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.     

Double cancer of plantar malignant melanoma and vulvar extramammary Paget’s disease

A 75‐year‐old woman presented with a 2‐year history of a pigmented nodular lesion on her left sole and a 9‐year history of a red infiltrative plaque on the vulva. The plantar lesion was a 15‐mm ulcerated nodule located at the center of a 25‐mm atypical pigmentation region; the nodule was clinically suspected to be a malignant melanoma. Histopathological analysis of the vulvar lesion biopsy sample indicated extramammary Paget’s disease (EMPD). There was no evidence of metastasis in the computed tomography (CT) and ¹⁸F‐fluorodeoxyglucose positron emission tomography scans. We simultaneously performed a wide excision of both lesions and a left inguinal sentinel lymph node biopsy. Melanoma cells were identified in the sentinel lymph nodes, and left radical lymph node dissection was performed after a course of neoadjuvant chemotherapy. All the lymph nodes that were resected during the second operation tested negative for melanomas, and the plantar lesion was diagnosed as a stage IIIB malignant melanoma (pT4b, Na2, M0). Thereafter, we administrated four courses of chemotherapy, and 8 months after the operation, there was no evidence of recurrence or metastatic lesions. We present a case report of double cancer: a plantar malignant melanoma and vulvar EMPD, and also discuss the possible genetic mutations responsible for these two tumors.     

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.     

Successful TS‐1 monotherapy as the second‐line treatment for advanced extramammary Paget's disease: A report of two cases

There is no standard chemotherapeutic treatment for advanced extramammary Paget's disease, though the effectiveness of some chemotherapy regimens, including docetaxel, has been reported. In this report, we report that TS‐1 monotherapy was effective in two patients with advanced extramammary Paget's disease after docetaxel treatment failure. TS‐1 monotherapy may be useful as the second‐line treatment for patients with advanced extramammary Paget's disease.     

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.     

Extramammary Paget's disease of the vulva: An annotated review of the current literature

Extramammary Paget's disease is a rare and unusual neoplastic entity that presents mainly on apocrine gland‐bearing skin. The vulva is the most common site of involvement but any area of the anogenital skin can be affected. Due to its rarity, variable clinical course and deceptive histological appearance it has a high misdiagnosis rate and both gynaecologists and dermatologists have limited experience in its management. The significance of the disease lies in its association with underlying malignancy as well as its inherent ability to invade the dermis and metastasise. The management is notoriously complicated and recurrence rates are high despite aggressive surgeries. Several alternative modalities are being explored, with results that are often variable and unpredictable. This review summarises the histopathological, clinical and therapeutic features of extramammary Paget's disease of the vulva reported in recent years.     

Successful treatment of combination therapy with tacalcitol lotion associated with sunscreen for localized Darier’s disease

We herein report a sporadic case of Darier’s disease localized to the bilateral side of the neck in a 39‐year‐old Japanese woman. Several clinical variants of Darier’s disease have so far been recognized including unilateral Darier’s disease, localized Darier’s disease, segmental Darier’s disease and acral Darier’s disease. Few cases of Darier’s disease, restricted to sun‐exposed areas such as the bilateral side of the neck, have been described in the published work. It remains controversial, however, whether ultraviolet exposure can induce the onset of Darier’s disease. Our patient’s skin lesions, which were resistant to previous treatment with corticosteroid, improved substantially with high‐concentration tacalcitol lotion and sunscreen. This is the first report on the efficacy of topical tacalcitol lotion associated with sunscreen for the treatment of localized Darier’s disease.     

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.     

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.     

Efficacy of photodynamic therapy with topical 5‐aminolevulinic acid using intense pulsed light for Bowen’s disease

Photodynamic therapy (PDT) with topical 5‐aminolevulinic acid (ALA) is reported to be an effective and safe treatment for superficial non‐melanoma skin cancers. We have developed an photodynamic therapy with topical δ‐aminolevulinic acid (ALA‐PDT) protocol using intense pulsed light (IPL) for treating Bowen’s disease (BD). Three patients diagnosed with BD by skin biopsy were recruited in this study. They received IPL treatment after 3 h of occlusive dressing with application of ALA. This protocol was repeated every 2 weeks for a total of five sessions. The treated areas did not show any signs of BD for more than 1 year; therefore, it appeared that the affected areas showed improvement in all the patients. No patients withdrew from the study because of side‐effects. ALA‐PDT with IPL as a light source is well tolerated by patients and is beneficial for treating BD.     

