Paget Cells Research Articles

Photodynamic Therapy Using a New Painless Light-Emitting Fabrics Device in the Treatment of Extramammary Paget Disease of the Vulva (the PAGETEX Study): Protocol for an Interventional Efficacy and Safety Trial

BackgroundExtramammary Paget disease of the vulva (EMPV) is a rare skin disorder commonly seen in postmenopausal Caucasian females that appears clinically as red, eczematous, pruriginous, and sometimes painful lesions. Although most cases are noninvasive, EMPV may be associated with an underlying or distant adenocarcinoma. EMPV has a chronic and relapsing course. The reference treatment is based on local surgical excision with negative margins. However, disease frequently extends far from the visible lesion, and surgical margins are frequently positive. Topical photodynamic therapy (PDT) is an established treatment modality for various dermatooncologic conditions. For example, red light irradiation with the Aktilite CL 128 and Metvixia (Galderma SA) as a photosensitizing molecule is a conventional protocol approved and widely used in Europe for PDT treatment of actinic keratosis, but this treatment is not yet widely used for EMPV because it has never clearly been demonstrated and is very painful.ObjectiveThe aim of the study is to investigate the efficacy and safety relating to the medical device PAGETEX as a new painless PDT device using Metvixia in the treatment of vulvar Paget disease. The primary end point is the disease control rate at 3 months in 30% of the patients included, defined as stability, partial response, or total response, considering the extent of the lesion. Secondary end points are the disease control rate at 6 months, patient quality of life, level of pain experienced by the patient at each PDT session, severity of erythema, presence of protoporphyrin IX in Paget cells after each PDT session, and overall satisfaction level of the patient.MethodsThe trial is an interventional, exploratory, simple group, nonrandomized, and single center (Lille University Hospital) study. Twenty-four patients will be included according to Simon’s optimal plan. Therapeutic procedure is based on a cycle of two PDT sessions with the PAGETEX medical device at 15-day intervals (Metvixia incubation during 30 minutes and 635 nm red light illumination with a low irradiance for 2 hours and 30 minutes for a total fluence of 12 J/cm²). At the assessment session, 3 months after inclusion, if the control of the disease is partial or null, the patient will complete another cycle of two PDT sessions. A final evaluation will be performed in all patients at 6 months. Analyses will be performed using SAS version 9.4 software (SAS Institute Inc). The characteristics of the patients at baseline will be described; qualitative variables will be described by numbers and percentages, and quantitative variables will be described either by the mean and standard deviation for Gaussian distribution or by the median and interquartile range (ie, 25th and 75th percentiles). The normality of the distributions will be tested by a Shapiro-Wilk test and checked graphically by histograms.ResultsFirst patient was included in September 2019 and clinical investigations are planned until August 2022. The final results of this study are expected to be available in January 2023.ConclusionsThis clinical trial aims to evaluate the efficacy and safety of a new PDT protocol for the treatment of EMPV. The PAGETEX device could become the treatment of choice if it is effective, painless, and easy to implement and use in hospitals.Trial RegistrationClinicalTrials.gov NCT03713203; https://clinicaltrials.gov/ct2/show/NCT03713203International Registered Report Identifier (IRRID)PRR1-10.2196/15026

Paget's disease of the nipple in a Her2-positive breast cancer xenograft model.

