Search

Abstract: Mammary Paget disease is a rare form of breast cancer, which typically presents as an eczematous plaque on the nipple or surrounding skin. It is often a clinical diagnosis that is confirmed with skin biopsy. Histologic hallmarks of mammary Paget disease include large, pleomorphic, malignant, ductal epithelial cells within the epidermis. Chronic lichenoid inflammation may be seen in the papillary dermis but is not diagnostic. Because mammary Paget disease often overlies ductal carcinoma in situ or invasive carcinoma of the breast, prompt bilateral mammography is warranted. We report a case of Paget disease of the nipple with negative breast imaging that was originally misdiagnosed due to a dense lichenoid infiltrate obscuring the neoplasm., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Abstract: Male breast cancer comprises less than 1% of all breast cancer cases. Mammary Paget disease (MPD) represents a subset of breast cancer that presents with skin changes of the nipple and areola, and is frequently misdiagnosed clinically due to similarities with other disease states, leading to an average delay in diagnosis of 1 month to 2 years. Pigmented mammary Paget disease (PMPD) is an uncommon variant of MPD that clinically and histologically resembles malignant melanoma. Due to variable immunohistochemical staining patterns, analysis can be challenging and often requires interpretation of panels for accurate diagnosis. We present a rare case of PMPD in a male, originally diagnosed both clinically and histologically as malignant melanoma, to highlight the diagnostic challenges that this entity presents, and to review staining patterns which may be useful in its diagnosis., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Nipple adenoma is a rare proliferative lesion that originates from the lactiferous ducts of the nipple. Though it is benign, the typical presentation includes suspicious symptoms-a firm nodule, crusting erosion, and/or discharge from the nipple. These findings can raise concern for malignancy and in particular, Paget's disease. We report two cases of this uncommon entity, highlighting the variable clinical presentation and keys to the diagnostic evaluation and management., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Paget's disease was first described in 1874 as an eczematoid changes of the nipple associated with underlying breast carcinoma. Extra-mammary Paget's disease (EMPD) is rare with involvement of the male genitalia described in small case series and management options varying according to location and extent. The diagnosis of EMPD requires a high index of clinical suspicion and close liaison with the multidisciplinary team, particularly histopathology. We present two cases of EMPD affecting the male external genitalia that highlight important learnings in the presentation, diagnosis, and management of EMPD.

Objective: To investigate the expression of MSI1 and HER2 in mammary Paget's disease, and the correlation between the expression levels of MSI1 and HER2 and the clinicopathologic characteristics and prognosis of the patients. Methods: Clinical data and paraffin-embedded specimens of 34 pairs of mammary Paget's disease and underlying breast cancer were collected at the Department of Pathology, Affiliated Lianyungang Oriental Hospital of Xuzhou Medical University from March 2011 to December 2019. Immunohistochemistry was used to detect the expression of MSI1 and HER2 in mammary Paget's disease and the accompanying breast cancer, and to analyze the correlation between the expression levels of MSI1 and HER2 and their clinicopathologic features, as well as their influence on prognosis. Results: In mammary Paget's disease, the positive rate of MSI1 was 91.2% (31/34) and the positive rate of HER2 was 88.2% (30/34); the expression of MSI1 and HER2 was positively correlated ( P =0.001, r =0.530). The expression of MSI1 was positively correlated with menopausal status ( r =0.372, P =0.030) and lymph node metastasis ( r =0.450, P =0.008). HER2 expression was positively correlated with menopausal status ( r =0.436, P =0.010), and negatively correlated with ER expression ( r =-0.365, P =0.034). The co-expression of MSI1 and HER2 was positively correlated with age ( r =0.347, P =0.044) and menopausal status ( r =0.496, P =0.003), and negatively correlated with ER expression ( r =-0.461, P =0.006). Conclusions: MSI1 and HER2 are highly expressed in mammary Paget's disease and their expression levels are positively correlated. The correlation analysis between clinicopathological features and prognosis suggests that both of them may be involved in the occurrence and development of mammary Paget's disease and are potential therapeutic targets for mammary Paget's disease.