Dermoscopic features of Bowen’s disease in Asians

Background Previously, dermoscopic features of Bowen’s disease (BD) were extensively investigated in two studies, but there were some discrepancies. The dispute necessitated a further study concerning the dermoscopic features of BD. Objective To describe the dermoscopic features of BD in Asians and to assess dermoscopy as a post‐treatment monitoring tool of BD. Materials and methods Dermoscopic examinations of histopathologically diagnosed 26 BD lesions were performed to evaluate for the presence of various dermoscopic features. In addition, the correlating changes of dermoscopic features and histopathological results before and after treatments were assessed in five patients with BD. Results Dermoscopically, 10 lesions were pigmented and 16 lesions were non‐pigmented. The most frequent dermoscopic findings of BD were vascular structures (96%) and a scaly surface (96%). Among vascular structure, glomerular vessels were most frequently observed (77%). The other vascular structures in our study were linear irregular vessels, dotted vessels, polymorphous/atypical vessels and arborizing vessels. Among five patients who had been treated with either photodynamic therapy or 5% imiquimod cream, four patients revealed disappearance of dermoscopic vascular structures, but one patient showed remaining vascular structures after treatment. Skin biopsy from treated lesions disclosed clearance of BD in four patients who had no vascular structures but remaining BD in the patient whose dermoscopic finding displayed no disappearance of vascular structures. Conclusions Vascular structures, especially glomerular vessels plus a scaly surface, were common dermoscopic findings of BD in Asians. In addition, existence of dermoscopic vascular structures after treatment appears to be associated with residual disease.     

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.     

Efficacy of low‐dose 5‐fluorouracil/cisplatin therapy for invasive extramammary Paget's disease

Extramammary Paget's disease (EMPD) is one of the cutaneous adenocarcinomas. The effective chemotherapy for advanced EMPD has not been established. This study was designed to evaluate the efficacy of combination 5‐fluorouracil (500 mg/body, 7 days/week) and cisplatin (5 mg/body 5 days/week) for invasive EMPD. Seventeen EMPD patients with multiple metastases who visited our dermatology clinic between October 2004 and May 2016 (mean age, 76.9 years; 10 men, seven women) were retrospectively analyzed. Eight EMPD patients underwent low‐dose 5‐fluorouracil/cisplatin therapy and nine patients chose best supportive care. The average number of treatment cycles was 12.3. All patients had a confirmed response, four (50%) showed a partial response, two (25%) stable disease and two progressive disease. The median times to progression‐free and overall survival were 25.0 and 77.4 weeks, respectively. There was no severe (grade 3 and 4) adverse event. Although not significant, the survival of the patients treated with low‐dose 5‐fluorouracil/cisplatin therapy showed a trend toward improved survival as compared with best supportive care (P = 0.08, log–rank test). This regimen had low risk and relatively high disease control rate, suggesting that this regimen be recommended as one of the treatment options for advanced EMPD.     

Chemotherapy reaction induced by ixabepilone,a microtubule stabilizing agent,mimicking extramammary Paget's disease in a patient with breast carcinoma

The histopathologic characteristics of reactions caused by the many novel anticancer agents are under‐recognized. We report a case of a 67‐year‐old female with locally advanced metastatic breast cancer, who initially presented with an extensive reticulated erythematous patch on the trunk caused by intravascular metastases confirmed by a skin biopsy. Owing to disease progression, she was started on ixabepilone, a mitotic inhibitor. While receiving ixabepilone, another skin biopsy was obtained and initially interpreted as extramammary Paget's disease. However, the biopsy showed metaphase arrest of numerous keratinocytes in the basilar and suprabasilar epidermis. Atypical epithelial cells were only present in the intravascular spaces similar to the initial biopsy. Given the temporal association between the initiation of ixabepilone therapy and the epidermal mitotic arrest, a diagnosis of chemotherapy reaction to ixabepilone was rendered. Ixabepilone is an analog of epothilone, a microtubule stabilizer causing mitotic arrest of the cell cycle approved for the treatment of metastatic and locally advanced treatment‐resistant breast cancer. The demonstration of epidermal mitotic arrest caused by ixabepilone is without precedent. The case emphasizes the importance of considering a chemotherapy reaction in the histologic differential diagnosis of epidermal mitotic arrest in a cancer patient receiving chemotherapy.     

