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This disease presents as a persistent dermatitis of the nipple. There is a red, oozing, crusted lesion which is often unresponsive to topical steroid and antibiotics. The alert physician may biopsy the nipple revealing the characteristic changes. Under the microscope, there is a proliferation of malignant epithelial cells scattered throughout the epidermis. The cells have abundant pale staining cytoplasm surrounding a hyperchromatic nucleus with prominent nucleoli. This disorder is a breast cancer and in almost every case, there is an underlying breast carcinoma present. Most commonly, this is an infiltrating ductal carcinoma but occasionally a ductal carcinoma in situ (DCIS) may be present. Overall, this cancer is rare, comprising 1-2% of all patients with breast carcinoma.

Theories on pathogenesis suggest that the cancer cells have migrated to the nipple from the underlying ducts. Another theory suggests that a field cancerization occurs with the carcinoma developing within the nipple and underlying ductal system.

The task of the pathologist is to differentiate this disease from histological simulators. The two most important are malignant melanoma and Bowen's disease. At times, the pathologist must rely on immunohistochemical stains. The most helpful staining pattern is an absence of S-100 staining and positive staining for c-erb-B2 oncogene (Her2-neu) and epithelial membrane antigen. The cells may be mucin positive. The cells also stain positive for CAM 5.2 (a low molecular weight cytokeratin) and EMA.


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INCIDENCE 1-4% of all patients with breast cancer



Klinefelter's syndrome associated with breast carcinoma and Paget's disease of the nipple.

Moshakis V, Fordyce MJ, Griffiths JD.

Clin Oncol 1983 Sep;9(3):257-61 Abstract quote

We describe a patient with Klinefelter's syndrome associated with multi-focal breast carcinoma and Paget's disease of the nipple. Reviewing the 16 previously documented cases in the world literature, it is apparent that patients with this syndrome have an increased incidence of breast carcinoma.

There is no evidence to date to suggest that such tumour is morphologically or biologically different from breast cancer in females and normal men.


Out Coexistent pemphigus vulgaris and Paget's disease of the nipple. An immunohistochemical study.

Rae V, Gould E, Ibe MJ, Penneys NS.

J Am Acad Dermatol 1987 Jan;16(1 Pt 2):235-7 Abstract quote

We report the coexistence of pemphigus vulgaris and Paget's disease of the nipple in a patient with a documented history of pemphigus and a 2-year complaint of an eczematous breast lesion.

A biopsy taken from the lesion showed the characteristic histologic features of both pemphigus and Paget's disease of the nipple. Immunohistochemical technics revealed intercellular IgG deposits characteristic of pemphigus and intracellular staining with antibody to epithelial membrane antigen in the cytoplasm of Paget's cells.

This report is the first describing the coexistence of these two distinct disease entities in one tissue sample. This case underscores the necessity of early biopsy of recalcitrant nipple lesions even in the presence of another, well-documented skin disorder.



Intraepidermal cells of Paget's carcinoma of the breast can be genetically different from those of the underlying carcinoma.

Morandi L, Pession A, Marucci GL, Foschini MP, Pruneri G, Viale G, Eusebi V.

Department of Oncology, Section of Pathology, University of Bologna, Ospedale Bellaria, Italy.

Hum Pathol. 2003 Dec;34(12):1321-30 Abstract quote.  

Paget's carcinoma (PC) of the breast is characterized by neoplastic cells of "glandular" type located within the epidermis of the nipple-areolar complex, often associated with an underlying ductal carcinoma, either in situ or invasive.

At present the origin of PC cells is controversial, although there is a widespread opinion that PC cells are "foreign" elements to the epidermis resulting from an epidermotropic migration of neoplastic elements from an underlying ductal carcinoma. An alternative view is that some cases result from neoplastic transformation of preexisting, innocent intraepidermal clear cells of the nipple-areolar complex (Toker cells) that migrate from nonneoplastic ducts. Consequently, 10 cases were studied using methods for clonality (ie, loss of heterozygosity and mitochondrial DNA displacement loop sequence analysis).

Microdissection of intraepidermal neoplastic cells and of cells from underlying duct carcinomas and metastases was performed. In no fewer than 2 cases, PC cells were genetically different from underlying lesions, which showed consistent homology among themselves.