Purpose: To classify the molecular subtypes of Paget's disease of the breast, and then compare them with general breast cancer to get deeper understanding of this disease and offer better management of associate patients in clinical decisions., Methods: We used immunohistochemistry to examine 42 cases of this disease by antibodies against estrogen and progesterone receptors, Ki-67, as well as human epidermal growth factor receptor 2 (HER-2). Due to damage and loss of specimens, etc., we obtained 36 pathological specimens from the 42 patients. For 30 of 36 pathological specimens (83.3%), we obtained a complete molecular subtype. Cause the other 6 pathological specimens have missing immunohistochemistry items. For patients with bilateral breast cancer, only information on the side with PDB is listed. For patients with recurrence, only information on the first onset was included. We finally compared and studied the molecular subtype of 26 samples. We calculated the relative frequencies of molecular subtypes including luminal A, luminal B, HER-2-enriched, and basal-like and compared them between PDB and general breast carcinomas in other studies., Results: The luminal A and B subtype were found, respectively, in 3 (11.5%) and 6 (23.1%) of all patients, and 15 cases of HER-2-enriched subtype was detected (57.7%). In addition, 2 (7.7%) showed a basal-like subtype., Conclusion: The molecular subtypes of common breast cancer and PDB-associated breast cancer differ. Luminal subtypes are the most common in the former, while within our samples HER-2 positive subtype was the highest in PDB-associated breast carcinoma. With further understanding of this disease, rational therapies will be applied in different patients and cures for PDB and PDB-associated carcinoma will be achieved., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Trichorhinophalangeal syndrome type 1 (TPRS1) expression has been found to be highly sensitive and specific for breast carcinomas. The frequency of TRPS1 expression in cutaneous neoplasms such as mammary Paget disease (MPD) and extramammary PD (EMPD) is currently unknown. We assessed the utility of TRPS1 immunohistochemistry (IHC) in the evaluation of MPD, EMPD, and their histopathologic mimics, squamous cell carcinoma in situ (SCCIS) and melanoma in situ (MIS)., Methods: Twenty-four MPDs, 19 EMPDs, 13 SCCISs, and 9 MISs were subjected to immunohistochemical analysis using anti-TRPS1 antibody. The intensity (none, 0; weak, 1 + ; moderate, 2 + ; strong, 3 + ) and proportion (<1%, absent; 1%-25%, focal; 26%-75%, patchy; >75%, diffuse) of TRPS1 expression were recorded. Relevant clinical data were documented., Results: TPRS1 expression was present in 100% (24/24) of MPDs, with 88% (21/24) of MPDs exhibiting strong, diffuse immunoreactivity. Sixty-eight percent (13/19) of EMPDs showed TRPS1 expression. Intriguingly, EMPDs lacking TRPS1 expression were consistently of perianal origin. TRPS1 expression was seen in 92% (12/13) of SCCISs but was absent in all MISs., Conclusions: TRPS1 may be useful to distinguish MPDs/EMPDs from MISs, but its utility is limited in distinguishing them from other pagetoid intraepidermal neoplasms such as SCCISs., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Paget's disease of the nipple comprises approximately 1 % of all breast cancers, and presents with unilateral eczematoid changes to the nipple, areola or surrounding skin. Symptoms can be pain, itching or stinging in the area., Case Presentation: A female patient in her sixties presented to the skin clinic 18 months after initial detection of a rash surrounding her left nipple. Earlier ultrasound and mammography had not indicated pathology. Clinical suspicion and punch biopsies revealed a ductal carcinoma in situ. Surgical excision had to be repeated three times before the underlying malignancy was totally removed., Interpretation: Eczematoid changes in the nipple area are associated with underlying ductal carcinoma or a carcinoma in situ, and biopsies should be taken.

Purpose: Little is known about the prognostic value of androgen receptor (AR) status in mammary Paget's disease (MPD). The purpose of this study was to explore AR status and the distribution of molecular subtypes in MPD as well as the relationship between AR expression and clinicopathological factors and to evaluate its prognostic value., Methods: We analyzed 170 MPD patients of varying subtypes. AR expression was verified by immunohistochemical staining, and the correlations between AR expression and clinicopathological characteristics and survival status were analyzed. We further investigated 91 MPD patients with invasive ductal carcinoma (MPD-IDC)., Results: AR was expressed in 55.3% of overall MPD patients, and 78.2% had the human epidermal growth factor receptor 2 (HER2) overexpression subtype. AR positivity was significantly correlated with BMI (P = 0.037) and pathological N stage (P = 0.023). Multivariate analysis indicated that pathological T stage and pathological N stage were independent prognostic factors for overall survival (OS). The positive AR group was significantly associated with better OS (P = 0.014). Among 91 MPD-IDC patients, AR was expressed in 56.0%, and 80.0% had the HER2 overexpression subtype. AR positivity was significantly correlated with pathological N stage (P = 0.033). Multivariate analysis indicated that AR and pathological T stage were independent prognostic factors for OS. Furthermore, AR positivity was significantly related to better OS (P = 0.005) in MPD-IDC patients as well as in patients with the HER2 overexpression subtype (P = 0.029)., Conclusion: Our results confirmed that AR is a potential biomarker for evaluating the prognosis of patients., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Paget's disease of the breast typically affects postmenopausal women and is associated with an underlying malignancy. Skin changes are a common presenting symptom, as well as a lump, nipple discharge, pain and changes to the nipple shape. Imaging options include ultrasound for women under the age of 35 years or mammogram and ultrasound for women over the age of 40 years. The definitive diagnostic investigation is a tissue core biopsy. Cases are discussed by a multidisciplinary team to decide on the optimal management strategy. Management options are typically surgical and include breast-conserving surgery or mastectomy in addition to oncoplastic techniques. Sentinel lymph node biopsy is performed in all patients undergoing surgery. Adjuvant chemotherapy, radiotherapy or endocrine therapy can be used to treat concomitant invasive disease or ductal carcinoma in situ.

Paget's disease of the breast is a rare type of cancer that affects the skin of the nipple and usually the areola. At the same time, most patients also have one or more tumors in the immediate vicinity of the focus of mammary Paget's disease. This tumor must be distinguished from normal or atypical Toker cells, and also differentiated from diseases such as Bowen's disease of the nipple and melanocytic lesions of the nipple and areola region, including nipple melanoma and BAP1-inactivated nevus (Wiesner nevus). Currently, there is no routine pathological diagnostic algorithm for these conditions. The aim of the work is to formulate a clear clinical and morphological algorithm for diagnosing Paget's disease of the breast and Toker cells, Bowen's disease of the nipple and areola, as well as melanoma and BAP1-inactivated nevi of the above localizations. Surgical material obtained from patients with Paget's disease of the breast (18), Toker cells of the nipple (2), Bowen's disease of the nipple (6), melanoma of the nipple (1), BAP1-inactivated nevus (1) was studied. The material was examined histologically with hematoxylin and eosin staining, Alcian blue and PAS reaction, as well as immunohistochemically with the following panel of antibodies: CD138, p53, CK8, CK7, HER2/neu, EMA, HMB-45, Melan A, S-100, p63, p16 and BAP1. An easy-to-learn pathoanatomical algorithm for diagnosing Paget's cancer has been developed, which will be especially useful for pathologists who encounter pathology of the nipple and areola in their work.

