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.     

Distal phalangeal metastasis of extramammary Paget's disease

A rare case of phalangeal metastasis of extramammary Paget's disease in a 68-year-old man is described. The patient developed an erythematous, slightly elevated area in the pubic region. A biopsy specimen demonstrated numerous, large, rounded cells with ample pale-staining cytoplasm proliferating in the epidermis. With a diagnosis of extramammary Paget's disease, he underwent wide local excision and inguinal node dissection. Eleven months postoperatively, the patient developed a tender, red, swollen right ring finger. Bone X-ray showed that the distal phalanx of the ring finger had completely dissolved. Histopathological examination demonstrated proliferation of tumor cells in the adipose tissue. They had poorer and darker cytoplasm than the Paget's cells in the epidermis of the pubic region. Immunohistochemically, these cells showed the same staining pattern as did the Paget's cells at the primary site. Accordingly, the patient was diagnosed with distal phalangeal metastasis of extramammary Paget's disease. Two weeks after the appearance of the distal phalangeal metastasis, the patient died of cancerous pleurisy. It has been reported that patients with phalangeal metastasis have a very poor prognosis.     

A case of metastatic extramammary Paget's disease that responded to combination chemotherapy.

Extramammary Paget's disease is considered to be a malignant tumor originating from the sweat glands. Some cases of extramammary Paget's disease infiltrate the dermis and metastasize to the regional lymph nodes. No standard treatment has been established for advanced cases. Few previous studies of the treatment for metastatic Paget's disease have revealed an effective regimen. The prognosis of metastasized cases is very poor. We encountered a patient in whom extramammary Paget's disease had metastasized to the lymph nodes beyond the regional lymph nodes and systemic chemotherapy was partially effective. Combination chemotherapy consisted of mitomycin C 3.5 mg/m2 and epirubicin 50 mg/m2 on day 1, vincristine 0.6 mg/m2 on days 1 and 7, cisplatin 30 mg/m2 from days 1 to 3, and 5-fluorouracil 350 mg/m2 from days 3 to 7. After two courses of chemotherapy, the metastatic lymph nodes decreased in size by more than 90% compared to that before chemotherapy. We defined the treatment effect of this regimen as a partial response (PR). Microscopic examination of the resected lymph nodes revealed replacement of metastatic lesions by fibrous tissue, suggesting a therapeutic effect. Anorexia, alopecia, and leukopenia (neutropenia) have been reported as toxicities, but all were tolerated. Our results may provide useful indications for the management of this tumor. This particular combination chemotherapy is recommended for extramammary Paget's disease patients with systemic nodal metastases.     

Docetaxel induced durable response in advanced extramammary Paget's disease: a case report

The patient was a 54-year-old Japanese man with a seven-month history of an eroded lesion on the scrotum. Skin biopsy confirmed the diagnosis of extramammary Paget's disease, and a CT scan revealed multiple metastases to the lymph nodes along the iliac artery and aorta. The patient underwent combination chemotherapy with mitomycin C, epirubicin, vincristine, cisplatin, and 5-fluorouracil. After two courses of the regimen, the primary lesions on the scrotum regressed, however, the lymph node metastases did not respond. A regimen of continuous administration of low-dose cisplatin and 5-fluorouracil was not effective for the metastases either. Hence, administration of docetaxel at a dose of 60 mg/m2/every four weeks was started. After two courses, the lymph node metastases decreased by 75% compared to the pre-treatment size, and the effect was judged a partial response. The major toxicities were neutropenia, alopecia, pitting edema, and facial erythema, but these were tolerable. Five courses of this regimen were followed by four courses of weekly administration of 25 mg/m2 docetaxel. The partial response persisted for more than 12 months and the patient was able to enjoy daily life. Docetaxel may be an effective drug for patients with advanced extramammary Paget's disease.     

Sequential use with imiquimod and surgery in extramammary Paget's disease

Extramammary Paget's disease is an uncommon intraepithelial adenocarcinoma which occurs in areas rich in apocrine glands. Although surgery is the treatment of choice, numerous noninvasive treatments have been tried. There are studies that have demonstrated the efficacy of imiquimod to treat Extramammary Paget's disease, but we found no mention in the literature of its use as neoadjuvant therapy previous to surgery excision. We present a case of a large plaque of extramammary Paget's disease successfully treated with imiquimod and minor surgery of the residual disease.     

Mammary and extramammary Paget's disease

Paget''s disease, described by Sir James Paget in 1874, is classified as mammary and extramammary. The mammary type is rare and often associated with intraductal cancer (93-100% of cases). It is more prevalent in postmenopausal women and it appears as an eczematoid, erythematous, moist or crusted lesion, with or without fine scaling, infiltration and inversion of the nipple. It must be distinguished from erosive adenomatosis of the nipple, cutaneous extension of breast carcinoma, psoriasis, atopic dermatitis, contact dermatitis, chronic eczema, lactiferous ducts ectasia, Bowen''s disease, basal cell carcinoma, melanoma and intraductal papilloma. Diagnosis is histological and prognosis and treatment depend on the type of underlying breast cancer. Extramammary Paget''s disease is considered an adenocarcinoma originating from the skin or skin appendages in areas with apocrine glands. The primary location is the vulvar area, followed by the perianal region, scrotum, penis and axillae. It starts as an erythematous plaque of indolent growth, with well-defined edges, fine scaling, excoriations, exulcerations and lichenification. In most cases it is not associated with cancer, although there are publications linking it to tumors of the vulva, vagina, cervix and corpus uteri, bladder, ovary, gallbladder, liver, breast, colon and rectum. Differential diagnoses are candidiasis, psoriasis and chronic lichen simplex. Histopathology confirms the diagnosis. Before treatment begins, associated malignancies should be investigated. Surgical excision and micrographic surgery are the best treatment options, although recurrences are frequent.     