Paget's disease (PD) of the breast is an uncommon disease of the nipple usually accompanied by an underlying carcinoma, often HER2 + , and accounting for 0.5-5% of all breast cancer. To date, histogenesis of PD of the breast remains controversial, as two theories-transformation and epidermotropic-have been proposed to explain this disease. Currently, animal models recapitulating PD of the nipple have not been described. HER2-enriched DT13 breast cancer cells were injected into the mammary fat pad of NOD scid gamma null (NSG) female mice. Immunohistochemical staining and pathological studies were performed on tumor samples, and diagnosis of PD of the nipple was confirmed by expression of proteins characteristic of Paget cells (epidermal growth factor 2 (HER2), androgen receptor (AR), cytokeratin 7 (CK7), cytokeratin 8/18 (CK8/18), and mucin 1 (MUC1)). In addition, DT13 cells grown in 2D culture and in soft agar assays were sensitive to in vitro treatment with pharmacological inhibitors targeting Her2, adenylyl cyclase, mTOR, and PI3K signaling pathways. Mice developed tumors and nipple lesions that were detected exclusively on the tumor-bearing mammary fat pad. Tumor cells were positive for proteins characteristic of Paget cells. In vitro, DT13 cells were sensitive to inhibition of Her2, adenylyl cyclase, mTOR, and PI3K signaling pathways. Our results suggest that injection of HER2 + DT13 cells into the mammary fat pad of NSG mice recapitulates critical aspects of the pathophysiology of PD of the nipple, supporting the epidermotropic theory as the more likely to explain the histogenesis of this disease.

Invasive Mammary Paget Disease Without an Underlying Breast Cancer: A Case Report

Abstract Mammary Paget disease (MPD) is a malignant lesion of the nipple-areolar complex and considered an intraepidermal sign of an underlying invasive or in situ carcinoma. In rare instances, mammary Paget cells can invade the dermis. Comprehensive literature review identified 33 such cases. Here, we report a case of a 48-year-old female with invasive MPD, without an associated underlying breast cancer. Only five such presentations are reported. With a presentation of right nipple-areolar excoriation for 2 years, skin punch biopsy was performed and reported as “Paget disease.” Further evaluation with bilateral mammograms failed to show any primary mass or calcifications. Bilateral breast MRI revealed focal nonmass enhancement in upper outer quadrant in both breast, the biopsy of which showed benign breast tissue. Right breast nipple areolar complex resection demonstrated MPD extensively involving the epidermis. Multiple foci of invasive ductal carcinoma are present, growing downward into the nipple dermis, the largest focus being 0.2 cm in greatest dimension. No lymphovascular invasion is identified. The mammary Paget cells are positive for Cam 5.2 and epithelial membrane antigen (EMA) and negative for keratins 7 and 20. The invasive tumor cells are strongly positive for estrogen receptor (100%) and progesterone receptor (75%) and equivocal (2+) for Her2/Neu. FISH analysis showed amplification for HER2 (HER2/CEP17 ratio: 2.75). Four right axillary sentinel lymph nodes are negative for carcinoma. Two of the five patients with invasive MPD described in the literature, and without underlying breast cancer, had a sentinel lymph node biopsy performed. Isolated tumor clusters were present in one of these two cases. In summary, we describe a rare case of invasive MPD without an underlying breast cancer. Although sentinel lymph nodes are important to assess metastasis, further cases are required to evaluate the significance and prognosis of this rare entity.

Extramammary Paget's disease

Extramammary Paget's disease (EPD) is arare, slowly growing, cutaneous adenocarcinoma with an incidence of 0.1-2.4 per 1,000,000 inhabitants. Histologically, EPD is characterized by the presence of epidermal Paget's cells, similarly to mammary Paget's disease. The EPD is typically divided into primary EPD (typeI) and secondary EPD (typeII associated with colorectal carcinoma and typeIII associated with urogenital carcinoma). From aclinical point of view, EPD is unspecific commonly mimicking chronic inflammatory skin disorders. This unspecific clinical picture can impede and delay the diagnosis of EPD. The treatment of choice for local EPD is the micrographically controlled excision. The extent of the infiltration of adnexal structures should be histologically determined prior to topical therapies, such as imiquimod and superficial ablative therapy. The complete excision of the tumor can be challenging due to ill-defined borders. In the metastatic stage the EPD has apoor prognosis. Controlled clinical trials for systemic treatment are still lacking.

Pre-Paget cells: Evidence of keratinocyte origin of extramammary Paget's disease.