Therefore, it is suggested that the rule of epidermotropism by neoplastic cells from an underlying carcinoma is not applicable to all cases, and that in some cases PC cells might be the result of neoplastic transformation of preexisting intraepidermal nonneoplastic cells. Consequently, the underlying tumors are coincidental neoplastic lesions (collision tumors).
Reduced E-cadherin expression correlates with disease progression in Paget's disease of the vulva but not Paget's disease of the breast.

Department of Obstetrics and Gynaecology, Royal Free and University College Medical School (Hampstead Campus), University College London, London, UK.

Mod Pathol. 2008 Oct;21(10):1192-9. Abstract quote

The growth and metastasis of many cancers is due in part to loss of cell-cell adhesion. E-cadherin, plakoglobin and beta-catenin are important in cell adhesion. Our aim was to examine the presence of these molecules in Paget's disease of the vulva and Paget's disease of the breast, and to correlate any differences in their expression with the presence of invasive disease or an underlying carcinoma.

Sixty-three archival cases of Paget's disease of the vulva, including eight associated with invasive disease, and 23 archival cases of Paget's disease of breast, which included 10 cases with ductal carcinoma in situ alone, four cases with both ductal carcinoma in situ and invasive carcinoma, and five cases with underlying invasive carcinoma alone, were analysed immunohistochemically for expression of E-cadherin, plakoglobin and beta-catenin proteins. The respective mRNAs were also detected by in situ hybridisation using digoxigenin-labelled cRNA probes. Seventy-six percent (41/54) of Paget's disease of vulva cases had >50% of Paget cells expressing the E-cadherin protein, compared with 28 % (2/7) of Paget's disease vulva with invasive disease. This result was significant, with a P-value of 0.039. Twenty-five percent (14/55) of the intraepidermal Paget's disease of the vulva cases had >50% of Paget cells expressing the plakoglobin protein, compared with 12% (1/8) of cases of Paget's disease of vulva with invasive disease, and for beta-catenin, 9% (5/55) of the non-invasive Paget's disease of the vulva had >50% of Paget cells expressing beta-catenin, compared with 12% (1/8) of Paget's disease of the vulva cases with invasive disease. Sixty-five percent (15/23) of the Paget's disease of the breast had >50% of Paget cells expressing E-cadherin, and for plakoglobin and beta-catenin it was 17% (4/23) and 28% (6/21), respectively. The results were not significant.

The results suggest that reduced expression of E-cadherin may have a role to play in the pathogenesis of invasive Paget's disease of the vulva. Abnormal plakoglobin expression may be involved in the formation of some cases of Paget's of the vulva and the breast.

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

Mai KT.

Division of Anatomical Pathology, Department of Laboratory Medicine, The Ottawa Hospital, Civic Campus, and Department of Pathology and Laboratory Medicine, University of Ottawa, Ottawa, Ontario, Canada.

Histopathology 1999 Dec;35(6):567-76 Abstract quote

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.


Study of neu-protein expression in mammary Paget's disease with and without underlying breast carcinoma and in extramammary Paget's disease.

Meissner K, Riviere A, Haupt G, Loning T.

Department of Dermatology, UKE, University of Hamburg School of Medicine, Federal Republic of Germany.

Am J Pathol 1990 Dec;137(6):1305-9 Abstract quote

Correlation between neu/c-erbB-2/Her-2 gene amplification and overexpression of the neu gene product has been reported in tumors of glandular origin, especially ductal breast carcinomas.

Formalin-fixed and dewaxed sections from 23 cases of mammary (MPD) and 9 cases of extramammary (EPD) Paget's disease were immunohistochemically stained by means of the monoclonal antibody 3B5 directed against an intracellular domain of the neu gene protein. All MPDs exhibited a distinct membrane staining of tumor cells independent of the presence of ductal breast carcinomas found in 18 cases. All these breast carcinomas also were positive for neu staining. In contrast to MPD, all EPDs were negative. Normal epidermis was always negative. Northern blot analysis sustained the immunohistologic findings in that the presence of neu mRNA could be demonstrated in two of three cases with MPD. Negativity in one case was due to dilution effects by nontumor cells.

Our results suggest that Paget cells of mammary and extramammary localization, although very similar phenotypically, derive from different genetic accidents. Furthermore neu positivity in all MPDs and all underlying ductal carcinomas suggests common genetic alterations for both tumors. However the finding of five neu protein-positive MPDs without associated ductal breast carcinomas may suggest a somewhat different transformation process.


