Loss of Wnt-5α is associated with an invasive phenotype of extramammary Paget's disease

Background: The Wnt (wingless‐type MMTV integration site) gene family encodes secretory signaling molecules that play a diverse biological role in the regulation of normal and pathological processes, including cell growth, differentiation and oncogenesis. However, the role of Wnt genes in the development of extramammary Paget's disease remains unknown. Objective: To investigate the expression of Wnt‐1, Wnt‐5α and their downstream genes, β‐catenin and c‐Myc, in extramammary Paget's disease. Methods: Paraffin‐embedded specimens of extramammary Paget's disease (33 specimens from 22 patients), including 7 specimens with dermal invasion and 4 with lymph node metastasis, were examined immunohistochemically for Wnt‐1, Wnt‐5α, β‐catenin and c‐Myc. Seven normal genital skin specimens served as controls. Results: The expression levels of Wnt‐1 and β‐catenin in extramammary Paget's disease were significantly correlated with each other; however, their expression levels in the invasive extramammary Paget's disease were similar to those of wholly intraepithelial extramammary Paget's disease. Nuclear expression of c‐Myc was significantly higher in the invasive extramammary Paget's disease in comparison with intraepithelial extramammary Paget's disease. Interestingly, the expression of Wnt‐5α in invasive extramammary Paget's disease was significantly downregulated compared to wholly intraepithelial extramammary Paget's disease. Conclusion: The Wnt‐1/β‐catenin pathway may not play an important role in the progression of extramammary Paget's disease. The loss of Wnt‐5α, however, may play a role in the invasiveness of extramammary Paget's disease. Xie L, Hayashida S, Furue M. Loss of Wnt‐5α is associated with an invasive phenotype of extramammary Paget's disease.     

Extramammary Paget's disease mimicking acantholytic squamous cell carcinoma in situ: a case report

Background: Extramammary Paget's disease (EMPD) is an uncommon skin neoplasm characterized by Paget's cells with pale‐staining cytoplasm in the epidermis, and cases with distinguished acantholysis but lacking characteristic Paget's cells were rarely reported in the literature. Methods: An 80‐year‐old male with lesion on scrotum was screened histologically and immunohistologically for the diagnosis of his tumor. Results: Histological examination showed acanthosis with cellular atypia and focal acantholysis, consistent with acantholytic squamous cell carcinoma in situ (SCCIS). No characteristic Paget's cells were observed in low magnification. Immunohistochemical staining showed carcinoembryonic antigen (CEA), cytokeratin 7 (CK7) and cytokeratin 8 (CK8) to be strongly expressed in the nests and singly arranged large tumor cells, and the surrounding epidermis was positive for CK5/6 and negative for CEA. Sporadic periodic acid‐schiff (PAS)‐positive cells could be seen in some areas. Conclusions: These findings strongly indicated the diagnosis of EMPD mimicking acantholytic SCCIS. Du X, Yin X, Zhou N, Zhang G, Shi H, Cao S. Extramammary Paget's disease mimicking acantholytic squamous cell carcinoma in situ: a case report.     

An Immunohistochemical Study of BCA-225 in Various Skin Cancers

We performed an immunohistochemical study of BCA-225, which is a glycoprotein secreted by the T47D breast carcinoma cell line and recognized by monoclonal antibody BRST-1 (clone name: CU-18), in normal skin and various skin cancers. In normal skin, BCA-225 was positive only in the secretory portion of both eccrine and apocrine glands and in mature cells of the sebaceous gland. We observed 10 cases of squamous cell carcinoma of the skin, 10 cases of basal cell carcinoma without sebaceous differentiation, 3 cases of basal cell carcinoma with sebaceous differentiation, 6 cases of malignant trichilemmoma, 8 cases of eccrine porocarcinoma, 3 cases of ductal carcinoma, 1 case of malignant clear cell hidradenoma, 1 case of apocrine adenocarcinoma, 6 cases of extra-ocular sebaceous carcinoma, 5 cases of extramammary Paget's disease with underlying adenocarcinoma, and 11 cases of extramammary Paget's disease without underlying adenocarcinoma. Most of the cases of sweat gland carcinoma, basal cell carcinoma with sebaceous differentiation, sebaceous carcinoma, and extramammary Paget's disease were positive for BCA-225, while none of the cases of squamous cell carcinoma, basal cell carcinoma without sebaceous differentiation, or malignant trichilemoma were positive. Based on these findings, we believe that BCA-225 is useful in distinguishing tumors with sweat gland and sebaceous differentiation and extramammary Paget's disease from tumors without such differentiation.     