Extramammary Paget's disease (EMPD) is a carcinoma of the genital, perianal, and, rarely, axillary skin. The malignant Paget cells migrate extensively in the epidermis before invading the underlying dermis. Toker cells and keratinocytes have both been suggested as the cells of origin of EMPD. Paraffin sections of eight cases of EMPD were immunohistochemically stained for carcinoembryonic antigen, a known marker for Paget cells. The presence of carcinoembryonic antigen in some keratinocytes in all of the observed cases of EMPD suggests that EMPD originates from keratinocytes. Thus, keratinocytes containing carcinoembryonic antigen are pre-Paget cells.

Malassezia-derived aryl hydrocarbon receptor ligands enhance the CCL20/Th17/soluble CD163 pathogenic axis in extra-mammary Paget's disease.

Malassezia yeast play a role in the pathogenesis of chronic dermatitis, especially in apocrine areas, by polarizing the local immunologic background to a Th2/Th17 state through aryl hydrocarbon receptor (AhR)-dependent pathways. Extra-mammary Paget's disease (EMPD) is an adenocarcinoma of apocrine origin, and except for cases associated with Malassezia yeast and their metabolites, the lesions typically develop in areas not exposed to environmental material. The purpose of this study was to investigate (a) the immunomodulatory effects of Malassezia metabolites on normal human keratinocytes (NHKCs), focusing on interleukin (IL)-17 and related cytokines/chemokines (IL-23, IL-36γ, CCL20), (b) the expression of these factors in lesion-affected skin in EMPD and (c) the activation of tumor-associated macrophages (TAMs) by these factors. Malassezia metabolites augmented the expression of cytochrome P450, family 1, subfamily A, polypeptide 1 (CYP1A1), CCL20 and IL-36γ mRNA in NHKCs in vitro. In lesion-affected skin of patients with EMPD, epidermal keratinocytes expressed CYP1A1 and CCL20. In addition, Paget cells expressed CCL20 and IL-23. IL-17-producing cells were distributed adjacent to Paget cells. Compared to healthy donors, patients with EMPD exhibited significantly increased serum levels of soluble (s)CD163, CXCL5, CXCL10 and CCL20. In addition, serum levels of sCD163 decreased significantly following tumor resection. Our study demonstrates a possible mechanism for the development of EMPD involving AhR-mediated signalling by epidermal keratinocytes and RANKL-induced recruitment of Th17 cells and TAMs.

Extramammary Paget disease

In 1874, Sir James Paget first described Paget disease of the nipple, also known as mammary Paget disease. In 1889, extramammary Paget disease (EMPD) of the scrotum and penis was identified. Although mammary and extramammary Paget disease are both characterized by epidermal Paget cells and share a similar clinical presentation, their uniqueness lies in anatomical location and histogenesis. EMPD presents as an erythematous plaque on apocrine gland bearing areas (i.e. vulva, perineum, perianal region, scrotum, and penis) in older men and women. It can be a focal, multifocal, or an ectopic process. Immunohistochemical staining allows for differentiation between primary and secondary EMPD in addition to the many other disease entities that clinically resemble this malignancy. When diagnosing a patient with EMPD, a full history and physical should be performed given the possibility of an underlying malignancy. Surgical excision currently is first line therapy and the prognosis is often favorable. Recent advances within the field have examined the expression of chemokine receptors within tumors, which may be applicable in determining prognosis. This review addresses the history, epidemiology, pathogenesis, clinical presentation, histopathology, differential diagnosis, diagnosis, management, and new observations with respect to extramammary Paget disease.

Treatment Effects Can Mimic Recurrent Extramammary Paget Disease in Perianal Skin.