Dear Editor,Mammary Paget's disease (MPD) is an adenocarcinoma localized within the epidermis of the nipple and/or the areola of the breast, and it is as a rule associated with a carcinoma of the underlying lactiferous ducts, where it usually starts. MPD is relatively rare, observed in 0.7-4.3% of all breast cancers (1). We present a patient with MPD and atypical clinical finding as an annular plaque. A 74-year-old Japanese woman with a past medical history of hypothyroidism presented with a 6-month history of an itching plaque on the left areola. The patient had been treated with the application of topical steroids for a duration of approximately 5 months, and showed no clinical improvement. Physical examination showed a pink plaque encircling the nipple on the left areola (Figure 1, a). The right nipple and areola appeared normal (Figure 1, b). No palpable masses were detected within either breast. A 3.5 mm punch biopsy of the skin at the 6 o'clock position of the left areola was performed. Histological examination showed single and small aggregations of atypical cells with large hyperchromatic nuclei and pale-staining, ample cytoplasm throughout the epidermis. There was a lymphocytic infiltration in the dermis (Figure 1, c). Immunohistochemical studies were positive for CK7 and negative for S-100 and HMB45. With the diagnosis of MPD, the patient underwent a partial mastectomy of the left breast center area, consisting of surgical excision of the left nipple, the adjacent surrounding areolar skin, and subcutaneous tissues. Subsequently, radiation therapy for the residual breast was prepared. As has been described in detail by Kanitakis, the skin lesion develops insidiously as a scaly, fissured, or oozing erythema of the nipple and, more rarely, the areola. Advanced lesions present as a well-demarcated, round, ovoid, or polycyclic eczema-like plaque with a pink or red hue. It is occasionally slightly infiltrated and has an erosive, oozing, scaly, or crusted surface. The lesions are almost invariably unilateral, showing centrifugal spread. Retraction or ulceration of the nipple are often noted (1). The present case exhibited a very rare clinical finding of a plaque encircling the nipple, which has not been reported previously. It was initially difficult to establish the diagnosis of MPD, and biopsy was needed to obtain a definitive diagnosis. Differential diagnosis of MPD comprises eczema as atopic dermatitis or contact dermatitis, erosive adenomatosis, and malignant skin condition such as Bowen's disease, superficial basal cell carcinoma, or superficially spreading melanoma. As in the present case, individuals presenting with an annular plaque are often considered to have sebaceous hyperplasia. Sebaceous hyperplasia is a common, benign skin condition involving hypertrophy of the sebaceous glands, common in middle-aged or older adults (2). These lesions can be single or multiple and manifest as yellow, soft, small papules. These papules are occasionally seen around the nipple, forming an annular plaque. In general, sebaceous hyperplasia is described as yellow-colored papules among Caucasians. However, caution is needed, since it is characterized by skin-colored papules among some Asians.In the present case, some pigmentation (2 to 3 mm in diameter) was observed on the left nipple. Pigmented MPD have been reported, and the mechanism underlying the pigmentation is not yet fully understood, but it has been proposed that Paget cells may release melanocytic chemoattractants or basic fibroblast growth factors that stimulate the proliferation of melanocytes within the tumor nests (3). The possibility of physiological pigmentation cannot be ruled out in the present case; on the other hand, the possibility of pigmented MPD cannot be ruled out either, since no pigmentation was observed on the right nipple.

Pigmented mammary Paget's disease is a very rare variant of mammary Paget's disease linked to an underlying carcinoma in almost all cases. We present the case of a 62-year-old female patient who came to our attention for the evaluation of a monolateral asymptomatic pigmented lesion of the right nipple, which turned out to be a pigmented mammary Paget's disease unassociated to an underlying malignancy - an extremely rare entity only anecdotally reported in literature. The two main peculiarities of our patient's lesion, the importance of immunohistochemistry in the differential diagnosis and the theories on its pathogenesis are discussed. Further studies are necessary to establish the best treatment options. Click here for the corresponding questions to this CME article., (© 2022 The Authors. Clinical and Experimental Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.)

We report a unique case of a post-menopausal female who presented with a lesion on the areola. A biopsy of the lesion demonstrated a pagetoid intraepithelial neoplasm suggesting a differential diagnosis of mammary Paget disease and pagetoid Bowen disease. Excision of the lesion confirmed the diagnosis of mammary Paget disease with typical histological appearance. This case is extremely rare since both keratin 7 and ERBB2 were negative, and there was no evidence of underlying in situ or invasive carcinoma.

Mammary Paget's disease is a disorder of the nipple-areola complex of the breast that, while rare, is often associated with an underlying carcinoma. The typical aspect is usually an eczematoid change of the nipple or a red and ulcerative nipple's lesion or erythematous and crusted lesion, with or without mass-like lesion and infiltration and inversion of the nipple. It was described at first by Sir James Paget in 1874, [1] who classified the disease in mammary and extramammary type. The mammary type (Paget' s Breast Cancer: PBC) has rare frequency. PBC occurs in 0.5-5% of all cases of breast cancer, it affects the mouth of the excretory ducts of the nipple, which is characterized by lesion of nipple's large ducts. PBC can be a superficial lesion or a nodule-tumor and it can be associated with underlying carcinoma in situ (DCIS) in more than 95% of cases, especially in postmenopausal women. In a small percentage of cases, PBC can also be associated with an invasive breast cancer. Accuracy in the diagnostic phase, in order to distinguish PBC from others diseases is paramount and histological examination of lesion's biopsy has a crucial role. Prognosis and treatment depend on the type of underlying breast cancer and are based on the stage of cancer, but more importantly, on the prompt of an adequate multidisciplinary diagnostic pathway. KEY WORDS: Histopathological Report, Oncological Outcomes Paget's Breast Cancer.

