Comparative study of breast cancer with or without concomitant Paget disease: An analysis of the SEER database.

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.

Paget's disease of the male breast: case report and a point of view from actual literature.

INTRODUCTION: Paget disease of the nipple in man is a very rare breast cancer, and there are not standard procedures or guidelines. In any cases, a Paget's disease could hide an invasive ductal breast cancer. CASE DESCRIPTION: We report the case of a 77-years old man affected by Alzheimer's disease, who presented to our attention because of an ulcerated palpable mass in the right nipple. A biopsy of the lesion showed "intra-epidermic proliferation of epitelioid cells, associated with linfo-plasmacellular infiltration of superficial dermis, compatible with Paget's disease (pTis)". We discussed the case in the multidisciplinary meeting and decided to subject the patient to surgery, so a right mastectomy plus sentinel lymph node biopsy (SLNB) were performed. Histo-pathological examination revealed "invasive ductal carcinoma of the breast, associated with a small component of in situ ductal carcinoma and Paget's disease of the nipple with superficial ulceration". Resection margins were free. Sentinel lymph node was negative. Biological features were as follows: ER 95%, PR 60%, Her-2/neu 1+, Ki-67 35%. The patient was discharged in the third post-operative day in good conditions. In the following weeks the patient's healing process was good and free of complications. CONCLUSIONS: Clinical recognition of Paget's disease is very important also in man, because it can be the alarm bell for an underlying invasive ductal breast cancer, often more aggressive than in woman.

Breast implant-associated anaplastic large cell lymphoma in a Li-FRAUMENI patient: a case report.

BACKGROUND: Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a rare malignancy, recently recognized as a provisional entity by the World Health Organization. Although increasing data have been published on this entity in recent years, a great number of patients and health professionals remain unaware of this diagnosis. CASE PRESENTATION: We herein report the case of a 56-year-old female with Li-FRAUMENI syndrome who presented with late right-sided recurrent breast swelling after prophylactic adenomastectomy with implant reconstruction. Imaging scans revealed an heterogeneous mass adjacent to the implant fibrous capsule. A biopsy of the lesion rendered the diagnosis of a BIA-ALCL. CONCLUSIONS: This case presents similarities with previous reports, but also some particularities, which should be stressed in order to make the diagnosis the earliest possible. The most distinct feature is that this is the second report of BIA-ALCL arising in the setting of Li-FRAUMENI syndrome.

An unusual case of mammary Paget’s disease in a woman with psoriasis.

Mammary Paget’s disease (MPD) is a malignant breast tumor, which is characterized by intraepidermal infiltration from malignant glandular epithelial cells. Often it may include an underlying ductal carcinoma in situ or an invasive ductal carcinoma. Clinically it appears as an erythematous patch, moist or crusted, with or without desquamation that in some cases becomes ulcerated, causing infiltration and inversion of the nipple. We report the clinical case of a 60-year-old woman, treated in our department for psoriasis, presenting with erythema of nipple and areola with nipple erosion, ulceration and poor secretion. Suspecting Paget’s disease of the nipple, radiological exams (mammography and breast MRI) were performed. A biopsy for histological examination was carried out and confirmed the diagnosis of mammary Paget’s disease. MPD is sometimes difficult to diagnose both clinically and radiologically, therefore it is important to distinguish from other conditions: in literature MPD is reported in differential diagnosis with psoriasis given its similar clinical features, and in some cases MPD has been treated with topical and systemic steroids due to a wrong diagnosis. However, the concomitance, in the same individual, of mammary Paget’s disease and psoriasis has never been described.

Paget's disease of the nipple.

Paget's disease of the breast is a disorder of the nipple-areola complex that, while rare, is often associated with an underlying carcinoma. It is characterized by eczematoid changes of the nipple. Two theories have been proposed to explain the pathogenesis of Paget's disease. The Epidermotropic, which is the most accepted theory, suggests that Paget's cells originate from ductal cancer cells that had migrated from the underlying breast parenchyma. It is supported by the predominance of breast cancer markers found in Paget's disease. This article provides an overview of Paget's disease of the breast with special attention to immunohistochemistry and raises the question of new therapeutic approaches.

