Extramammary Paget's Disease of External Genitalia with Bowenoid Features

Extramammary Paget''s disease (EMPD) is an uncommon intraepithelial adenocarcinoma, primarily affecting the apocrine-bearing skin. Bowen disease is an intraepithelial squamous cell carcinoma having the potential to become invasive carcinoma. The histopathological concomitant features between EMPD and Bowen disease have been described. One theory is that primary EMPD arises multicentrically, within the epidermis from the pluripotent stem cells. Herein, we describe a case of EMPD that had bowenoid features, and review the previous cases associated with the origin of EMPD.     

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.     

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.     

Expression profiles of ProEx C and Ki67 in squamous cell carcinoma in situ of the skin and their relationship with human papillomavirus genotypes

Background: ProExC is a new marker for identification of precursor lesions of cervical carcinoma. Its utility in noncervical squamous cell carcinoma in situ (SCCIS) such as Bowen's disease (BD) and actinic keratosis (AK) where human papillomavirus (HPV) plays a role has not been elucidated. Our aim was to ascertain the immunohistochemical features and clinical utility of ProExC in SCCIS of the skin. Methods: HPV presence was tested in SCCIS (38 BD and 7 AK) using GP5+/6+ and Short PCR fragment (SPF) primers and subsequently genotyped. Histopathologic sections were stained for ProExC and Ki67. A set of non‐neoplastic skin proliferative lesions were included for immunohistochemical evaluation [14 psoriasis (PS) and 6 psoriasiform dermatitis (PSD)]. Results: HPV was detected in 18.9% BD. ProExC and Ki67 in the whole epidermis thickness was observed in 86.5 and 37.1% BD, respectively (p < 0.0001). ProExC and Ki67 were restricted to the lower third of the epidermis in PS and PSD. Conclusions: ProExC expression is not associated with HPV in SCCIS of the skin. Proliferating cells are better delineated in SCCIS by ProExC which may be useful to assess the extent of these lesions. Different immunohistochemical profiles seen in neoplasic and non‐neoplastic skin lesions suggest diverse alteration of cell‐cycle kinetics. Sánchez‐Hernández M, Conesa‐Zamora P, García‐Solano J, Corbalán‐Vélez R, Martínez‐Barba E, Pérez‐Guillermo M. Expression profiles of ProEx C and Ki67 in squamous cell carcinoma in situ of the skin and their relationship with human papillomavirus genotypes.     

Cytokeratin 10-negative nested pattern enables sure distinction of clonal seborrheic keratosis from pagetoid Bowen's disease

Background: The histopathologic pattern of clonal seborrheic keratosis (SK) is quite similar to the nested pattern of pagetoid Bowen's disease [squamous cell carcinoma in situ (SCCIS)], and differentiation between the two can be challenging, especially when only small pieces are available for interpretation. Methods: Eleven examples of clonal SK and 13 examples of pagetoid SCCIS were examined histopathologically (tabulating necrotic keratinocytes, suprabasal mitoses, infiltrate, parakeratosis housing plump nuclei, crowding of nuclei) and immunohistochemically (using Ki‐67, bcl‐2, cytokeratin 7 and cytokeratin 10). Sensitivity, specificity, p‐values (Fisher's exact test, two‐tailed) and positive/negative likelihood ratios (+LR/?LR) were calculated. Results: Significant differences were seen with regard to crowding (p = 0.0009) and mitoses (p = 0.0006); however, only complete absence of necrotic keratinocytes or of crowding appeared to be diagnostically convincing for a diagnosis of clonal SK (?LR < 0.01). Significant differences were also seen with bcl‐2 (p = 0.0005) and cytokeratin 10 antibodies (p < 0.00001). Both markers displayed a typical nested pattern in clonal SK, nests being bcl‐2‐positive and cytokeratin 10‐negative. Cytokeratin 10‐negative nests were the most convincing criterion for differentiation between clonal SK and pagetoid SCCIS (+LR > 10, ?LR < 0.01). Conclusions: The most reliable marker to distinguish clonal SK from pagetoid SCCIS is cytokeratin 10 when it spares nests. Other criteria that assist in the differential diagnosis are bcl‐2 expression, absence of crowding and of mitoses. Böer‐Auer A, Jones M, Lyasnichaya OV. Cytokeratin 10‐negative nested pattern enables sure distinction of clonal seborrheic keratosis from pagetoid Bowen's disease.     