Differential Expression of Mucin Genes in Mammary and Extramammary Paget's Disease

Shih-Fan Kuan, M.D. , Ph.D. ; Anthony G. Montag, M.D. ; John Hart, M.D. ; Thomas Krausz, M.D. ; Wendy Recant, M.D.

From the Department of Pathology, University of Chicago Hospitals, Chicago, Illinois, U.S.A.

Am J Surg Pathol 2001;25:1469-1477 Abstract quote

Paget's disease (PD) of the skin is characterized by intraepidermal adenocarcinoma cells, which contain clear cytoplasm and abundant mucin. Nearly all cases of mammary PD (MPD) are associated with underlying ductal carcinoma of the breast, whereas in the majority of cases of extramammary PD (EMPD) no underlying regional malignancy is identified. Mucins are high molecular weight glycoproteins produced by epithelial cells. Different mucin genes are expressed in various types of tissues such as mammary glands, intestinal mucosa, and adnexal structures of the skin.

We studied the immunohistochemical expression of apomucin MUC1, MUC2, MUC5AC in MPD, and EMPD. MUC1 is commonly expressed in most cases of PD. MUC5AC is a unique mucin that is exhibited in the majority of cases of EMPD, but not in any MPD. Of the 13 patients with MPD who all had associated breast ductal carcinoma, both Paget cells and underlying ductal carcinoma exhibited the phenotype (MUC1+MUC2–MUC5AC–). This mucin phenotype is also expressed by Toker cells, which have been identified in the epidermis of five of 50 nipples in mastectomies without MPD. Of the three patients with perianal PD who all had associated rectal adenocarcinoma, Paget's cells expressed MUC2 constantly but expressed MUC1 and MUC5AC variably. Seven patients with intraepidermal vulvar PD and two patients with scrotal–penile PD had no identifiable underlying malignancy. Paget cells from all of these nine cases of EMPD expressed a uniform phenotype of mucin (MUC1+MUC2–MUC5AC+). One case of vulvar PD associated with underlying apocrine carcinoma had a phenotype (MUC1+MUC2–MUC5AC–) identical to that of normal apocrine glands. The skin appendage and Bartholin's glands from 20 normal-appearing vulvar skin samples and anal glands from 10 hemorrhoidectomies were also studied. Only Bartholin's gland expressed a mucin phenotype identical to that of intraepidermal EMPD.

The results of the present study indicate that 1) MPD may arise from either mammary glands or epidermal Toker cells, 2) intraepidermal EMPD in the anogenital areas may arise from ectopic MUC5AC+ cells originating from Bartholin's or some other unidentified glands, and 3) unique expression of MUC2 in perianal PD indicates its origin from colorectal mucosa. We conclude that the study of mucin gene expression is useful in identifying the histogenesis of PD.




Mammographic appearances in Paget's disease of the breast.

Sawyer RH, Asbury DL.

Department of Radiology, Withington Hospital, Manchester.

Clin Radiol 1994 Mar;49(3):185-8 Abstract quote

The mammographic appearances in 17 patients with Paget's disease of the breast were retrospectively reviewed.

Appearances were normal in only five cases. Microcalcification was present in 10 including one where it encircled the nipple. A radiologically-visible tumour was seen in nine breasts with carcinoma being diagnosed in a further three by the pattern of calcification alone. Multifocal tumours were present in four breasts but no lymphadenopathy or contralateral tumours were seen.

Despite high quality radiography a tumour was only detected in 71% of cases of Paget's disease and radiographers should be trained to recognize the condition clinically. Patients without a visible tumour may be suitable for radiotherapy.




Paget's disease of the nipple without clinically and radiologically detectable breast tumor. Histochemical and immunohistochemical study of 44 cases.

Vielh P, Validire P, Kheirallah S, Campana F, Fourquet A, Di Bonito L.

Department of Pathology, Institut Curie, Paris, France.

Pathol Res Pract 1993 Mar;189(2):150-5 Abstract quote

Paget's disease of the nipple is a rare lesion nearly always associated with an underlying breast cancer, clinically impalpable and radiologically undetectable in about 40% of the patients. Fourty-four cases (28 mastectomies and 16 biopsies of the nipple) of Paget's disease of the nipple without clinically and radiologically detectable breast tumor were retrospectively studied by means of histochemistry and immunohistochemistry.

