget's disease (EMPD) is an uncommon skin neoplasm that usually affects the elderly population and occurs in the genital, anorectal, or axillary areas. The recommended treatment of EMPD involves surgical excision, including Mohs micrographic surgery; however, surgery is associated with a high rate of recurrence. There have been reports of successful treatment of recurrence with monochemotherapy involving topical imiquimod 5% cream. We report a case of EMPD recurrence after surgery that was resistant to imiquimod monotherapy but that completely resolved after imiquimod was combined with topical 5-fluorouracil (5-FU) and retinoic acid. To our knowledge, this is the first reported case of imiquimod combination therapy with 5-FU and retinoic acid for the treatment of recurrent EMPD.     

Spa-1和Ki-67在乳房外Paget病肿瘤组织中的表达

目的 探讨Spa-1在乳房外Paget病发生和转移中可能的作用.方法 取17例原位乳房外Paget病和12例侵袭性乳房外Paget病患者皮损及9例正常人皮肤组织,用免疫组化分别检测Spa-1和Ki-67的表达.结果 Spa-1在胞质中显色,Ki-67在胞核中显色.Spa-1和Ki-67仅少量表达于正常人皮肤基底层,在乳房外Paget病肿瘤组织中的表达明显高于正常人皮肤(P<0.01).Spa-1在侵袭性乳房外Paget病肿瘤组织中表达明显高于原位乳房外Paget病(P<0.01).乳房外Paget病肿瘤组织中Spa-1的表达与Ki-67的表达呈正相关.结论 Spa-1在乳房外Paget病的发生发展中可能起作用.

Abstract：

Objective To investigate the potential role of Spa-1 in the development and metastasis of EMPD.Methods Tissue specimens were resected from 17 patients with primary EMPD,12 patients with invasive EMPD and 9 normal human controls.Immunohistochemistry was performed to measure the expression of spa-1 and Ki-67.Results Positive staining was observed for Spa-1 in cytoplasm,and for Ki-67 in cell nuclei.Spa-1 and Ki-67 were weakly expressed in the basal layer of normal skin.The expression of Spa-1 and Ki-67 in EMPD tissue were statistically higher than those in the normal control tissue (both P<0.01).Increased expression of Spa-1 was noted in invasive EMPD tissue compared with in situ EMPD tissue.The expression of Spa-1 was positively correlated with that of Ki-67 in the tissue of EMPD.Conclusion Spa-1 may play a certain role in the initiation and progression of EMPD.     

Serum cytokeratin 19 fragment 21-1 and carcinoembryonic antigen combination assay as a biomarker of tumour progression and treatment response in extramammary Paget disease

Extramammary Paget's disease (EMPD) is a rare skin cancer affecting the genitals and armpit regions. EMPDs occur mainly in Caucasian women and Asian men over the age of 60, in less than 0.6 per 100,000 people. Basic treatment is excision (removal) by operation, yet metastasis, meaning that it has spread, is seen in around 10% of patients. If the cancer is spreading, it is really important to detect this and start treatment as early as possible, since in late stages the disease can be hard to treat. A biomarker, or marker, is a molecule found in blood, different levels of which correspond with how well the body responds to a treatment, or to how the disease will progress. Carcinoembryonic antigen (CEA) and cytokeratin 19 fragment 21-1 (CYFRA 21-1) are both biomarkers for certain other cancers, and it has been suggested that they might also be markers for monitoring tumour progression in EMPD; however, neither the accuracy of, nor correlation between, these markers have been examined in EMPD patients. This study from Japan aimed to find out the usefulness and relationship of CEA and CYFRA21-1 levels in blood of EMPD patients in various progression states of the disease. A total of 30 EMPD cases were included in this study. In all early-stage patients, CEA and CYFRA were within normal levels. In advanced-stage patients, CEA and CYFRA were elevated in 79% and 63%, respectively. Either CEA or CYFRA was found to be elevated in 95% of the advanced patients, indicating that a certain number of patients have raised levels of only one of the markers. In addition, both of the markers also correlated well with the treatment responses in all patients. This study revealed that examining both CEA and CYFRA may help to detect advanced-stage EMPD patients, and that they are useful for monitoring treatment responses.     

Imiquimod 5% cream as a therapeutic option for extramammary Paget's disease

A wide local excision is the standard treatment for extramammary Paget's disease (EMPD), though this treatment often leads to permanent anogenital mutilation and functional impairment. The purpose of our study is to evaluate the efficacy and safety of the topical application of imiquimod 5% cream for non‐invasive EMPD. We examined nine patients with EMPD. Eight of the nine patients were treated with imiquimod 5% cream three times per week for 16 weeks; one case was treated for 6 weeks. The response rate was 100% including five complete remissions. Local irritation was observed in three patients, which was controlled by a provisional withdrawal of the treatment. These results suggest that imiquimod 5% cream may be considered an alternative therapeutic option for the treatment of non‐invasive EMPD.     

Concordant overexpression of p-FAK and p-ERK1/2 in extramammary Paget’s disease

Focal adhesion kinase (FAK) is a tyrosine kinase which is at the crossroad of extracellular signal-regulated kinase-1/2 (ERK1/2), PI3K/Akt, MAPK and JAK/STAT signaling pathways. We have previously reported that p-ERK1/2, p-Akt, p38MAPK and p-STAT3 are overexpressed in extramammary Paget’s diseases (EMPD), this study aimed to examine the expression of phosphorylated (p)-FAK and p-ERK1/2 proteins in EMPD and to evaluate the relationships among them. Paraffin-embedded EMPD specimens (35 tissue samples from 33 patients with primary EMPD, including two samples of metastatic lymph nodes from two of the 33 patients) were subjected to immunohistochemical staining for p-FAK and p-ERK1/2. All of the 35 EMPD specimens, including all of six invasive EMPD and two metastatic lymph node specimens, showed cytoplasmic overexpression of p-FAK and nuclear overexpression of p-ERK1/2. The expression levels (% positive cells) of p-FAK and p-ERK1/2 (88.34 ± 14.66 and 91.26 ± 11.21%) in EMPD were significantly higher than those in normal skin (22.38 ± 2.13 and 29.00 ± 4.44%), respectively. The expression levels of p-FAK (95.38 ± 4.57%) and p-ERK1/2 (96.25 ± 5.01%) in the advanced EMPD showed slightly higher than that in the non-invasive EMPD (86.26 ± 15.99 and 89.78 ± 12.15%), respectively. There exhibited a significantly high positive correlation between expression levels of p-ERK1/2 and p-FAK in EMPD. The present study shows that the concordant overexpression of p-FAK and p-ERK1/2 in EMPD which is associated with the grade of malignancy of EMPD, indicating that p-FAK and p-ERK1/2 may play pivotal roles in the tumorigenesis and further malignant transduction of EMPD.