The histologic differential diagnosis of perianal Paget disease includes malignant melanoma, pagetoid spread of squamous cell carcinoma, and secondary involvement by colorectal carcinoma. While consideration of these entities is useful when establishing a diagnosis, it does not apply when patients with Paget disease undergo surveillance for recurrent disease. Treatment of perianal Paget disease consists of a combination of surgical excision with skin grafts and topical chemotherapeutic agents that induce cytologic alterations in benign cells and simulate recurrent malignancy. To evaluate the therapy-related changes and possible diagnostic pitfalls in patients with Paget disease, we reviewed 412 posttreatment tissue samples from 3 women with primary perianal Paget disease who underwent wide excision, skin grafting, and topical 5-fluorouracil therapy. Biopsy samples from engrafted skin often displayed single and clustered cells with hyperchromatic nuclei dispersed in the deep epidermis. Similar cells were scattered throughout all levels of the epidermis in biopsy samples following topical chemotherapy. The abnormal cells were negative for cytokeratin 7 (CK7) and mucicarmine in both situations. Disease ultimately recurred in all patients; some Paget cells showed classic features with eosinophilic or mucinous cytoplasm and eccentric nuclei, whereas others were smaller with less conspicuous atypia. All Paget cells showed strong, membranous CK7 staining. In short, treatment of perianal Paget disease can elicit cytologic abnormalities in benign epithelial cells that simulate the cytologic features of recurrent disease, and can diminish the atypia of Paget cells. Immunohistochemical stains for CK7 can be helpful when evaluating surveillance samples from these patients.

Paget\u2019s disease derived in situ from reserve cell hyperplasia, squamous metaplasia, and squamous cell carcinoma of the esophagogastric junction: a case report

BackgroundExtramammary Paget’s disease (EMPD) of the esophagus is a rare tumor, with most cases originating from invasive adenocarcinoma of the esophagus. Pure esophageal Paget’s disease, in which no underlying invasive carcinoma component is present, is extremely rare. In this report, we describe a case of EMPD of the esophagogastric junction with no evidence of invasive carcinoma.Case presentationAn 81-year-old Japanese woman with a 2-week history of abdominal distension presented to our hospital for assessment. Endoscopic examination revealed a mild elevated granular lesion, with a slightly depressed irregular mucosa, in the distal esophagus, with EMPD confirmed by biopsy. Thoracoscopic esophagectomy with lymph node dissection was performed, with Paget cells observed on microscopic examination in the lower part of the esophageal epithelium. Only a few Paget cells stained positively for PAS/Alcian blue. Immunohistochemically, negative staining for CK5 and p63 were identified in the Paget cells, with positive staining for CK7. Furthermore, an intraepithelial squamous cell carcinoma, with squamous metaplasia and reserve cell hyperplasia, was observed in the gastric mucosa of the esophagogastric junction, adjacent to the Paget cells.ConclusionsEMPD of the esophagus is a rare disease. We report a case of EMPD that was probably derived from a gastric squamous cell carcinoma, with squamous cell metaplasia and reserve cell hyperplasia, in the esophagogastric junction, which, to our knowledge, is the first report of this type of EMPD in the clinical literature.

Surgical Treatment for Extramammary Paget's Disease.

Extramammary Paget's disease (EMPD) is a rare, slow growing non-melanoma skin cancer.Diagnosis is often significantly delayed, since clinical presentation may resemble common benign dermatoses. Treatment is characterized by high recurrence rates. This is in part due to ill-defined margins and by frequent development of satellites. Improvement of outcome needs a better preoperative planning with fluorescence diagnostics or scouting biopsies. Mohs micrographic surgery has some advantages for patients, such as reduced relapse rates and prolonged relapse-free survival. Improved identification of Paget cells in cryosections by immunostainings or alternatively the use of delayed Mohs with formalin-fixed material reduces the rate of false-negative results. Surgery remains the cornerstone of treatment.

Clinical Benefits of Preoperative Conventional Fluorescence Diagnosis in Surgical Treatment of Extramammary Paget Disease.