Paget disease of the breast is an uncommon malignant tumor with an inferior outcome. Therefore, establishing nomograms to predict the survival outcomes of breast Paget disease patients is urgent. Clinicopathological and follow-up data of breast Paget disease patients diagnosed between 2010 and 2016 were retrieved through the Surveillance, Epidemiology, and End Result (SEER) database. The significant factors were screened out, and then those factors were utilized to build two valuable nomograms. The discriminative ability of nomograms was investigated using concordance-index (C-index), while the predictive accuracy and benefits were evaluated using calibration curves and decision curve analysis. Finally, a total of 417 breast Paget disease patients were enrolled. Tumor grade, histological type, American Joint Committee on Cancer (AJCC) stage, surgery, chemotherapy, and marital status were confirmed as independent overall survival (OS)-related factors; tumor grade, histological type, AJCC stage, and age were associated with independent cancer-specific survival (CSS)-related factors. The values of the C-index for OS nomogram acquired were 0.827 and 0.745 for training and validation cohorts, respectively. Meanwhile, the corresponding values of the C-index to CSS nomogram were 0.890 and 0.655, respectively. The calibration curves and decision curve analysis indicated that both nomograms had an excellent performance. Finally, the nomogram-based risk stratification system indicated that all breast Paget disease patients could be classified into low- and high-risk groups and showed distinct outcomes. In conclusion, two valuable nomograms incorporating various clinicopathological indicators were established for breast Paget disease patients. These prognostic nomograms provide accurate prognostic assessment for breast Paget disease patients and help clinicians select appropriate treatment strategies.

Background/aim: Paget’s disease (PD) of the breast is a very rare presentation of breast malignancy, accounting for 1%–3% of all primary breast tumors. We aimed to evaluate and compare the clinicopathological features and clinical outcome of PD accompanied by in situ carcinoma and invasive cancer., Materials and Methods: We used the archive of our pathology laboratory retrospectively for age, sex, history of surgery, histopathological findings, treatment modalities, and follow-up information. We used the Kaplan–Meier method for survival analysis., Results: There were 46 female patients diagnosed with PD. In 39 (84.7%) patients, invasive carcinoma accompanied PD, while 7 (15.3%) patients had ductal carcinoma in situ. The median age at diagnosis was 53.5 years. The median follow-up period was 47 months. Of the 39 invasive carcinoma, 10 (25.6%) died during the follow-up period. Invasive ductal carcinoma group had a mean overall survival of rate of 57.8 ± 6.6 months. According to univariate analysis, only the tumor type was found to impact overall survival (p < 0.001)., Conclusions: The current study displayed the tumor type as the only parameter affecting overall survival in the invasive carcinoma group. Although it was not statistically significant, breast cancers accompanied by PD were found to be predominantly advanced stage tumors, high grade, hormone receptor negative, and HER2 positive., Competing Interests: None declared., (This work is licensed under a Creative Commons Attribution 4.0 International License.)

Mammary Paget's disease accounts for 1% to 3% of all breast tumors and manifests as a chronic eczematous lesion of the areolar skin. It can occur without any underlying neoplasia or can be present in association with an underlying invasive and/or in situ carcinoma of the breast. The present report describes a challenging nipple punch biopsy showing an infiltration of the lower third to two-thirds of the epidermis by large, ovoid, neoplastic cells. The morphology was consistent with mammary Paget's disease, although immunohistochemistry for cytokeratin-7 (CK7) was repeatedly negative. This resulted in an initial misdiagnosis and, subsequently, a delay in the patient's follow-up. Additional immunohistochemistry for GATA binding protein 3 (GATA3) and human epidermal growth factor receptor 2 (HER2), as well as a second opinion of a breast pathologist, resulted in the diagnosis of mammary Paget's disease. The aim of this article is to raise awareness among pathologists and prevent them from misdiagnosing CK7-negative Paget disease of the breast.

Backgound: This study aims to identify the expression of lipoma preferred partner (LPP) in Paget disease (PD) and to further understand the pathogenesis of PD., Methods: Tissue microarray was used to evaluate the expression of LPP by immunohistochemistry in 40 PD patients. The results of LPP expression were combined with clinical and histopathological characteristics. Patient files were analyzed retrospectively., Results: Twenty-one cases were mammary Paget disease (MPD) and 19 extramammary Paget disease (EMPD) involving the vulva, scrotum, and penis. LPP was expressed in PD and this expression was significantly greater in MPD versus EMPD (P = .031). The expression of LPP in MPD was significantly related with age (P = .009) and expression of Ki-67 (P = .011). No statistically significant differences were observed in LPP expression as related to sex, body location, and time of PD diagnosis., Conclusions: While LPP is expressed in both MPD and EMPD, the intensity of this expression is greater in MPD. LPP expression is positively correlated with Ki-67 and is more prevalent in middle-aged versus senior MPD patients. Further research is needed to determine its potential role in tumorigenesis and distribution., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2020 the Author(s). Published by Wolters Kluwer Health, Inc.)