Double involvement of extramammary Paget's disease in the genitalia and axilla

We here reported a case of an 82-year-old man with double involvement of extramammary Paget's disease in the genitalia and axilla. Physical examination revealed erythema and reddish tumors on the pubic area and scrotum and irregular-shaped erythema on the left axilla. The skin biopsy sample from the genital area showed Paget's cells in the epidermis and upper dermis. The specimen from the left axilla showed Paget's cells scattered in the epidermis but not in the dermis.     

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.     

Extramammary Paget's disease/carcinoma successfully treated with a combination chemotherapy: report of two cases

We have treated two patients with extramammary Paget's disease/carcinoma (EMPD/C), a 62-year-old woman and a 78-year-old man. In both patients, lymph nodes in the areas of the bilateral inguinal, external iliac arteries, and abdominal aorta were affected. After surgery, they underwent 5 courses of systemic combination chemotherapy at 4-week intervals to residual or recurrent lymph node metastasis. Each course consisted of 3.5 mg mitomycin C and 50 mg epirubicin (day 1), 0.6 mg vincristine (days 1 and 7), 30 mg cisplatin (days 1, 2, and 3), and 350 mg 5-fluorouracil (days 3, 4, 5, 6, and 7). The affected lymph nodes in both patients subsided in response to the chemotherapy. Positron emission tomography (PET) scans confirmed the complete remission of lymph node metastasis in Case 1. In Case 2, they were reduced by more than 90% on computed tomography (CT) scans. Adverse effects included leukocytopenia, vomiting, hypesthesia, and constipation, all of which disappeared after the completion of chemotherapy. While surgery with wide local excision is the treatment of choice in patients with EMPD/C, there is currently no standardized treatment for advanced cases with metastasis. We describe two patients with EMPD/C whose metastatic lesions responded well to this combination of chemotherapy.     

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.     

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: A Report of 22 Cases in Chinese Males

Extramammary Paget's disease (EMPD) is more frequently seen in Caucasian females than in males (3.2:1 female: male ratio). During the past 14 year period, we have collected 22 patients, all Chinese males, with EMPD. They presented with eczema-like lesions in the early stages in the genital or perianal regions. Histological sections showed Paget cells within the epidermis or skin appendages and even within the dermis. No underlying adnexal carcinoma or adjacent internal carcinoma could be detected after thorough examinations. Mode of therapy and outcome are presented. EMPD seems to affect more males than females in Orientals. The incidence of concomitant malignancy in Chinese male patients with genital Paget's disease seems to be much lower than that in Caucasians. However, if EMPD involves the glans penis or perianal area, a search for internal malignancy is still warranted.     

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.     

Paget's disease arising near a male areola without an underlying carcinoma.

We report a 56-year-old man with Paget's disease occurring near the left areola without any underlying breast carcinoma. Histologically, there was no evidence suggesting continuity with a lactiferous duct, accessory breast, or microscopic gynecomastia. We review previous case reports of Paget's disease occurring in unusual sites and discuss their nomenclature from the histogenetic point of view.     

Evaluation of positron emission tomography imaging to detect lymph node metastases in patients with extramammary Paget's disease

Patients with extramammary Paget's disease (EMPD) have a relatively good prognosis, when spread of the tumor cells is limited to the epidermis. However, invasive EMPD has a poor prognosis, when the patients have regional lymph node metastasis. Detection of nodal metastasis is thus mandatory to manage EMPD. To evaluate the ¹⁸F‐fluorodeoxyglucose positron emission tomography (FDG‐PET) imaging to assess lymph node metastasis, 15 patients with histologically proven primary EMPD were enrolled in this study. All patients underwent whole‐body PET prior to sentinel lymph node biopsy (SLNB). The maximum standardized uptake value (SUVmax) of more than 2.5 was evaluated as positive PET indicative of malignancy. Among 14 cases with the primary genital lesions, 11 cases underwent bilateral SLNB of the inguinal nodal basin and the remaining three cases unilateral SLNB. One case with a primary axillary lesion underwent unilateral SLNB of the axillary nodal basin. Therefore, a total of 26 regional basins were investigated. In general, nodal basins can be categorized into four groups: (i) histologically negative and PET negative (true negative); (ii) histologically positive and PET negative (false negative); (iii) histologically positive and PET positive (true positive); and (iv) histologically negative and PET positive (false positive) groups. In the 26 nodal basins, there were 19 true negative and seven true positive cases, and neither false negative nor false positive cases were observed. The mean SUVmax was significantly higher in the true positive basins (8.03 ± 3.34) than in the true negative basins (0.26 ± 0.56). The SUVmax value may be useful for detection of nodal metastasis.     

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.     

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.