Histochemical study showed that Paget cells were PAS positive and diastase resistant, and alcian blue positive at pH 2.5 in 32% and 18%, respectively. Immunohistochemical study showed that Paget cells were EMA and c-erbB-2 positive in 100% and 84%, respectively. Four of the six EMA positive and c-erbB-2 negative cases of Paget's disease of the nipple in which the underlying tumor could be pathologically analyzed were associated with ductal carcinoma in situ of cribriform or mixed types.

These findings are helpful for differentiating Paget's disease from other lesions of the nipple, namely Bowen's disease and eczema which do not react with both antibodies, and from nipple adenoma which exhibits a positive staining with anti-EMA antibody and no reactivity with anti-c-erbB-2 antibody.

A case of mammary Paget's disease without an underlying carcinoma: microscopic analysis of the DNA content in Paget cells.

Mori O, Hachisuka H, Nakano S, Maeyama Y, Sasai Y.

Department of Dermatology, Kurume University School of Medicine, Japan.

J Dermatol 1994 Mar;21(3):160-5 Abstract quote

A 72-year-old woman had a 7-year history of a scaly red area on the right breast which had enlarged asymptomatically. A biopsy of the nipple was taken, and, following the finding of Paget's disease, a modified radical mastectomy was carried out.

On histological examination of the entire breast specimen by serial sections, no evidence of an intraductal adenocarcinoma was found. Fractionation of Paget cells was performed from the epidermis. Stripped skin was treated with EDTA and trypsin, and epidermal cell suspensions were obtained. They were layered onto discontinuous Percoll gradients and centrifuged. Paget cells fell into three fractions with densities of 1.041, 1.058, and 1.078. Electronmicroscopically, the purity of fractionated cells obtained by this method ranged from 55 to 74% with viabilities of from 70 to 90%.

Microscopic analysis of the DNA content in these cells was performed. The DNA histogram was close to the normal ploidy. This may explain why the mammary Paget's disease lesions in this case enlarged rather slowly.


Bilateral Paget Disease of the Nipple Associated With Lobular Carcinoma In Situ Application of Immunohistochemistry to a Rare Finding

Sunati Sahoo, MD, Ileana Green, MD, and Paul P. Rosen, MD

From the Department of Pathology, New York Presbyterian Hospital–Weill Cornell Medical Center, New York, NY (Drs Sahoo and Rosen); and the Department of Pathology, Lenox Hill Hospital, New York, NY (Dr Green)

Arch Pathol Lab Med 2002;Vol. 126, No. 1, pp. 90–92. Abstract quote

We report synchronous bilateral Paget disease derived from lobular carcinoma in situ in a 53-year-old woman who underwent bilateral mastectomy. The epidermis of both nipples contained small cells with a moderate amount of pale-staining cytoplasm. The nuclei had fine chromatin and identifiable nucleoli.

The cells were strongly immunoreactive with cytokeratin 7 and displayed nuclear estrogen receptor reactivity. The underlying mammary gland showed involvement by lobular carcinoma in situ with pagetoid spread into lactiferous ducts, which was confirmed by lack of immunoreactivity for E-cadherin.


Paget's disease of the breast in a man without underlying breast carcinoma.

O'Sullivan ST, McGreal GT, Lyons A, Burke L, Geoghegan JG, Brady MP.

University Department of Surgery, Cork Regional Hospital, Ireland.

J Clin Pathol 1994 Sep;47(9):851-2 Abstract quote

A case of histologically confirmed Paget's disease of the breast in a 72 year old man, without underlying breast carcinoma, is reported.

This report raises questions about the pathogenesis of this condition and suggests that Paget's disease is an independent, intraepidermal carcinoma rather than a direct extension of intraductal carcinoma of the breast to the nipple and areola.

Paget's disease of the male breast.

Desai DC, Brennan EJ Jr, Carp NZ.

Department of Surgery, Lankenau Hospital, Wynnewood, Pennsylvania 19096, USA.

Am Surg 1996 Dec;62(12):1068-72 Abstract quote

A histopathologically proven case of Paget's disease of the breast in a 47-year-old male induced a review of the 32 cases in the world's literature. Paget's disease usually presents in the 5th and 6th decades of life without any obvious racial predilections.

The most frequent presenting signs include ulceration, eczema, nipple discharge, bleeding, and crust formation. At the time of presentation, 50 per cent of the patients have a palpable breast mass, positive lymph nodes, or both.