Paget's disease as a local recurrence after nipple-sparing mastectomy: clinical presentation, treatment, outcome, and risk factor analysis.

BACKGROUND: Paget's disease is a rare clinical and histological type of local recurrence (LR) after breast cancer treatment both in case of conservative surgery or nipple-sparing mastectomy (NSM) with or without intraoperative radiation. METHODS: We performed an analysis of 861 NSM with electron beam intraoperative radiotherapy (ELIOT) patients treated at the European Institute of Oncology from 2002 to 2008, focused on Paget's disease local recurrence. RESULTS: In 861 patients (713 invasive carcinoma and 148 intraepithelial neoplasia), there were 36 local recurrences (4.18%), and among these were 7 Paget's disease local recurrences (0.8%). Median follow-up was 50 months. Four cases presented with nipple areola complex (NAC) erosions, two crusted lesions, and one ulcerated NAC. The average latency period from the NSM to Paget's disease local recurrence is 32 months (range, 12-49). Complete NAC removal was performed in all seven recurrences. The average follow-up after NAC removal was 47.4 months (range, 20-78). We found neither locoregional relapse nor metastatic event in this group. All patients were alive without disease. CONCLUSIONS: Paget's disease local recurrence can be found in a significant proportion after NSM. Any suspicious lesion on NAC requires prompt pathological confirmation. Primary carcinoma with ductal intraepithelial neoplasia or invasive ductal carcinoma with extensive in situ component, negative hormonal receptor, high pathological grade, overexpression of HER2/neu, and "HER2 positive (nonluminal)" subtype tend to be significantly associated with more Paget's disease local recurrence and should be followed carefully.

Histological type and grade of breast cancer tumors by parity, age at birth, and time since birth: a register-based study in Norway.

BACKGROUND: Some studies have indicated that reproductive factors affect the risk of histological types of breast cancer differently. The long-term protective effect of a childbirth is preceded by a short-term adverse effect. Few studies have examined whether tumors diagnosed shortly after birth have specific histological characteristics. METHODS: In the present register-based study, comprising information for 22,867 Norwegian breast cancer cases (20-74 years), we examined whether histological type (9 categories) and grade of tumor (2 combined categories) differed by parity or age at first birth. Associations with time since birth were evaluated among 9709 women diagnosed before age 50 years. Chi-square tests were applied for comparing proportions, whereas odds ratios (each histological type vs. ductal, or grade 3-4 vs. grade 1-2) were estimated in polytomous and binary logistic regression analyses. RESULTS: Ductal tumors, the most common histological type, accounted for 81.4% of all cases, followed by lobular tumors (6.3%) and unspecified carcinomas (5.5%). Other subtypes accounted for 0.4%-1.5% of the cases each. For all histological types, the proportions differed significantly by age at diagnoses. The proportion of mucinous and tubular tumors decreased with increasing parity, whereas Paget disease and medullary tumors were most common in women of high parity. An increasing trend with increasing age at first birth was most pronounced for lobular tumors and unspecified carcinomas; an association in the opposite direction was seen in relation to medullary and tubular tumors. In age-adjusted analyses, only the proportions of unspecified carcinomas and lobular tumors decreased significantly with increasing time since first and last birth. However, ductal tumors, and malignant sarcomas, mainly phyllodes tumors, seemed to occur at higher frequency in women diagnosed <2 years after first childbirth. The proportions of medullary tumors and Paget disease were particularly high among women diagnosed 2-5 years after last birth. The high proportion of poorly differentiated tumors in women with a recent childbirth was partly explained by young age. CONCLUSION: Our results support previous observations that reproductive factors affect the risk of histological types of breast cancer differently. Sarcomas, medullary tumors, and possible also Paget disease, may be particularly susceptible to pregnancy-related exposure.