Ultrasound (US) is an attractive diagnostic approach to identify both common and uncommon nipple pathologies, such as duct ectasia, nipple abscess, nipple leiomyoma, nipple adenoma, fibroepithelial polyp, ductal carcinoma in situ (restricted to nipple), invasive carcinoma, and Paget's disease. US is the reliable first-line imaging technique to assess nipple pathologies. It is useful to identify and characterize nipple lesions. Additionally, we have presented the mammography and MRI outcomes correlated with histopathologic features for the relevant cases., Competing Interests: The authors have no potential conflicts of interest to disclose., (Copyright © 2020 The Korean Society of Radiology.)

The classical Paget's disease of the nipple is histologically characterized by tumor cell infiltration originating in intraductal or invasive breast carcinoma, immunohistologically by a frequent overexpression of HER2 and clinically by eczema-like changes of the nipple and areola. Variants with different histological, immunohistological, and clinical features are observed in nonclassical forms of Paget's disease, such as isolated Paget's disease of the nipple, anaplastic Paget's disease, Paget's disease with invasion, and pigmented Paget's disease of the nipple. In the differential diagnosis of Paget's disease, benign changes have to be considered, including Toker cell hyperplasia, nipple eczema, and rare dermatoses.

Background: We examined the vascularity of mammary Paget disease histologically to confirm the increased blood flow observed previously by clinical imaging. The relationships among blood vessel density (BVD), histopathological parameters of blood flow in the nipple, and the expression of angiogenic factors such as basic fibroblast growth factor (bFGF) and vascular endothelial growth factor A (VEGFA) were examined., Methods: We calculated the average CD34-positive BVD and podoplanin (D2-40)-positive lymphatic vessel density (LVD) and the proportion of proliferating of endothelial cells in 14 Paget disease, 3 dermatitis biopsy, and 14 age-matched control cases. As a parameter related to blood flow in the nipple, the total CD34-positive blood vessel lumen area relative to the entire nipple area was measured in each Paget disease and control case using an automated image analysis system. Immunohistochemical expression of bFGF and VEGFA in Paget cells was also examined., Results: The average BVD and LVD were significantly higher in the Paget disease cases than in the dermatitis (p = 0.003) and control (p < 0.001) cases. The proportion of proliferating endothelial cells was also increased in the Paget disease cases. The ratio of the CD34-positive blood vessel lumen area to nipple area was also significantly higher in the Paget disease than control cases (p = 0.003). The average BVD was correlated with the average LVD (r = 0.734, p < 0.001) and ratio of the blood vessel lumen area to nipple area (r = 0.692, p < 0.001). Immunohistochemical expression of bFGF was strong in all Paget disease cases, with a significantly higher expression score in the Paget disease than dermatitis (p = 0.003) and control (p < 0.001) cases. The bFGF, but not VEGFA, expression score, was strongly correlated with the average BVD (r = 0.818, p < 0.001) and ratio of the blood vessel lumen area to nipple area (r = 0.503, p = 0.006)., Conclusion: These results provide direct histopathological evidence of a marked increase in nipple blood flow in Paget disease detected by clinical imaging. bFGF is considered to play a pivotal role in angiogenesis in mammary Paget disease.

Mammary Paget's disease is rare and comprises about 0.62% of all breast cancer cases, only 1.65% of which occur in male patients. This case report involves a 76-year-old man who presented to his primary care physician with an itching, scaly, unilateral lesion involving the nipple skin. He underwent wide local excision of the lesion for a diagnosis of Bowen's disease (squamous cell carcinoma in situ ). Histologic examination of the specimen revealed mammary Paget's disease with ductal carcinoma in situ in the underlying breast tissue. A panel of immunohistochemical stains revealed the Paget cells to be positive for cytokeratin 7, MUC1, GATA3, and androgen receptor and negative for cytokeratins 5/6, p63, SOX10, and MART-1/Melan-A. Paget cells were also negative for estrogen receptor and progesterone receptor, and positive for HER2/neu. However, the underlying ductal carcinoma in situ was positive for both estrogen receptor and progesterone receptor and negative for HER2/neu. This discordance, supported by the current literature, suggests an alternative etiology for Paget's disease in certain cases that cannot be explained by the well-established epidermotropic and transformative theories of Paget's disease evolution.