Microalbuminuria as an early marker of renal involvement in Behcet’s disease: it is associated with neurological involvement and duration of the disease

Background Despite its nature as a systemic vasculitis, renal involvement is known to occur infrequently in Behçet’s Disease (BD). Objectives Our aim was to investigate proteinuria, microhematuria and microalbuminuria in 24‐h urine and evaluate subclinical or symptomatic renal involvement in BD patients. Methods Two hundred and eleven patients who fulfilled the International Behçet’s Disease criteria were included in the study. After urine analysis, five of 12 patients who were found to have proteinuria underwent renal biopsy, while 199 patients without proteinuria were investigated for microalbuminuria (MA). Results A total of 34 (16.1%) patients were found to have renal involvement including 22 (11.1%) with MA and 12 with proteinuria (5.6%). Renal biopsies resulted as focal glomerulosclerosis in three, membranous glomerulosclerosis in one and secondary amyloidosis in two patients. Neurological involvement was found to be significantly more prevalent in patients with MA (P <0.01). Neurological involvement and duration of disease (≥10 years) was found to increase the risk for MA by 21.75‐fold and 5.03‐fold, respectively. Though age over 40 years, thrombophlebitis, HLA B51 haplotype and opthalmological involvement were not found to be significantly associated with MA; these parameters increased the risk for MA. Conclusions Renal involvement may be more prevalent in BD than it has been recognized; it usually presents with asymptomatic microhematuria, proteinuria and/or microalbuminuria; therefore clinicians must check 24‐h urine for the presence of proteinuria, microhematuria and microalbuminuria; especially in patients who are aged over 40 years, have a longer duration of the disease and multisystem involvement.     

Serum cytokeratin 19 fragment 21‐1 is a useful tumor marker for the assessment of extramammary Paget's disease

Cytokeratin 19 fragment 21‐1 (CYFRA 21‐1) has been used as a tumor marker for several malignancies. However, to date, no studies have assessed whether CYFRA 21‐1 could be a useful marker for extramammary Paget's disease (EMPD). The present study aimed to evaluate the significance of CYFRA 21‐1 as a serum tumor marker for EMPD progression. Concentrations of serum CYFRA 21‐1 and carcinoembryonic antigen (CEA) in 13 cases of EMPD were measured prior to undergoing treatment at Sapporo Medical University Hospital from January 2014 to May 2016. Four of the 13 patients had lymph node metastases at diagnosis, but none had distant metastases. Immunohistochemistry indicated that all 13 primary tumors and four metastatic tumors in lymph nodes were positive for cytokeratin 19. Although none of the 13 patients showed high serum CEA levels, six patients (46.2%) had elevated serum CYFRA 21‐1. Furthermore, CYFRA 21‐1 was reduced in association with post‐treatment tumor reduction in all six patients. Among these six patients, four developed recurrence and metastasis during the follow‐up period. CYFRA 21‐1 was re‐elevated in all four of these patients; however, serum CEA was elevated only in the patient with distant metastasis. These results suggest that CYFRA 21‐1 is more sensitive compared with CEA, and can be useful as a tumor marker for evaluating tumor progression and treatment efficacy in patients with EMPD.     

Treatment efficiency of combining photodynamic therapy and ionizing radiation for Bowen’s disease

Background Topical 5‐aminolevulinic acid photodynamic therapy (ALA‐PDT) is widely used for treating Bowen’s disease (BD), but recurrence and tumour cell persistence after ALA‐PDT is sometimes problematic. Radiation therapy (RT) is also effective for BD, but is limited by its side‐effects, such as refractory ulcers. Objective The objective of the study was to observe a synergic effect of combination therapy with ALA‐PDT and RT for BD cases that did not respond effectively to prior ALA‐PDT. Methods Subjects were BD patients whose lesion did not show complete remission or showed recurrence after prior ALA‐PDT. A total of four cases involving four lesions were studied (three male and one female, mean age 69.5). ALA ointment (20%) was applied to the lesions. After 4 to 6 h, subjects received combination therapy consisting of excimer‐pumped dye laser radiation at 630 nm (50 J/cm²) followed by electron‐beam radiation (3 Gy). The combination therapy was repeated every 2 to 3 days for a total of four treatments. The lesions were evaluated clinically or histologically after the final combination therapy session. Results Following combination therapy, all of the lesions disappeared. Recurrence was not detected during the observations periods, which averaged 14.0 months in duration. Conclusion Our results indicate that the cure rate of BD could be improved by combination therapy with ALA‐PDT and RT. Compared with conventional RT, the synergetic effect of this therapy might reduce the dose of radiation required, thereby also reducing skin side‐effects such as refractory ulcers.