Enfermedad de Paget mamaria: caso clínico y revisión de la literatura / Paget’s disease of the breast: clinical case and literature review

La enfermedad de Paget mamaria es una patología poco común en la mama, sin embargo, tiene gran importancia por su alta asociación a carcinoma mamario y porque requiere de un alto índice de sospecha. Se presenta el caso de una mujer de 56 años con enfermedad de Paget mamaria con focos microscópicos de invasión y compromiso linfonodal masivo. Se realiza una revisión de esta patología, con especial énfasis en la sospecha, diagnóstico, manejo, estadificación, tratamiento y pronóstico desde el punto de vista médico y quirúrgico.

Paget disease of a nipple graft following completion of a breast reconstruction with a nipple-sharing technique.

Surgical treatment of breast cancer can have a profound impact on patients both physically and psychologically. Postmastectomy breast reconstruction can significantly decrease the psychologic distress that a breast cancer patient experiences. Whereas breast mound reconstruction was initially thought to be sufficient, surgeons and patients have recognized the importance of nipple-areolar reconstruction. The following is a case report of a patient who developed Paget disease of a left nipple graft after left mastectomy and reconstruction with a TRAM flap and nipple sharing from the right breast. This case report provides a unique 14-year retrospective review of a clinical course and to our knowledge is the first reported case in the English literature of Paget disease developing in a nipple reconstructed from the contralateral nipple using the nipple-sharing technique.

Paget's disease of the nipple as local recurrence after breast-conservation treatment for early-stage breast cancer.

Breast conservation treatment (BCT) for early-stage breast cancer is associated with survival rates comparable with mastectomy but has the risk of ipsilateral breast tumor recurrence, including Paget's disease of the nipple. A small number of cases of Paget's disease presenting as local recurrence following BCT for breast cancer have been previously reported. Between 1977 and 2002, 2181 women with early-stage breast cancer were treated with BCT at the Hospital of the University of Pennsylvania. In this cohort, there were 183 local treatment failures, 4 of which were cases of Paget's disease (2.2%), which are reported herein. These local recurrences developed 1.8, 3.8, 7.3, and 9.7 years after diagnosis of the patients' primary tumors. Three of the 4 primary cancers were invasive ductal carcinomas, with an associated intraductal component, and 1 was ductal carcinoma in situ. All 4 patients were successfully given salvage therapy consisting of mastectomy with or without tamoxifen, with follow-up times of 20.9, 10.6, 3.1, and 3.8 years. Paget's disease as local recurrence after BCT is uncommon and can be treated with salvage therapy if detected early.

Paget's disease of the breast: a clinical perspective.

Paget's disease of the breast is a rare disorder of the nipple-areola complex often associated with an underlying in situ or invasive carcinoma. Eczematoid changes of the nipple-areola complex and persistent soreness or itching should raise suspicion of this disease. The histogenesis of Paget's disease of the breast continues to be debated and is important when considering treatment options. The epidermotropic theory suggests that Paget's cells are ductal carcinoma cells that have migrated from an underlying carcinoma of the breast parenchyma to the epidermis of the nipple. The in situ transformation theory has been proposed to explain the development of this disorder in patients in whom an underlying mammary carcinoma is not found or when there is an underlying carcinoma anatomically remote from the nipple-areola complex. Paget's cells are believed to arise as malignant cells in the epidermis of the nipple independent from any other pathologic process within the breast parenchyma. The current standard treatment of biopsy-proven Paget's disease involves mastectomy, although some studies have proposed the use of breast conservation therapy for patients in whom an underlying breast cancer cannot be located. We propose a treatment algorithm for patients presenting with Paget's disease of the breast.

Pathogenesis of Paget's disease: epidermal heregulin-alpha, motility factor, and the HER receptor family.