Background: The aim of this study was to present several cases of benign and malignant nipple lesions and contribute to diagnosis and differential diagnosis., Methods: A retrospective study was conducted on 13 patients. All of the patients were evaluated by ultrasonography, and 11 of them had pathological results. We analyzed the clinical and sonographic features., Results: There were 3 malignant lesions, 7 benign lesions, and 3 congenital nipple dysplasia, listed as follows:Malignant lesions (n = 3, 23%): Paget's disease (PD, n = 3, 23%). All of the patients with PD showed unilateral nipple erosion, discharge, and pain. The ultrasound showed abundant blood flow (n = 3, 23%); 2 patients (n = 2, 15%) had microcalcifications.Benign lesions (n = 7, 54%): Adenoma of the nipple (n = 2, 15%). One patient (n = 1, 8%) had nipple erosion and discharge. Two patients (n = 2, 15%) had a palpable nodule in the nipple. The ultrasound of both patients (n = 2, 15%) showed regular-shaped, clear border nodule with abundant blood flow (n = 2, 15%).Leiomyoma of the nipple (n = 1, 8%): This male patient was characterized by unilateral nipple enlargement and pain. The ultrasound showed a regular nodule with absent blood flow.Plasma cell mastitis (n = 2, 15%): Two patients showed unilateral nipple inversion and pain. One patient (n = 1, 8%) showed swollen and redness. The 2 patients showed a lesion in the gland around the nipple present as an irregular shape and unclear boundary hypoechoic mass.Nipple wart (n = 2, 15%): Two patients showed a unilateral soft exogenous neoplasm. Both of the patients showed a hypoechoic wart; the echo was similar to the nipple, the border was clear, and had no blood flow in the wart.Nipple Dysplasia (n = 3, 23%): Accessory nipple (n = 3, 23%). Two patients (n = 2, 15%) had accessory nipples in the subcoastal area, 1 patient (n = 1, 8%) in the areolar. All of the patients' sonographic features were the same as the nipple.The positive predict value (PPV) of the clinical symptoms: Erosion and discharge are both 75% (P < 0.05). The PPV of the US manifestations: irregular shape, indictinct margin, abundant blood flow, microcalcification, thicken skin in diagnosing malignant lesions are 60%,60%,60%,100%,100%, respectively (P < 0.05)., Conclusions: The characteristic sonographic features together with clinical symptoms contribute to the diagnosis of nipple lesions.

Paget disease of the nipple is a rare presentation of breast cancer. It is sometimes mistaken for a benign skin condition of the nipple and surrounding areola, which can significantly delay the diagnosis and treatment. In over 90% of cases there is an underlying carcinoma, either ductal carcinoma in situ (DCIS) or invasive breast cancer. We present a rare case of Paget disease of the nipple without the typical characteristics, detected by simple nipple scraping technique. A 62-year-old woman presented with a small fissure on the left nipple with scant clear nipple discharge. There were no other changes to the nipple-areola complex. The mammography and ultrasound were unremarkable. However, nipple scraping provided the immediate cytological diagnosis of Paget disease. Breast MRI with core biopsy showed high grade ductal carcinoma in situ with suggestion of microinvasion, confirmed histologically after mastectomy. Nipple scraping is a simple and inexpensive technique, which can be used in the office without anesthesia and with minimal discomfort to the patient. It could allow for significantly earlier cancer detection and treatment at the earliest stage of breast cancer. However, if the results are negative, full thickness biopsy may be needed if clinically indicated.

Background: Primary Extra-mammary Paget's disease (EMPD) is a very rare cutaneous adenocarcinoma affecting anogenital or axillary regions. It is characterized by a prolonged course with recurrences and eventually distant metastatic spread for which no specific therapy is known., Methods: Eighteen EMPD (13 vulvar and five scrotal) and ten mammary Paget's disease (MPD) cases were comprehensively profiled for gene mutations, fusions and copy number alterations, and for therapy-relevant protein biomarkers)., Results: Mutations in TP53 and PIK3CA were the most frequent in both cohorts: 7/15 and 5/15 in EMPD; 1/6 and 4/7 in MPD HER2 gene amplification was detected in 4/18 EMPD (3 vulvar and 1 scrotal case) in contrast to MPD where it was detected in the majority (7/8) of cases. TOP2A gene amplification was seen in 2/12 EMPD and 1/6 MPD, respectively. Similarly, no difference in estrogen receptor expression was seen between the EMPD (4/15) and MPD (3/10). Androgen receptor was also expressed in the majority of both cohorts (12/16 EMPD) and (7/8 MPD).Here ARv7 splice variant was detected in 1/7 EMPD and 1/4 MPD cases, respectively. PD-L1 expression on immune cells was exclusively observed in three vulvar EMPD. In contrast to MPD, six EMPDs harbored a "high" tumor mutation burden (≥10 mutations/Mb). All tested cases from both cohorts were MSI stable., Conclusions: EMPD shares some targetable biomarkers with its mammary counterpart (steroid receptors, PIK3CA signaling pathways, TOP2A amplification). HER2 positivity is notably lower in EMPD while biomarkers to immune checkpoint inhibitors (high TMB and PD-L1) were observed in some EMPD. Given that no consistent molecular alteration characterizes EMPD, comprehensive theranostic profiling is required to identify individual patients with targetable molecular alterations., (© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Purpose: 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., Methods: 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., Results: 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., Conclusions: 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.

Introduction: Mammary Paget's disease (MPD) is a rare cutaneous manifestation. Epidemiologically, more than half of the MPD patients concurrently have underlying invasive ductal carcinoma (MPD-IDC), and their prognosis remains poor despite multimodal treatments of breast cancer have markedly improved patients' survival. Accordingly, it is crucial to seek out novel therapeutic targets of MPD-IDC. As an emerging biological marker, the value of androgen receptor (AR) in MPD-IDC is inconsistent. Our objectives were to investigate the associations between AR and clinicopathological factors, and to explore its prognostic value in MPD-IDC., Methods: We retrospectively analyzed data from 103 MPD-IDC patients, and immunohistochemical staining was used to determine their AR statuses., Results: AR was expressed in 44 patients (42.7%), and AR expression was significantly correlated with body mass index (BMI) (p = 0.038) and axillary lymph node (ALN) status (p = 0.025). Kaplan-Meier curves showed that AR positivity was significantly associated with better overall survival (OS) in MPD-IDC patients (p = 0.019) and estrogen receptor-negative MPD-IDC patients (p = 0.039). Multivariate Cox regression analysis revealed that AR was not an independent prognostic indicator of disease-free survival (DFS) or OS in MPD-IDC patients (p = 0.395 and p = 0.073, respectively)., Conclusions: In contrast to AR-negative tumors, patients with AR-positive ones were more likely to have lower BMI, no ALN metastasis, and better OS. AR-targeted treatments for MPD-IDC may add to existing therapeutic approaches to improve their effectiveness., (© 2020 S. Karger AG, Basel.)