When entertaining the diagnosis of Paget's disease of the breast using morphologic characteristics of the cells, the diagnosis of malignant melanoma and Bowen's disease (intraepithelial squamous cell carcinoma) must be included in the differential diagnosis. Certain differences will be seen between these three entities based on specific cell staining and the uptake of certain tumor markers. There is no evidence that this disease behaves differently in males versus females, but the 5-year survival for males is worse: 20 to 30 per cent in males versus 30 to 50 per cent in females.

The treatment of this disease must focus on the pathology of the underlying tumor. Current treatment involves modified radical mastectomy or radical mastectomy for Stage I and II tumors. Adjuvant chemotherapy, radiation, and tamoxifen are also used depending on the nodal and receptor status of the tumor.

Paget's disease of the male breast associated with intraductal carcinoma.

Bodnar M, Miller OF 3rd, Tyler W.

Department of Dermatology, Penn State Geisinger Health System, Danville, Pennsylvania 17822, USA.

J Am Acad Dermatol 1999 May;40(5 Pt 2):829-31 Abstract quote

Paget's disease of the breast is a rare condition with an incidence of 3% to 5% of all mammary malignancies. Of all malignant breast cancer, 1% occurs in male patients, and thus, Paget's disease of the male breast is extremely rare.

We present a case of intraductal carcinoma of the male breast presenting as Paget's disease.


Paget's disease in an adolescent arising in a supernumerary nipple.

Martin VG, Pellettiere EV, Gress D, Miller AW.

Department of Pathology, Lutheran General Hospital, Park Ridge, IL 60068.

J Cutan Pathol 1994 Jun;21(3):283-6 Abstract quote

Paget's disease of the breast generally affects middle-aged and older females. In the majority of cases, it is considered to be the result of epidermal spread from a contiguous mammary duct carcinoma.

We report the first case in an adolescent female with an accessory nipple. The histomorphology and immunophenotypic findings support the hypothesis of in situ transformation and suggest a histologic spectrum exists in terms of cytologic atypia.


Acantholytic anaplastic Paget's disease.

Department of Pathology, University of Nevada School of Medicine, Las Vegas, NV, USA.

J Cutan Pathol. 2009 Mar;36(3):374-80. Abstract quote

Classic Paget's disease (PD) can be diagnosed relatively easily by histopathologic examination. 'Anaplastic' variant of this disease is a less-recognized subset that may pose as a diagnostic challenge and pitfall.

We describe two cases who presented with scaly erythematous plaques on their nipple/areola. In the first patient, there was no palpable mass and imaging studies were negative. The second case presented with a lesion 5 years after a lumpectomy. Initial shave biopsies revealed histopathologic changes indistinguishable from Bowen's disease with no readily identifiable classic Paget's cells, associated with prominent superficial acantholysis. The neoplastic cells were negative for mucin, GCDFP-15, negative/minimally positive for CEA and strongly positive for CK7 markers. A high-grade ductal carcinoma in situ in the underlying breast was ultimately found in both cases. Anaplastic PD is a rare variant of this disease that histologically mimics Bowen's disease with an associated prominent superficial acantholysis. There is mucin, CEA and GCDFP-15 negativity with positive CK7 reaction.

A high index of suspicion along with a complete immunohistochemical panel should be considered in evaluating any Bowenoid neoplasm of the breast skin, particularly in superficial skin shave biopsies along with negative imaging studies and no palpable mass clinically.

Paget's disease of the nipple resembling an acantholytic disease on microscopic examination.

Wolf R, Bernstein-Lipschitz L, Rothem A.

Dermatology Service, Barzilai Medical Center, Ashkelon, Israel

Dermatologica 1989;179(1):42-4 Abstract quote

Two biopsies of an erosive lesion of the nipple had an appearance of an acantholytic disease without showing malignant cells. Only a third biopsy through the nipple with removal of a larger portion revealed some nests of atypical, large cells with clear cytoplasm, typical of Paget's disease.

Immunohistochemical findings with carcinoembryonic antigen confirmed the diagnosis of Paget's disease of the nipple. This is the first case of Paget's disease which shows extensive acantholysis on microscopic examination and which resembles pemphigus vulgaris histologically. Acantholytic diseases are easily distinguished from Paget's disease and have never been mentioned in the differential diagnosis of this disease.

A large biopsy through the nipple with the removal of a liberal portion of the nipple is suggested in every case of a suspected unilateral lesion of the nipple in order to avoid the overlooking of small nests of Paget's cells, as in our first biopsies, showing a histological picture of an acantholytic disease.


Anaplastic Paget's disease.

Rayne SC, Santa Cruz DJ.