BACKGROUND AND METHODS: In Paget's disease of the breast, the epidermis of the nipple is infiltrated by large neoplastic cells of glandular origin. It has been hypothesized that the spread of Paget cells through the nipple epidermis is induced by a motility factor that acts via the HER2/NEU receptor. To test this hypothesis, we characterized and purified a motility factor released by keratinocytes and identified its target receptors in specimens from patients with Paget's disease and in SK-BR-3 breast adenocarcinoma cells, which overexpress HER2/NEU. RESULTS: We isolated the motility factor from keratinocyte-conditioned medium and sequenced tryptic peptides. These sequences were used to identify the motility factor as heregulin-alpha, which is released by skin keratinocytes. Heregulin-alpha induces spreading, motility, and chemotaxis of SK-BR-3 cells, as does motility factor. Motility factor activities of heregulin-alpha are inhibited by monoclonal antibody AB2, directed against the extracellular domain of HER2/NEU, which blocks the binding of heregulin-alpha. We used in situ hybridization to show that normal epidermal cells produce heregulin-alpha messenger RNA and that heregulin receptors, HER3 and/or HER4, as well as their coreceptor HER2/NEU, are expressed by Paget cells. CONCLUSIONS: Heregulin-alpha is a motility factor that is produced and released by normal epidermal keratinocytes and thus plays a key role in the pathogenesis of Paget's disease. Paget cells express heregulin receptors HER2/NEU, as well as HER3 and/or HER4, both of which function as a co-receptor of HER2/NEU. Binding of heregulin-alpha to the receptor complex on Paget cells results in the chemotaxis of these breast cancer cells, which eventually migrate into the overlying nipple epidermis.

Morphological evidence for field effect as a mechanism for tumour spread in mammary Paget's disease.

AIMS: The histogenesis of mammary Paget's disease is controversial. The purpose of this study was to investigate the mechanism of tumour spread in the nipple epidermis by examining 28 cases of mammary Paget's disease associated with underlying intraductal carcinoma. METHODS AND RESULTS: The atypical cells in the epidermis displayed a spectrum of cytological changes ranging from small-sized atypical cells located in the basal cell layer to large-sized atypical cells characteristic of Paget's cells in the upper layer of the epidermis. Serial sectioning revealed the presence of isolated, scattered and small atypical cells in the basal cell layer at the periphery of the epidermal lesion. The atypical cells, including those in the basal cell layer showed positive immunostaining for cytokeratin 7 and Her2/neu oncoprotein. Electron microscopy examination demonstrated the presence of intercellular junctions of desmosomal-like or desmosomal types between tumour cells and adjacent squamous cells. Furthermore, examination of the intraductal carcinoma of the breast tissue in cases of Paget's disease as well as control cases of intraductal carcinoma also revealed areas of skip lesions of intraductal carcinoma. CONCLUSIONS: In view of these changes, it is unlikely that tumour expansion or tumour cell motility are sufficient explanations to account for the pattern of tumour spread in both the epidermis and the duct epithelium with skip lesions. A 'field effect' in the duct system harbouring intraductal carcinoma and the adjacent epidermis may play an important role in the tumour cell spread in the epidermis as well as in the ductal epithelium.

Enfermedad de Paget del pezón: controversia etiológica, diagnóstica y terapéutica / Paget's disease of the nipple: ethiological, diagnostic and therapeutical controversies