Background: We aimed to analyze the association between Paget's disease (PD) and breast cancer (BC) subtypes and compare the effect of breast-conserving surgery (BCS) as a local treatment with mastectomy for PD., Materials and Methods: Data of patients with histologic type International Classification of Diseases-0-3 8540-8543 who were treated from 1973 to 2014 were retrieved from the Surveillance, Epidemiology, and End Results database of the National Cancer Institute. A chi-square test was used to identify differences in categorical data among different groups. Overall survival (OS) was analyzed using the Kaplan-Meier method, log-rank test, Cox proportional hazards models, sequential landmark analysis, and propensity score-matched analysis., Results: The study cohort included 5398 patients. Triple-negative BC accounted for the fewest patients with PD-only (1/22, 4.54%), Paget's disease-ductal carcinoma in situ (PD-DCIS) (3/48, 6.25%), and Paget's disease-invading ductal carcinoma (PD-IDC) (23/352, 6.53%). According to the results of the log-rank test and Cox analysis, the 10-year OS rates were similar for the BCS and mastectomy subgroups among patients with PD-DCIS or PD-IDC. Furthermore, there were no significant differences in survival benefits among the different surgeries after propensity score matching. Landmark analyses for OS of patients with PD-DCIS or PD-IDC surviving more than 1, 3, and 5 y showed no significant differences in survival. There were statistical differences in 10-year OS rates for patients with PD-DCIS or PD-IDC who underwent radiation therapy, or not, following BCS (both, P < 0.001)., Conclusions: For patients with PD-DCIS or PD-IDC, breast conservation therapy with lumpectomy and radiation is an effective local treatment strategy, compared with mastectomy., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Most mammary Paget disease (MPD) is associated with underlying in situ or invasive breast cancer. The objective of this study was to compare the clinicopathological characteristics and survival outcomes between breast cancer with Paget disease (PD) and breast cancer alone., Methods: From the Surveillance, Epidemiology, and End Results (SEER) database, 2000-2015, of the US National Cancer Institute, we identified 1569 women who had PD with invasive ductal carcinoma (PD-IDC) and 1489 women who had PD with ductal carcinoma in situ (PD-DCIS). Independent demographic and clinicopathological variables as well as survival outcomes of these patients were compared to patients with the corresponding breast cancer without concomitant PD., Results: PD-IDC and PD-DCIS both had worse survival outcomes and poorer tumor characteristics than the corresponding disease without PD. Contrary to in the breast cancer alone groups, in the breast cancer with PD groups, the HR status (P = 0.182 in PD-IDC and P = 0.371 in PD-DCIS), HER2 status (P = 0.788 in PD-IDC and P = 0.643 in PD-DCIS), and combined molecular subtype (P = 0.196 in PD-IDC and P = 0.853 in PD-DCIS) were not found to affect disease prognosis. After matching tumor characteristics and treatment approaches, PD-IDC as well as PD-DCIS exhibited no significant difference in disease prognosis with corresponding IDC and DCIS. Finally, by comparative analysis, a kind of PD-DCIS (ICD-O-3 code 8543/3) showed many invasive behaviors (31.8% of 8543/3 patients had stage I-III cancer) and was associated with worse survival outcomes than the other type of PD-DCIS., Conclusions: Breast cancer with concomitant PD was associated with more aggressive tumor characteristics and worse survival outcomes. The HR status, HER2 status, and combined molecular subtype could not affect the prognosis of breast cancer with PD. Moreover, a portion of the PD-DCIS cases were invasive breast cancer cases that required special treatment., (© 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Objective: To present one case of Paget's disease (PD) of the breast without associated ductal carcinoma, and to conduct a review of the literature on its diagnosis and treatment., Materials and Methods: 59-year-old woman with a two-year history of a chronic erythematous, ulcerated, itchy lesion in the left nipple, initially treated dermatologically with topical steroids with no improvement, finally visits a primary healthcare institution in the city of Tunja, Colombia for diagnosis. A biopsy and histochemical testing were performed to make the diagnosis and the lesion was then treated with central quadrantectomy. The post-operative pathology testing was negative for malignancy, without recurrence at one-year follow-up. A search was conducted in the PubMed, SciELO, ProQuest, ScienceDirect and Google Scholar databases using the terms "Paget´s Disease," "Breast Neoplasms," "Mammography," "Ultrasonography," Mammary," "Biopsy," and "Mastectomy," tracking bibliographic review articles, editorials, reports and clinical case series in English and Spanish, without time limitation., Results: Overall, 11 publications were included consisting of 5 case reports, 3 case series, 1 review of the literature based on a clinical case, and 2 letters to the editor describing cases related to Paget's disease of the nipple with no associated carcinoma. The diagnosis was based on the clinical suspicion of the disease and a biopsy of the lesion. Histochemistry was useful for the differential diagnosis: treatment options ranged from mastectomy to nipple-areolar complex resection. Radiotherapy has also been used., Conclusions: The diagnosis of Paget's disease with no associated ductal carcinoma is based on early clinical suspicion and histopathology of the nipple- areolar complex. There is no consensus regarding surgical management of this lesion. Follow-up studies of this subgroup of patients treated with radiotherapy or conservative surgery are required., Competing Interests: None declared, (Copyright© 2019 This is an open-access article distributed under the terms of the Creative Commons Attribution License by-nc-nd/4.0.)