Department of Pathology, St. John's Mercy Medical Center, St. Louis, Missouri 63141-8221.

Am J Surg Pathol 1992 Nov;16(11):1085-91 Abstract quote

Six cases of a distinct, histologically anaplastic variant of mammary Paget's disease are described. Patients ranged in age from 40 to 85 years. All patients had scaling erythematous lesions confined to the nipple; none had palpable breast masses.

Histologically, the lesions had features resembling Bowen's disease, including full-thickness epidermal atypia, loss of nuclear polarity, and marked cytologic anaplasia. Intraepidermal acantholysis was a distinctive feature in all cases. In some biopsies, small groups and single typical Pagetoid cells were seen within the areas of confluent Bowen-like change.

Immunohistochemically, carcinoembryonic antigen (CEA) was positive in three of six patients; epithelial membrane antigen (EMA) in five of six patients, and cytokeratin AE1/AE3 in three of six patients. Mucicarmine stains were uniformly negative. In our series, anaplastic Paget's disease was associated with concomitant invasive ductal carcinoma in three of six patients (50%). This percentage is significantly higher than that previously reported for patients with Paget's disease and without palpable breast mass. Histologic features that are helpful in distinguishing between anaplastic Paget's disease and Bowen's include cleft-like acantholysis, absence of dyskeratotic cells, and persistence of basal cell layer. More rarely, but very helpful when present, are underlying ductal carcinoma, intracellular lumina, and associated conventional Paget's disease. Immunohistochemistry results were variable and of relative value.

Our study suggests that a nipple lesion histologically resembling Bowen's disease is likely to represent anaplastic Paget's disease.


Paget's disease in an epidermal cyst.

Stephenson TJ, Cotton DW.

Dermatologica 1987;174(4):186-90 Abstract quote

A case of Paget's disease involving both the epidermis of the nipple and an adjacent epidermal cyst is reported. Immunohistochemistry showed similarity between the infiltrating cells in both sites and those of the underlying mammary adenocarcinoma.

Epidermal cysts may be involved in a variety of disease processes which affect the epidermis in general and, unless they are subjected to careful histopathological examination, these diseases may be overlooked.

Pigmented Paget disease--a diagnostic pitfall mimicking melanoma.

Department of Oncology-Pathology, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden.

Am J Dermatopathol. 2009 May;31(3):223-6. Abstract quote

Pigmented mammary and extramammary Paget disease are rare entities in both males and females that mimic melanoma both clinically and histologically. Furthermore, Paget disease can be associated with increased number of benign melanocytes, thus resulting in additional diagnostic difficulty, especially when only hematoxylin and eosin-stained sections are examined and a limited immunohistochemical study is performed.

Using standard hematoxylin and eosin-stained sections and routine immunohistochemical studies, we describe and characterize 7 cases of pigmented extramammary and mammary Paget disease. In all cases, malignant epithelial cells showed intracytoplasmic pigment, along with an immunohistochemical epithelial phenotype. In 2 of the cases, immunohistochemistry revealed numerous dendritic processes positive for melanocytic markers, thus resulting in an initial diagnosis of melanoma. Careful analysis confirmed that the immunolabeling corresponded to cytoplasmic labeling of melanocyte dendrites surrounding tumor cells.

The correct diagnosis of pigmented Paget disease can be reached after close histologic examination and detailed evaluation of immunohistochemical studies. The latter are especially important in some extraordinary cases in which there may be an associated intraepithelial melanocytic hyperplasia.

Paget's disease of the nipple simulating malignant melanoma in a black woman.

Peison B, Benisch B.

Rahway Hospital, New Jersey

Am J Dermatopathol 1985;7 Suppl:165-9 Abstract quote

A lesion of Paget's disease arising in the skin of the nipple in a black woman is reported. The lesion simulated histologically a malignant melanoma because of the abundance of melanin within neoplastic cells in the epidermis as well as within the underlying ductal carcinoma of the breast.

It was only after differential staining that the diagnosis of Paget's disease could be substantiated unequivocally.

Pigmented Mammary Paget Disease and Pigmented Epidermotropic Metastases From Breast Carcinoma

Luis Requena, M.D.; Martín Sangueza, M.D.; Omar P. Sangueza, M.D.; Heinz Kutzner, M.D.