El 1 por ciento (16 casos) de todos los pacientes tratados por cáncer de mama durante los 18 años en estudio presentaron Enfermedad dePaget del Pezón (EPP). La edad promedio fue de 67 años, (rango de 42 a 87) y la media de 67 años. Seis pacientes presentaron nódulo palpable (37 por ciento): 4 presentaron Carcinoma Ductal Infiltrante (CDI) y dos Carcinoma Intraductal (CID). En 10 pacientes sin masa palpable (62 por ciento), no se observó carcinoma subyacente en 4 casos (sólo Paget), cinco presentaron CID y uno CDI. Se obtuvieron registros mamográficos en 13 pacientes de los cuales diez presentaron microcalcificaciones y en dos casos asociados a nódulos espiculados. Mastectomía Radical Modificada (MRM) fue practicada en 11 pacientes, cinco de ellas sin y seis con disección axilar. De estas últimas sólo dos presentaron metástasis. Cuatro pacientes fueron tratadas con resección del complejo areola pezón solamente. En 13 casos de los 16 se pudo evaluar receptores estrogénicos (RE), receptores progestínicos (EP), antígeno epitelial de membrana (EMA) y la oncoproteína C-erb-2 tanto el el Paget como en el tumor subyacente. Todos los carcinomas fueron de alto grado histológico y nuclear. El EMA y la oncoproteína C-erb-2 fueron positivos en todos los Paget y en los 10 cánceres subyacentes. En ningún caso se observó recidiva o metástasis con una sobrevida libre de enfermedad de 100 por ciento y un seguimiento promedio de 63 meses

Enfermedad de Paget del pezón: controversia etiológica, diagnóstica y terapéutica / Pagets disease of the nipple: ethiological, diagnostic and therapeutical controversies

El 1 por ciento (16 casos) de todos los pacientes tratados por cáncer de mama durante los 18 años en estudio presentaron Enfermedad dePaget del Pezón (EPP). La edad promedio fue de 67 años, (rango de 42 a 87) y la media de 67 años. Seis pacientes presentaron nódulo palpable (37 por ciento): 4 presentaron Carcinoma Ductal Infiltrante (CDI) y dos Carcinoma Intraductal (CID). En 10 pacientes sin masa palpable (62 por ciento), no se observó carcinoma subyacente en 4 casos (sólo Paget), cinco presentaron CID y uno CDI. Se obtuvieron registros mamográficos en 13 pacientes de los cuales diez presentaron microcalcificaciones y en dos casos asociados a nódulos espiculados. Mastectomía Radical Modificada (MRM) fue practicada en 11 pacientes, cinco de ellas sin y seis con disección axilar. De estas últimas sólo dos presentaron metástasis. Cuatro pacientes fueron tratadas con resección del complejo areola pezón solamente. En 13 casos de los 16 se pudo evaluar receptores estrogénicos (RE), receptores progestínicos (EP), antígeno epitelial de membrana (EMA) y la oncoproteína C-erb-2 tanto el el Paget como en el tumor subyacente. Todos los carcinomas fueron de alto grado histológico y nuclear. El EMA y la oncoproteína C-erb-2 fueron positivos en todos los Paget y en los 10 cánceres subyacentes. En ningún caso se observó recidiva o metástasis con una sobrevida libre de enfermedad de 100 por ciento y un seguimiento promedio de 63 meses (AU)

An electron microscopic study of clinical Paget's disease of the nipple.

An ultrastructural study of the epidermis from eight patients with clinical Paget's disease of the nipple supports the epidermotropic theory. There was no evidence that the Paget's cells originated from keratinocytes. We propose the hypothesis that Paget's cells represent transformed ductal cells, from the subjacent lactiferous ducts of the nipple, which have migrated into the epidermis, either as neoplastic cells or as normal ductal cells with secondary in situ transformation in the epidermis.

[Pathology of autografts of the nipple in mammaplasty. Apropos of 2 original cases]. / Pathologie des autogreffes de mamelon en reconstruction mammaire. A propos de deux observations originales.

Autologous nipple graft is a classical technique in nipple reconstruction. The authors present two cases of deferred development of specific lesions in the grafted nipple, including one historical case of Paget's disease. After reviewing the current state of knowledge concerning Paget's disease of the nipple and in the light of these two cases, the authors discuss the histogenesis of this disease and the pathology of the grafted nipple in reconstructive surgery.