In extramammary Paget disease (EMPD), initial margins of surgical excision are difficult to determine preoperatively. Fluorescence diagnosis (FD) may have utility as a noninvasive method for delineating tumor boundaries. The relationship between FD-delineated borders and results of multiple scouting biopsies (MSBs) in EMPD was investigated, evaluating the potential clinical role of FD. A cohort of 21 patients was studied, looking for consistencies between FD and MSB results. Initial surgical margins were determined by FD or FD plus MSB. All margins were subjected to frozen section analysis. Paget cells were identified in 88 of 117 (71.8%) biopsies obtained from FD borders. When used preoperatively with MSB in 9 patients, 96.4% of margins proved negative at initial resection stage. Using a 6-mm margin beyond FD borders in another 9 patients, 86.7% of margins were negative at initial stage. The maximum distance of excision beyond FD border was 12 mm. Fluorescence diagnosis borders (identified visually) correlated well with MSB histopathology. Fluorescence diagnosis is a useful method to delineate initial margins for surgical resection of EMPD.

Epidemiology of Female Breast Cancer in Ogun State: Intra- and Inter-regional Discuss

This study determined the prevalence of breast cancer in relation to age, reproductive status and population of Ogun State. Out of a total of 816 human cancer presentations observed between 2012 and 2016, 334 (40.9%) female breast cancer (with age range= 23 to 95 years and mean age= 50.3 years) were retrospectively reviewed. Result revealed five breast cancer types: Invasive ductal carcinoma (IDC), ductal carcinoma in situ (DCIS), Paget cell disease, medullary carcinoma and mucinous carcinoma. Invasive ductal carcinoma was the predominant breast cancer type (94.9%) while year 2016 had the highest number of breast cancer presentations (47%) at p<0.001). Result also showed that age range of 41-50 years and 61-70 years had the highest prevalence and incidence of breast cancer, respectively (p<0.001). Reproductive age (23-45 years) had the highest frequency of invasive ductal carcinoma and Paget cell disease when compared with other age groups (p<0.001). Result also showed interesting differences in prevalence of breast cancer types in Ogun State compared with other regions. The result revealed that IDC, DCIS, Medullary carcinoma, Mucinous carcinoma and Paget's cell disease are more prevalent in South-West, South-East, North-West, South-East, North-Central regions, respectively. In conclusion, our findings suggest that breast cancer occurrence is greatly influence by age, reproductive status and location.

The Paget Trial: A Multicenter, Observational Cohort Intervention Study for the Clinical Efficacy, Safety, and Immunological Response of Topical 5% Imiquimod Cream for Vulvar Paget Disease.

BackgroundVulvar Paget disease is a rare skin disorder, which is most common in postmenopausal Caucasian women. They usually present with an erythematous plaque that may show fine or typical “cake icing” scaling or ulceration that may cause itching, pain, irritation, or a burning sensation. Although most cases are noninvasive, vulvar Paget disease may be invasive or associated with an underlying vulvar or distant adenocarcinoma. The histological evidence of so-called “Paget cells” with abundant pale cytoplasm in the epithelium confirms the diagnosis. The origin of these Paget cells is still unclear. Treatment of choice is wide local excision with negative margins. Obtaining clear surgical margins is challenging and may lead to extensive and mutilating surgery. Even then, recurrence rates are high, ranging from 15% to 70%, which emphasizes the need for new treatment options. A number of case reports, retrospective case series, and one observational study have shown promising results using the topical immune response modifier imiquimod.ObjectiveThis study aims to investigate the efficacy, safety, and immunological response in patients with noninvasive vulvar Paget disease using a standardized treatment schedule with 5% imiquimod cream.MethodsTopical 5% imiquimod cream might be an effective and safe treatment alternative for vulvar Paget disease. The Paget Trial is a multicenter observational cohort study including eight tertiary referral hospitals in the Netherlands. It is ethically approved by the Medical-Ethical Committee of Arnhem-Nijmegen and registered in the Central Committee on Research Involving Human Subjects (CCMO) Register by as NL51648.091.14. Twenty patients with (recurrent) noninvasive vulvar Paget disease will be treated with topical 5% imiquimod cream three times a week for 16 weeks. The primary efficacy outcome is the reduction in lesion size at 12 weeks after end of treatment. Secondary outcomes are safety, immunological response, and quality of life. Safety will be assessed by evaluation of adverse events and tolerability of treatment. To evaluate the immunological response, various immunological markers will be tested on biopsy specimens taken before, during, and after treatment. Quality of life will be assessed with three questionnaires taken before, during, and after treatment.ResultsFirst results are expected in the summer of 2018.Trial RegistrationClinicalTrials.gov NCT02385188; https://clinicaltrials.gov/ct2/show/NCT02385188 (Archived by WebCite at http://www.webcitation.org/6sXygHuhP).