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.     

Polarized dermoscopy of mammary Paget disease

Mammary Paget''s disease is a rare intraepithelial adenocarcinoma, located on the nipple/areola complex, highly associated with breast cancer. Although the international literature emphasizes the dermatoscopic pattern of mammary Paget''s disease pigmented variant, the authors describe the dermoscopic findings of classical Paget''s disease and demonstrate the presence of chrysalis-like structures, criteria recently described in the literature and not yet reported in Paget''s disease.     

A Case of Triple Extramammary Paget's Disease

We report a 74-year-old Japanese man with triple extramammary Paget's disease; the genital and both of the axillar regions were simultaneously involved. Literature review revealed that 27 cases of triple extramammary Paget's disease have been reported in Japan, but there are no reports of triple extramammary Paget's disease from countries other than Japan, although 2 cases of double extramammary Paget's disease are reported. In all 28 cases, including our case, the genital lesion preceded the axillary lesions. All cases except one were male and only the exceptional female case was reported to have an the invasive tumor in the dermis. We speculate that extramammary Paget's disease may appear multi-centrically.     

Expression of E-Cadherin in Skin Carcinomas

In this study, we investigated the expression of E-cadherin in 31 cases of human skin carcinoma including basal cell carcinoma (BCC), squamous cell carcinoma (SCC), Paget's disease, Bowen's disease (invasive type), and trichilemmal carcinoma, by immunohistochemical staining using a monoclonal antibody specific for E-cadherin. Similar to the E-cadherin expression in normal epidermis, E-cadherin was strongly expressed in all samples of BCC on the cell borders, whereas marked decrease or loss of E-cadherin expression was found in the tumor cells of SCC, Paget's disease, and Bowen's disease (invasive type). On the other hand, E-cadherin expression of trichilemmal carcinoma was slightly reduced. Considering the clinical and histological features of these skin carcinoma, the reduction of E-cadherin expression is considered to be associated with the invasion and metastasis of human skin carcinoma.     

Axillary involvements in genital Paget's disease.

Simultaneous occurrence of bilateral axillary Paget's disease in a 61-year-old male with genital Paget's disease of 2 years' duration was presented. Invasive adenocarcimoma was found in the genital lesion. No regional lymph node metastases ware apparent. The lesions were excised in toto. There has been no recurrence 14 months later. Four previously reported cases of double or triple extramammary Paget's disease, together with two more cases were summarized. Generally, the axillary lesions were clinically insignificant, faintly erythematous patches and could hardly be identified without histological examination.     

A Case of Pigmented Mammary Paget's Disease

Pigmented mammary Paget''s disease is a uncommon clinicopathologic variant of mammary Paget''s disease, and this mimics malignant melanoma both clinically and histopathologically. Herein, we report on a rare case of pigmented mammary Paget''s disease. An 81-year-old woman presented with 2.5×1 cm sized, red and brown, eczematous plaque on her right areola, and she''d had this lesion for 3 years. Histopathology showed large, atypical cells with large nuclei and abundant pale cytoplasm throughout the epidermis. Dispersed melanocytes were noted in the epidermis and some of the Paget''s cells contained melanin within their cytoplasm. Immunohistochemical studies demonstrated that the intraepidermal pagetoid cells were positive for cytokeratin 7; in contrast, they were negative for S-100, Periodic-acid Schiff (PAS), Alcian blue at PH 2.5, HMB-45 and carninoembryonic antigen (CEA). We recommend that pigmented mammary Paget''s disease should be included in the differential diagnosis of pigmented lesions on the nipple.     

Familial Kaposi's sarcoma and Paget's disease of bone

Familial Kaposi's sarcoma and familial Paget's disease of bone have not previously been reported to occur in the one patient or the one family. We report on an 82-year-old female of Lebanese descent who was recently diagnosed with Kaposi's sarcoma and Paget's disease. Of the patient's eight siblings, seven had Paget's disease and two of these also had Kaposi's sarcoma. Histocompatibility leucocyte antigen (HLA) class I and II typing of the patient showed: A2, A3; B35, Bx; Bw6; Cw4; DRβ1*1101 (an HLA-DR5 subtype) DRβ3 and DQβ1*0301. Previous reports have described possible associations of familial Kaposi's sarcoma with HLA-DR5 and Paget's disease with DR2, DRβ1*1104, DPβ1*04and DQw1. Genetic factors and possible viral aetiologies fur each condition are reviewed.     