Am J Dermatopathol 2002; 24(3):189-198 Abstract quote

Pigmented mammary Paget disease is a rare clinicopathologic variant of mammary Paget disease. It has been described in female and male patients with intraductal mammary carcinoma extending to the epidermis of the nipple and areola through a lactiferous duct. Pigmented cutaneous metastases from breast carcinoma are uncommon variants of epidermotropic metastatic breast carcinoma. All these lesions may mimic malignant melanoma clinically and histopathologically. From a histopathologic point of view, involvement of the dermoepidermal junction by neoplastic cells of the mammary carcinoma seems to be a prerequisite for development of the clinical pigmentation.

We report three examples of pigmented mammary Paget disease and six cases of pigmented epidermotropic metastases from breast carcinoma, which were studied from both the histopathologic and immunohistochemical points of view. Two cases of pigmented mammary Paget disease and all cases of pigmented epidermotropic metastatic breast carcinoma showed the proliferation of dendritic melanocytes arranged as solitary units along the dermoepidermal junction and intermingled with the neoplastic cells of the mammary carcinoma in the superficial dermis. In one case of pigmented mammary Paget disease, there was abundant melanin within the cytoplasm of the Paget cells, but an increased number of melanocytes could not be demonstrated.

Local production of melanocytic chemotactic factor by neoplastic cells of the mammary carcinoma when they reach the dermoepidermal junction has been postulated as the cause of the melanocytic proliferation and clinical hyperpigmentation of these epidermotropic breast carcinomas. Another possibility is the phagocytosis or transfer of melanin from melanocytes to the intraepidermal neoplastic cells of the breast carcinoma. Pigmented mammary Paget disease and pigmented epidermotropic metastatic breast carcinoma should be differentiated from melanoma clinical and histopathologically.


Matrilysin-1 (MMP-7) and MMP-19 are expressed by Paget's cells in extramammary Paget's disease.

Kuivanen T, Tanskanen M, Jahkola T, Impola U, Asko-Seljavaara S, Saarialho-Kere U.

Department of Dermatology, Helsinki University Central Hospital and Biomedicum Helsinki, Helsinki, Finland.

J Cutan Pathol. 2004 Aug;31(7):483-91. Abstract quote  

BACKGROUND: Extramammary Paget's disease (EMPD) is a rare malignant neoplasm of apocrine gland bearing skin characterized by intraepidermal proliferation of adenocarcinoma cells. Tumor growth depends on the ability of tumor cells to migrate by proteolysis and on angiogenesis. The matrix metalloproteinase (MMP) enzymes have been implicated in both of these processes in other types of skin cancer. METHODS: The expression of MMP-1, MMP-2, MMP-3, MMP-7, MMP-9, MMP-13, and MMP-19 was analyzed by immuno- histochemistry and/or in situ hybridization in 27 EMPD and five mammary PD (MMPD) specimens. The distribution of laminin-5 (LN-5) and tenascin-C, two extracellular matrix proteins associated with tumor invasion, was studied by immunohistochemistry.

RESULTS: MMP-7 (matrilysin-1) and MMP-19 were the most frequently expressed MMPs in Paget's cells. Overexpression of MMP-2, MMP-9, or MMP-13, which is seen in many cancers, was not evident in EMPD. LN-5 and tenascin-C positivity did not correlate with the level of invasion. MMP-7, MMP-13, and MMP-19 were detected abundantly in MMPD, while MMP-9 was absent.

CONCLUSIONS: MMP expression did not generally associate with the level of invasion of EMPD. In three samples positive for MMP-7 and four samples positive for MMP-19, an underlying carcinoma was detected, suggesting the importance of these two MMPs as predictors of secondary EMPD or the putative origin of Paget's cells from the dermal adenocarcinoma cells of apocrine duct origin.

The ectopic expression of gastric mucin in extramammary and mammary Paget's disease.

Kondo Y, Kashima K, Daa T, Fujiwara S, Nakayama I, Yokoyama S.

Department of Pathology, Oita Medical University, Oita, Japan.

Am J Surg Pathol 2002 May;26(5):617-23 Abstract quote

The immunohistochemical analysis of the ectopic expression of gastric mucin has been used as a valuable tool for the identification of several neoplasms.