Spectrum of Changes in Anogenital Mammary-like Glands in Primary Extramammary (Anogenital) Paget Disease and Their Possible Role in the Pathogenesis of the Disease.

To determine whether a subset of primary extramammary Paget disease (EMPD) may originate in anogenital mammary-like glands (AGMLG), the authors studied 181 specimens of EMPD, detailing alterations in AGMLG. The latter were identified in 33 specimens from 31 patients. All patients were women, ranging in age from 38 to 93 years (median, 65 y). In all cases, lesions involved the vulva and in 1 patient the perianal skin was affected. Histopathologically, AGMLG manifested changes identical to columnar cell change (CCC) (87.1%), usual ductal hyperplasia (22.6%), columnar cell hyperplasia (CCH) (9.7%), oxyphilic (apocrine) metaplasia (6.5%), and atypical duct hyperplasia (3.2%). Four cases (12.9%), in addition to intraepidermal carcinoma, harbored invasive carcinoma. In all 4 of these, AGMLG displayed a range of alterations including ductal carcinoma in situ, CCC, and CCH. Three further cases (9.7%) showed ductal carcinoma in situ without any definite invasive carcinoma. Colonization of AGMLG by neoplastic Paget cells was noted in 6 cases. As CCC and CCH may be encountered in normal AGMLG, these alterations are unlikely to play a significant role in the pathogenesis of the disease. However, by analogy with mammary Paget disease, rare cases of primary EMPD may originate in AGMLG with a subsequent upward migration of the neoplastic cells into the epidermis and possible later breach through the basal membrane. Usual ductal hyperplasia and atypical duct hyperplasia can then be regarded as earlier precursor lesions, linking both ends of the spectrum.

Clinicopathological study of 56 cases of extramammary Paget's disease with or without acantholysis

Objective: To identify the clinicopathological features of extramammary Paget's disease(EMPD) and investigate the clinical and histopathological significance of acantholysis in EMPD. Methods: From June, 2010 to October, 2016, a total of 56 patients were diagnosed as EMPD in the Department of Dermatology, Peking Union Medical College Hospital. Clinical and histopathological data were retrieved from these patients' medical records and analyzed respectively. The cases were divided into two subgroups according to the histopathological pattern (with or without acantholysis): the acantholytic EMPD (AEMPD) group and the non-acantholytic EMPD (N-AEMPD) group. The clinicopathological data were compared and statistically analyzed between the two groups. Results: The AEMPD group included 22 cases (39.3%), while the N-AEMPD group included 34 cases (60.7%). The male: female ratio, the age of onset, and the median duration of the disease were 10∶1 vs 10.3∶1, (64±8)vs (64±10)years, and 42(4-240)months vs 48(3-120) months in the AEMPD and N-AEMPD groups, respectively, with no significant difference (all P>0.05). There was no significant difference in the severe dermal inflammation (27.3% vs 17.6%, P=0.600 ) and cytologic anaplasia(13.6% vs17.6%, P=0.979)between the AEMPD and N-AEMPD groups.Adnexal involvement or dermal invasion (72.7%) was significantly more common in cases with AEMPD, compared to cases with N-AEMPD (23.5%, P<0.001). And 17 cases in the AEMPD group (77.3%) were Hailey-Hailey-disease-like subtype. The recurrence rate after surgical management (29 cases) showed no significant difference between the two groups (1/12 vs 4/17, P=0.370). Conclusions: Acantholysis is common in EMPD. It is not associated with sex, the age of onset, and the duration of the disease. Acantholysis may indicate invasive growth of Paget's cells. Its occurrence has no association with severe dermal inflammation or cytologic anaplasia. Hailey-Hailey-disease-like subtype is the most common subtype in AEMPD, requiring careful consideration to avoid misdiagnosis. Postoperative recurrence is not associated with acantholysis in EMPD.