Intraepidermal and dermal Merkel cell carcinoma with squamous cell carcinoma in situ: a case report with review of literature

Merkel cell carcinoma (MCC), a rare aggressive primary cutaneous neuroendocrine carcinoma, occurs on sun‐damaged skin, especially in the elderly. Its unique co‐expression of cytokeratin 20 (CK20) and neuroendocrine markers, including neuron‐specific enolase (NSE), is diagnostic. Most MCCs are located in the dermis, rarely has an intraepidermal component been reported. We report a case of MCC with an intraepidermal component admixed with squamous cell carcinoma in situ (SCCIS). We were able to identify the differences in the immunohistochemical expression pattern between that of the intraepidermal and the dermal components. Most intraepidermal neoplastic cells of MCC in this case showed a less intense immunoreactivity to CK20 and NSE compared to that of dermal neoplastic cells. This case reports an unusual occurrence of combined SCC and MCC that shows both intraepidermal and dermal components. Sirikanjanapong S, Melamed J, Patel R. Intraepidermal and dermal Merkel cell carcinoma with squamous cell carcinoma in situ: a case report and review of literature.     

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.     

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.     

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.     

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.     

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.     

In situ carcinoma in a hybrid cyst: a case report

Follicular hybrid cysts including two or more components of the epithelial skin adnexa are very rare. The epithelial lining of hybrid cysts varies, and either contains epidermis, and trichilemmal squamous epithelium, or other epithelia of the skin adnexa. Hybrid cysts may also be associated with neoplasia, such as in situ carcinoma, Bowen's disease and squamous cell carcinoma. A 37‐year‐old female was complaining of a cyst on her scalp. The unilocular cystic lesion was lined with markedly atypical squamous cells with trichilemmal differentiation. Marked nuclear and cytological atypia, pleomorphism, numerous mitotic figures and atypical mitosis was detected in the squamous epithelium. The epithelium of the cyst was also composed of ductal structures lined with cuboidal epithelium. Immunohistochemical staining was positive for cytokeratin 7 (CK7) in both squamous and glandular epithelium. Luminal staining was shown by carcinoembryonic antigen (CEA), although gross cystic disease fluid protein‐15 (GCDFP‐15) was negative in the glandular epithelium. In addition, p16 tumor suppressor gene was strongly positive in both the squamous and glandular epithelium. Overall, the unique cystic lesion reported contained pilar squamous epithelium with in situ carcinoma and eccrine ductal structures, which was interpreted as a hybrid cyst composed of in situ trichilemmal carcinoma and a ductal eccrine component.     

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.     

Treatment of extramammary Paget's disease by radiotherapy

Summary Extramammary Paget's disease (EMPD) is a rare cutaneous malignancy, which usually occurs in the elderly. Wide local excision is the recommended treatment, although this may not always be feasible. We report our experience of EMPD treated by radiotherapy In five patients. The radiotherapy was well tolerated in each case, and there were no signs of recurrence during follow-up (6 months-8 years). This study shows that radiotherapy is a useful alternative therapy for EMPD. and should be considered particularly in elderly patients who may not tolerate surgery.     

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.     

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 of the groin with underlying carcinoma and fatal outcome

Extramammary Paget's disease (EMPD) is considered to be an intraepithelial adenocarcinoma. Typically involved anatomical sites are the vulvar, perianal, perineal, scrotal and penile regions. Clinically, the lesions present as well-defined, moist, erythematous plaques usually accompanied by pruritus. An unusual feature of EMPD is its association with cutaneous, adnexal-structure adenocarcinomas and its association with internal malignancies. Histopathological examination shows epidermal acanthosis and elongated rete ridges. Paget's cells are large intraepidermal cells with a large nucleous and abundant pale cytoplasm. Recent studies of perianal and vulvar EMPD have described distinct immunohistochemical subtypes termed cutaneous and endodermal. Cutaneous EMPD is characteristically positive for cytokeratin (CK)7, negative for CK20, and positive for gross cystic disease fluid protein (GCDFP)15+, whereas endodermal EMPD shows a CK7+ CK20+ GCDFP15− phenotype. Surgery remains the treatment of choice, with either wide surgical excision or Mohs' micrographic surgery. We present a case of EMPD with an underlying carcinoma, which combined immunohistochemical findings suggestive of the cutaneous subtype (positive for CK7, GCDFP15, mucin (MUC)1, human epidermal growth factor receptor (HER)2/neu positive) and the endodermal subtype, frequently associated with internal malignancy (CK20, MUC2, CDX-2 positve); however, our patient had no associated internal malignancy.     

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.     

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.