Immunobead and Density Gradient Purification of Paget Cells: In vitro Studies of Proliferation

Previous studies using primary monolayer cultures of epithelial cells from the involved epidermis of patients with mammary and extramammary Paget's disease investigated whether Paget cells proliferate as other malignant cells do. Although epithelial monolayers from the involved skin were maintained for approximately 45 days, no permanent cell lines were established. The proportion of carcinoembryonic antigen (CEA)-positive cells did not increase in the long-term cultures. Herein, we report studies of whether there is a real reduction of Paget cell numbers or if this is merely a decrease in the expression of CEA by the cells. Furthermore, we investigated whether Paget cells survive longer when cultured free from any potential inhibitory keratinocytes or other epidermal cells. Skin samples were obtained from one patient with mammary Paget's disease and three with extramammary Paget's disease; epidermal cells were cultured in vitro. An enrichment of Paget cells was carried out from the cultured epidermal cells by combining an anti-epithelial membrane antigen monoclonal antibody, binding to immunobeads, and density gradient centrifugation in Nycodenz. The separated cells were re-cultured in Keratinocyte-SFM serum-free media. The proportion of CEA-positive cells did not increase in the cultures, and the purified cells did not show any increase in survival times compared to the non-purified cultured cells. These results suggest that the decrease of CEA-positive cells noted during culture results from a decline in expression of CEA in the Paget cells. Paget cells in the involved epidermis do not proliferate significantly and thus differ from many other malignant cells.     

Umbilical Paget's disease and prostatic carcinoma

We report a case of umbilical Paget's disease occurring in a patient with a prostatic carcinoma. No other malignancy was found, and the patient was treated by surgical excision of the lesion. To our knowledge, the occurrence of extramammary Paget's disease of the umbilicus has not been reported previously. The clinical presentation, its association with prostatic carcinoma, and the possible pathogenesis are discussed.     

A Case of Paget's Disease of the Vulva Recurring in a Musculocutaneous Flap

A case of Paget's disease of the vulva which recurred in a reconstructed gracilis musculocutaneous flap without invasing adenocarcinoma is presented. The recurrent lesion was seen in the basal layer of the epidermis of the flap without invasion into the dermis. The possibility of an intraepidermal lateral invasion of Paget's cells into the epidermis of the flap is suggested.     

PAGET'S DISEASE OF THE SCBOTUM A CASE BEPOET

This case report concerns a 68-year-old man with Paget's disease of the scrotum and intraduct carcinoma of the underlying sweat glands. Bowen's disease, basal cell carcinoma and multiple keratoses were present on his hands. Mention is made of the association of cutaneous Pagefs disease with carcinoma in other sites.     

Mapping biopsy with punch biopsies to determine surgical margin in extramammary Paget's disease

It is difficult to determine the appropriate resection margin of extramammary Paget's disease (EMPD). A high recurrence rate is reported in spite of using Mohs micrographic surgery (MMS), which is performed commonly. Preoperative mapping biopsy is easier to perform than MMS. In Japan, the following method is recommended instead of MMS: well‐defined border and margins histologically confirmed by mapping biopsy should be resected with 1‐cm margin and ill‐defined border with 3‐cm margin. This study aimed to evaluate the accuracy of the Japanese guideline and to assess our mapping biopsy method compared with MMS. Preoperative mapping biopsy specimens were obtained beyond the clinical border for at least four directions in each patient. To confirm the presence of residual Paget's cells postoperatively, narrow specimens were obtained along the surgical margin. Retrospective evaluation of 17 EMPD patients was conducted concerning histological spread of Paget's cells and recurrence ratio. There were 86 directions showing a well‐defined border, and in 9.3% (8/86), Paget's cells were still observed at 1‐cm resection line. On the other hand, there were 21 directions showing an ill‐defined border, and unnecessary radical resection was performed in 90% (19/21) of directions with 3‐cm resection line. Although postoperative histological examination showed residual Paget's cells in 47% (8/17) of patients and additional resections were not performed, recurrence rate was only 5.9% (1/17). The resection line of EMPD should be based not on clinical features, but on mapping biopsy. Mapping biopsy is equivalent to MMS concerning recurrence rate and, though conventional, is useful method to treat EMPD.     