Chronic macerated plaques over the genitalia in an elderly female: A diagnostic challenge

Extramammary Paget's disease (EMPD) is a rare dermatosis occurring in sites rich in apocrine glands, such as the vulva, anogenital region, and axilla. It can be subdivided into primary and secondary disease. An 84-year-old female presented with itchy, whitish, oozy raised lesions over the genitalia and groin since 2 years, associated with burning sensation. Examination revealed erythema, maceration and white oozy plaques over bilateral groin folds, perineum, and labia majora. She was treated as candidal intertrigo with secondary infection, with antibiotics and antifungals with minimal improvement. Routine blood investigations were within normal limits. Skin biopsy done from the vulva showed Paget cells in the lower two-thirds of the epidermis. She was diagnosed to have EMPD and referred to the oncosurgeon for further management. We present this case due to the rarity of its occurrence and to emphasize the high index of clinical suspicion required for chronic, macerated, erythematous plaques over the perineum, which do not respond to conventional treatment, in an elderly patient.

Possible mechanisms of the crosstalk between Langerhans cells and regulatory T cells in extramammary Paget disease by receptor activator of nuclear factor kappa B (RANK) ligand/RANK pathways.

Extramammary Paget disease (EMPD) is a skin adenocarcinoma of apocrine gland origin, in which Paget cells express receptor activator of nuclear factor kappa B (RANK) ligand (RANKL) and matrix metalloproteinase (MMP)-7, and release soluble (s)RANKL into the tumour microenvironment. We previously reported that about 60% of the RANK+ cells among the stromal cells are M2 macrophages, but the identity of the remaining population of RANK+ cells is still unknown. To investigate the unknown subpopulation of RANK-expressing cells in EMPD. The main population of RANK-expressing cells in the epidermis was composed of epidermal Langerhans cells (LCs). To explore the effects of RANKL on LCs, we stimulated LCs generated from human CD34+ hematopoietic progenitor cells with graded concentrations of sRANKL. To further examine the correlation between LCs and regulatory T cells (Tregs) in EMPD, we employed immunohistochemical staining. sRANKL stimulation was shown to augment the production of C-C motif chemokine ligand 17 (CCL17) from LCs. We additionally demonstrated CCL17 expression by CD1a+ LCs in EMPD in an immunofluorescence study. Spearman's rank correlation test confirmed a correlation between the number of LCs and the number of Foxp3+ Tregs in the lesional skin of invasive EMPD. In addition, the numbers of Foxp3+ Tregs in the sentinel lymph nodes of metastatic EMPD were significantly higher than those of metastatic melanoma, which did not express RANKL. The findings suggest that the RANKL/RANK pathway in EMPD might contribute to the recruitment of Tregs and to maintenance of the tumour microenvironment.

