Primary melanoma of the nipple: Report of 10 cases including coexistence with Paget's disease.

Primary melanoma of the nipple (PMN) is exceedingly rare, with only single cases reported to date. We identified 10 patients with PMN: 5 females, 5 males, median age 55.5 years (range 29-66) at diagnosis of melanoma in situ (4 cases) or invasive melanoma (6 cases, Breslow depth 0.2 mm to 3.5 mm). Follow-up was available for all 10 patients (median 19 months, range 1-183). Nine patients had no evidence of disease; one patient died of disease (13.5 months) after presenting with a nodal metastasis. One case was exceptional, because the patient presented with a pigmented lesion that histopathologically exhibited co-existence of melanoma in situ and Paget disease, a challenging differential diagnosis due to immunohistochemical pitfalls in distinction between melanoma in situ and the pigmented variant of mammary Paget disease. Here we report the second largest series of PMN including a case of PMN colliding with mammary Paget disease, to raise awareness of these rare malignancies.

Melanoma Mimicker: Pigmented Mammary Paget Disease in a Man.

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.

Dense Lichenoid Inflammation in Paget Disease: A Diagnostic Pitfall.

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.

[Expression of MSI1 and HER2 in mammary Paget's disease and their correlation with clinicopathological features and prognosis].

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.

Extra-mammary Paget's disease of the penis.

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.

[Pathoanatomical algorithm for differential diagnosis of Paget's disease of the breast]. / Patologo-anatomicheskii algoritm differentsial'noi diagnostiki bolezni Pedzheta molochnoi zhelezy.

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.

[Paget's disease of the nipple]. / Pagets sykdom i brystvorten.

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.

Immunohistochemical expression of TRPS1 in mammary Paget disease, extramammary Paget disease, and their close histopathologic mimics.

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.

Paget's disease of the breast: diagnosis and management.

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.

A monolateral pigmented lesion of the 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.

Multidisciplinary management of mammary Paget's disease: recommendations to optimize oncological and aesthetic outcomes.

We read with interest the article of Francesca Maria Plutino entitled "A peculiar case of Paget's disease of the breast" and would like to make some considerations about this particular topic 1. Mammary Paget's Disease (MPD) or Paget's disease of the breast is an uncommon pathology which accounts for less than 5% of breast cancers 1-3. MPD occurs with alterations of the nipple-areolar complex (NAC) such as redness, eczema, bleeding ulceration and usually itching 1-3. In the era of personalized care, a careful multidisciplinary management is mandatory to optimize the results and minimize the risk of overtreatment 4; an adequate knowledge of the MPD, surgical skills and use of appropriate adjuvant therapies allow to reduce the risk of local recurrence and improve the aesthetic outcomes and patient's quality of life; however, a successful work can be more easily achieved thanks to the repetitive performance of some standardized tasks, such as 5: - an accurate radiological preoperative assessment with mammography and ultrasonography is important to identify associated glandular lesions; an underlying breast carcinoma (in situ and/or invasive) may be present up to about 80% to 90% of MPD although often without an evident breast mass or mammographic abnormality (2,5); therefore, all patients with MPD should also perform a magnetic resonance imaging to detect possible underlying occult breast carcinoma and define the true extent of disease 5,6; - a pathological diagnosis should be early established by nipple scrape cytology when a MPD is clinically suspected; full-thickness punch or wedge biopsy of the NAC may be necessary to accurately diagnose MPD; the histological examination must detect malignant intraepithelial carcinoma cells, also known as "Paget cells", in the epidermis of the NAC 2,3; a needle biopsy is also required for any suspicious glandular lesion identified by imaging and associated with MPD 5; - a multidisciplinary "Surgery Board" is mandatory to select the more adequate local treatment for the patient: breast-conserving surgery (BCS) followed by radiotherapy (RT) is the optimal local treatment when a NAC resection and wide local excision of any underlying cancer allows to achieve tumour-free margins and appropriate aesthetic outcomes 4,5,7; the oncoplastic techniques with the remodelling of breast tissue and placement of clips within the excision cavity as a landmark to guide adjuvant RT should always be used in BCS in order to optimize oncological and cosmetic results 5,8,9,10. Instead, skin-sparing mastectomy with immediate breast reconstruction is indicated for MPD associated to multicentric or extensive carcinoma, inadequate margins after BCS, contraindications to adjuvant RT and patient preference 5,8. Staging and surgical treatment of the axilla in MPD is based on the possible presence of underlying cancer; sentinel lymph node biopsy (SLB) is not necessary when BCS is used to treat pure MPD or MPD associate with ductal carcinoma in situ; SLB must be performed when MPD is associated with underlying invasive cancer and treated with breast-conserving surgery; SLB is always recommended when a mastectomy is performed in order to avoid complete axillary lymph node dissection in case an invasive component is revealed at final pathology of the gland (mastectomy precludes subsequent use of SLB) 5,7,8; - a multidisciplinary "Tumor Board" is crucial to choose the adjuvant treatment; whole breast radiation should be always performed after BCS and a radiation boost should be considered for the site of the resected NAC and any associated resected cancer site 2,4,5; adjuvant systemic therapies in patients with MPD should be based on biological features and the stage of the underlying cancer; no data are available to support the use of endocrine therapy in the MPD without an associated DCIS or invasive carcinoma 5. In conclusion, a dedicated multidisciplinary pathway with meticulous repetitive performance of some specific tasks could help to perform a successful work while optimizing oncological and aesthetic outcomes in patients with MPD.

A peculiar case of Paget's disease of the breast.

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.

Keratin 7 and ERBB2 Negative Mammary Paget Disease Without an Underlying in Situ and Invasive Carcinoma.

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.

Pigmented epidermotropic breast cancer metastases: A rare variant with a particularly unusual feature.

Pigmented epidermotropic breast cancer metastases are a rarity, often clinically misdiagnosed as melanocytic lesions. Histopathologically, they show a dermal proliferation of neoplastic metastatic cells that extend to the overlying epidermis in a pattern identical to that seen in primary Paget disease (PD). Differential diagnosis should be established with entities with a similar presentation, such as pigmented mammary PD and malignant melanoma. Immunohistochemistry may be useful for this purpose. We present a new case of pigmented epidermotropic breast cancer metastases with a particularly unusual feature: the absence of dermal infiltration by neoplastic cells, thus considered as pure epidermotropic metastatic involvement.

Paget's disease of nipple with dermal invasion: A case report.

BACKGROUND: Invasive mammary Paget's disease (MPD) is an extremely rare eczematous eruption on the nipple and areola with an invasion of the dermis by Paget cells. This entity can often be misdiagnosed and overtreated for invasive carcinoma of the breast. CASE: A 34-year woman presented with a 2-year history of right nipple eczema and right axillary lump for a month. Breast ultrasound revealed dilated intra-nipple lactiferous duct and an enlarged right axillary lymph node. Histopathology from biopsy revealed MPD with ductal carcinoma in situ (DCIS) whereas final histopathology after right modified radical mastectomy revealed Invasive MPD with DCIS and axillary metastasis. She underwent adjuvant chemotherapy and is under hormonal therapy with complete remission for 18 months. CONCLUSION: Awareness of invasive MPD is important to avoid misdiagnosis and probable radical treatment. Close follow-up is warranted due to limited knowledge regarding treatment and prognosis of invasive MPD.

Mammary Paget's Disease Presenting as an Annular Plaque.

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.