Mammary Paget's disease and extra‐mammary Paget's disease: two morphologically similar but biologically different diseases

Background: The cells of origin of mammary Paget's disease (MPD) and extra‐mammary Paget's disease (EMPD) have been a controversial subject. The purpose of this study is to examine the expression of the human epidermal growth factor receptor 2 (HER2) pathway members in these two diseases. Design: HER2, AKT, pAKT, PTEN, epidermal growth factor receptor (EGFR) and pEGFR were examined in 16 MPD and 14 EMPD cases. HER2 was graded on a scale from 0 to 3. A score of 3 was considered positive. For AKT, pAKT, PTEN, EGFR and pEGFR, a semi‐quantitative scoring system was used. A score >100 was considered positive. Fisher's exact test was used to analyze the data. Results: HER2 was overexpressed in 87.5% MPD and 35.7% EMPD. While AKT was expressed in all cases, pAKT was expressed in 87.5% MPD and 92.9% EMPD. Both EGFR and pEGFR were negative in all cases. PTEN was positive in 62.5% MPD and 71.4% EMPD. For pAKT+ group, HER2–/PTEN+ was recorded in 0% MPD and 38.5% EMPD (P = .01). Conclusions: In a subset of EMPD, AKT is not activated by HER2 overexpression or by loss of PTEN, which is not the case in MPD. These data suggest that these two diseases are biologically different. Liu W, Iqbal J, Khoury T. Mammary Paget's disease and extramammary Paget's disease: two morphologically similar but biologically different diseases.     

An Immunohistochemical Study of Sebaceous Carcinoma with Anti-Keratin Monoclonal Antibodies: Comparison with Other Skin Cancers

Formalin-fixed and paraffin-embedded tissue specimens of six cases of extraocular sebaceous carcinoma were studied immunohistochemically with eight anti-keratin monoclonal antibodies, 34βB4, 35βH11, Ks13.1, Ks19.1, PKK1, LP34, KL1 and AE1. The staining patterns of sebaceous carcinoma were compared with those of normal sebaceous glands and other skin cancers which should be distinguished from sebaceous carcinoma histopathologically. The other skin cancers compared were eccrine porocarcinoma, malignant clear cell hidradenoma, extramammary Paget's disease with underlying adenocarcinoma, malignant trichilemmoma, and squamous cell carcinoma. Most cases of sebaceous carcinoma were stained with 35βH11, Ks19.1, LP34, KL1 and AE1, while normal sebaceous glands were positive only with 35βH11, LP34, KL1 and AE1. By immunostaining, sebaceous carcinoma was distinguishable from extramammary Paget's disease with underlying adenocarcinoma, squamous cell carcinoma, malignant trichilemmoma, and eccrine porocarcinoma, but was not clearly distinguishable from malignant clear cell hidradenoma. These findings demonstrate that sebaceous carcinoma shows positive reactions with antibodies to simple epithelial keratin, probably as a result of neoplastic transformation, and that immunohistochemical examination using anti-keratin monoclonal antibodies is useful in distinguishing sebaceous carcinoma from several other skin cancers.     

Coincidence of Vitiligo and Paget's Bone Disease in a Patient

Paget's bone disease developed in a patient with vitiligo. Scrupulous physical examination excluded further systemic or cutaneous involvement. The immunological workup revealed a reversed CD₄/CD₈ ratio due to a very low CD₄ cell percentage and almost negligible responses to PHA as well as Con A, T cell mitogens. The pathogenic significance of these results, which point to phenotypic and functional T cell defects, is discussed.     

A Case of Mammary Paget's Disease without an Underlying Carcinoma: Microscopic Analysis of the DNA Content in Paget Cells

A 72-year-old woman had a 7-year history of a scaly red area on the right breast which had enlarged asymptomatically. A biopsy of the nipple was taken, and, following the finding of Paget's disease, a modified radical mastectomy was carried out. On histological examination of the entire breast specimen by serial sections, no evidence of an intraductal adenocarcinoma was found. Fractionation of Paget cells was performed from the epidermis. Stripped skin was treated with EDTA and trypsin, and epidermal cell suspensions were obtained. They were layered onto discontinuous Percoll gradients and centrifuged. Paget cells fell into three fractions with densities of 1.041, 1.058, and 1.078. Electronmicroscopically, the purity of fractionated cells obtained by this method ranged from 55 to 74% with viabilities of from 70 to 90%. Microscopic analysis of the DNA content in these cells was performed. The DNA histogram was close to the normal ploidy. This may explain why the mammary Paget's disease lesions in this case enlarged rather slowly.