RANKL expression is a useful marker for differentiation of pagetoid squamous cell carcinoma in situ from extramammary Paget disease

Pagetoid squamous cell carcinoma in situ (SCCIS) is a histopathologic variant of SCCIS composed of cells that display an abundant, pale-staining cytoplasm in a pagetoid distribution within the epidermis. As pagetoid SCCIS is sometimes difficult to differentiate from extramammary Paget disease (EMPD) histopathologically, specific markers for pagetoid SCCIS or EMPD are needed by dermatopathologists. In this report, we employed immunohistochemical staining for receptor of activated nuclear factor kappa ligand (RANKL) and programmed death-ligand 1 (PD-L1) in six cases each of pagetoid SCCIS and EMPD. The Paget cells strongly expressed RANKL in EMPD, whereas the atypical keratinocytes did not express RANKL in any of the six cases of pagetoid SCCIS. In all cases of pagetoid SCCIS, atypical keratinocytes expressed PD-L1. In EMPD, Paget cells expressed PD-L1 in half of the cases at a lower level of expression than was seen in the surrounding keratinocytes. This study suggested that RANKL, but not PD-L1, could be a marker to differentiate between pagetoid SCCIS and EMPD.

Paget's disease of the male breast: a case report.

The patient was a 91-year-old man with change in nipple appearance, itching and redness, and a palpable breast mass. At presentation, mammary Paget’s disease (PD) was clinically suspected. Skin biopsy was performed and showed epidermis invaded by Paget cells, characterized by hyperchromatic nuclei and abundant pale-staining cytoplasm. Computed tomography and mammary ultrasonography confirmed the absence of an underlying invasive carcinoma, and the patient underwent right mastectomy and sentinel lymph node biopsy (SLNB). Both sentinel lymph nodes were found to be negative perioperatively, and further axillary dissection was not performed. Pathological results revealed no malignancy under the nipple, yet the Paget cells were more widely spread than expected. The patient was followed up without the need of postoperative chemotherapy. Male mammary PD is an extremely rare breast cancer, and there is no standard preoperative assessment or operative procedure. Mammography is many times unable to detect possible underlying breast carcinoma in female patients with mammary PD, and previous studies have reported that the detection rate was less than 50 %. However, some researchers reported that magnetic resonance imaging (MRI) might be more detectable to confirm the extent of the cancer. The extent of the skin change around the nipple is often different from the actual perimeter of Paget cells. In extra-mammary PD, mapping biopsy is known to be useful to determine areas free of cancer. The benefits of SLNB have also been demonstrated for the management of less invasive breast cancers, and previous reports have shown that the use of SLNB is reasonable for treatment of mammary PD without underlying invasive cancer. MRI, mapping biopsy, and SLNB are all less invasive procedures and thus may be suitable for treatment of male mammary PD.

Androgen receptor, androgen-producing enzymes and their transcription factors in extramammary Paget disease

Extramammary Paget disease (EMPD) has been known to frequently express androgen receptor (AR). Therefore, androgens could play roles in the biological behavior of Paget cells. 5α-Reductase (5α-red) types 1 and 2 and 17β-hydroxysteroid dehydrogenase type 5 (17β-HSD5) are pivotal in situ regulators of androgen production in androgen-responsive tissues including androgen-dependent neoplasms. Therefore, in this study, we immunolocalized AR, androgen-producing enzymes, and their transcription factors to assess the state of in situ androgen production and actions and its correlation of invasiveness in EMPD. We studied 51 cases of EMPD with known clinicopathological status. AR, 5α-red1, 17β-HSD5, and β-catenin immunoreactivity was evaluated by using the modified H-score method while cyclin D1, p53, forkhead box protein P1, and a proliferation marker, Ki-67, were quantified using labeling index. The mean scores of AR, 5α-red1, and 17β-HSD5 in invasive EMPD were all significantly higher than noninvasive EMPD (P < .0001). Ki-67 labeling index as well as the cyclin D1 score was also significantly higher in invasive than noninvasive lesions of EMPD. These results demonstrated that androgen receptor and androgen-producing enzymes were both associated with cell cycle regulation and subsequently the invasiveness of EMPD lesions and could also indicate those above as potential markers of invasive potentials in EMPD.