Context.—: Paget disease of the breast, in most cases, represents intraepidermal spread of ductal carcinoma in situ. Molecular subtypes of invasive carcinoma of the breast have prognostic and therapeutic significance and show characteristic distribution. Little is known about the distribution of molecular subtypes in Paget disease of the breast., Objectives.—: To examine the distribution of molecular subtypes in Paget disease of the breast and to compare them to concurrent invasive carcinoma of the breast, if present., Design.—: We examined 48 cases of Paget disease of the breast with immunohistochemistry and antibodies against estrogen and progesterone receptors, human epidermal growth factor receptor 2 (HER2), and Ki-67, as well as HER2 chromogenic in situ hybridization, to classify the cases into molecular subtypes. Then, we compared the results to the molecular subtypes of associated invasive carcinoma of the breast, if present., Results.—: The HER2 subtype was the most common found in Paget disease of the breast, followed by the luminal B subtype and 2 cases of the triple-negative subtype. The associated invasive carcinoma cases were most often of the luminal B subtype, followed by the HER2 subtype and the triple-negative subtype. The molecular subtype of Paget disease and invasive carcinoma was congruent in most of the cases., Conclusions.—: Molecular subtypes of invasive carcinoma of the breast can already be detected in Paget disease. The distribution of molecular subtypes of Paget disease and of Paget disease-associated invasive carcinoma differs from invasive carcinoma without associated Paget disease, with the HER2 subtype overrepresented in Paget disease and associated invasive carcinoma and the luminal and triple-negative subtypes underrepresented.

Background: Mammary Paget disease and extramammary Paget disease (EMPD) have different prognoses. Because they are indistinguishable on histopathological grounds, they must be distinguished on a topographical basis., Objective: To study cases of Paget disease of the breast, which show similarities to EMPD., Methods: Cases were selected by 2 different approaches: (1) those with an exceptionally good evolution and no evidence of subjacent tumor and (2) those expressing MUC5AC., Results: Five cases were collected. All cases showed an indolent behavior with a known long clinical history in 2 cases (9 and 25 years, respectively) and a long follow-up in all cases but one (4-8 years). In all cases but one, surgery was performed, and no parenchymal tumor was found (either intraductal or infiltrating). All cases expressed cytokeratin 7 and MUC5AC without expression of MUC2, S100, or p40., Limitations: The short number of cases is a limitation of this study. In addition, case 5 is recent, so we have a very short follow-up., Conclusions: Some cases of mammary Paget disease behave like EMPD with slow progression and with no underlying associated tumor. Immunoexpression of MUC5AC might be a clue to identify them.

We report a case of invasive solid papillary carcinoma (SPC) of the nipple with Pagetoid extension to the skin and lymph node metastasis. SPC is an uncommon primary breast cancer accounting for less than 1% of all breast cancers. Only 2 cases occurring in the nipple have been reported. However, both cases were without Pagetoid extension or lymph node metastasis. The presently reported tumor consisted of irregularly shaped solid cell nests with delicate fibrovascular cores. The tumor cells had round nuclei with low-grade atypia and eosinophilic cytoplasm. Neuroendocrine differentiation was confirmed by immunohistochemical positivity for CD56, synaptophysin, and chromogranin A. Immunohistochemistry also confirmed the absence of myoepithelial cells around the tumor cell nests. Therefore, a diagnosis of invasive SPC was made. Additionally, tumor cell deposits in the intramammary and axillary lymph nodes were identified, and these deposits had the same histological characteristics as the invasive SPC of the nipple. The invasiveness of SPC can be difficult to determine. However, the tumor cell nests in the current case exhibited a retraction artifact, which is known to be associated with invasive carcinoma and a poor prognosis, as well as morphological patterns that have been previously identified as characteristic of invasive SPC. Although SPC is widely recognized as having a favorable outcome, the existence of exceptionally aggressive cases occurring in the nipple must be recognized. Additional cases of invasive SPC of the nipple are needed to analyze the clinicopathological correlation.

Background: Mammary and extra-mammary Paget disease is a rare form of intra-epithelial glandular neoplasm which is characteristically recurrent and necessitates multiple excisions that have an important impact on morbidity. Local immuno-modulating treatments have been applied with promising results, but the local immune markers of Paget disease have not been studied., Aim of the Study: To investigate the local immune micro-environment of Paget disease., Materials and Methods: Sixty-four specimens from 41 patients, including cases with multiple recurrences and underlying primary neoplasm, have been studied for their expression of CD3, PD-L1 and CTLA-4., Results: Nineteen cases were mammary; 22 were extra-mammary and involved the vulva, the anus, the inguinal region and the lower extremity. PD-L1 was not expressed by any neoplastic lesion or the associated lymphocytes. CTLA-4 expression was found in nine cases. Higher stromal CD3 expression and moderate levels of intra-epithelial CD3 expression were present in most cases. Biopsies, subsequent excision specimens and recurrences showed the same immunohistochemical profile of CD3 and PD-L1, although there were different levels of CTLA-4 in a few cases. The underlying lesions in mammary Paget disease showed the same immunohistochemical profile as the intra-epithelial neoplastic cells. The expression of the markers did not correlate with age, sex, localization or recurrence., Conclusion: Paget disease is characterized by an intense lymphocytic response, devoid of the immune-suppressive impact of the PD-L1 pathway, but with occasional CTLA-4 expression.