We performed an immunohistochemical examination of the expression of gastric, intestinal, and mammary-type mucins in 25 lesions from patients with extramammary Paget's disease (ExMPD) and in 10 lesions from patients with mammary Paget's disease (MPD). All ExMPD lesions were immunopositive for HGM-45, a marker of gastric surface mucous cells, whereas only 40% of MPD lesions were weakly immunopositive. No markers for gastric-gland mucous cells were found in almost all ExMPD and MPD lesions, and markers for intestinal mucin were recognized in only a few lesions. Antibodies specific for MUC1, a marker of mammary-type mucin, gave positive results in both ExMPD and MPD lesions at a higher frequency than antibodies specific for gross cystic disease fluid protein-15. Our analysis indicates that Paget's cells contain gastric surface-type mucin in ExMPD and they contain mammary-type mucin in both ExMPD and MPD.

The ectopic localization of mucosubstances may be a further step in the understanding of these lesions. Moreover, antibodies against MUC1 seem to be a useful tool for the diagnosis of both ExMPD and MPD.


Positive for:
CAM 5.2

Androgen receptors are frequently expressed in mammary and extramammary Paget's disease.

Liegl B, Horn LC, Moinfar F.

1Department of Pathology, Medical University of Graz, Graz, Austria.

Mod Pathol. 2005 Oct;18(10):1283-8. Abstract quote  

Mammary Paget's disease and extramammary Paget's disease are rare intraepithelial neoplasms. Mammary Paget's disease is almost exclusively associated with underlying invasive breast carcinoma or high-grade ductal carcinoma in situ (DCIS G3).
Extramammary Paget's disease arises in areas rich in apocrine glands and is suspected to have apocrine gland origin.

The aim of the study was to investigate the presence of estrogen receptor (ER), progesterone receptor (PR), androgen receptor (AR) and Her2/neu in a large number of cases.

We investigated 58 cases of mammary and 23 cases of extramammary Paget's disease. Formalin-fixed and paraffin-embedded tissues were analyzed using antibodies against AR, PR, ER and Her2/neu according to standardized procedures. In mammary Paget's disease, positive immunoreactions for Her2/neu, AR and ER were observed in 56 of 58 (97%), 51 of 58 (88%), and respectively in six of 58 (10%) cases. All cases of mammary Paget's disease were negative for PR and showed a coexpression of Her2/neu and AR in 51 out of 58 cases (88%). In extramammary Paget's disease, positive immunoreactions for AR, Her2/neu and ER were observed in 18 of 23 (78%), 12 of 23 (52%), and respectively in 1 of 23 (4%) cases. All cases of extramammary Paget's disease were negative for PR and showed a coexpression of AR and Her2/neu in 12 out of 23 cases (52%). In contrast to ER and PR, AR and Her2/neu are commonly expressed in mammary and extramammary Paget's disease.

The knowledge about frequent expression of AR in Paget's disease could lead to the development of a new adjuvant therapy, particularly in patients with recurrent disease.

Keratin profile of intraepidermal cells in Paget's disease, extramammary Paget's disease, and pagetoid squamous cell carcinoma in situ.

Lau J, Kohler S.

Department of Dermatology, and Department of Pathology, Stanford University, Stanford, CA, USA.


J Cutan Pathol. 2003 Aug;30(7):449-54. Abstract quote

BACKGROUND: Although the histopathologic differential diagnosis of pagetoid neoplasms is broad, unique histopathologic identifiers and clinical correlation can often identify the process. However, in the case of mammary Paget's disease (MPD) or extramammary Paget's disease (EPD) without an obvious underlying malignancy, distinction from pagetoid squamous cell carcinoma in situ (PSCCIS) can be challenging. Our goal was to better define the immunohistochemical staining patterns of these three entities in the hope of determining distinctive staining patterns.

METHODS: We evaluated nine cases of PSCCIS, five cases of MPD, and 10 cases of EPD with the immunohistochemical antibodies CAM 5.2 and CK 5/6. In addition, only PSCCIS was stained with CK 7, as the staining patterns of CK 7 in MPD and EPD are well known from prior studies.

RESULTS: CAM 5.2 diffusely stained all cases of MPD and EPD and failed to stain any case of PSCCIS. Furthermore, CK 7 only focally stained two of the 10 cases of PSCCIS. CK 5/6 was difficult to interpret due to the high functional background staining of the normal keratinocytes in the epidermis.

CONCLUSIONS: Based on these results, our data supports the use of CAM 5.2 and CK 7 immunoperoxidase markers in differentiating between difficult cases of PSCCIS and MPD or EPD. An antibody panel consisting of S-100, CAM 5.2, and CK 7 will aid in the accurate diagnosis of almost all pagetoid neoplasms of the breast or genital skin.

An immunohistochemical study of the presence of c-erbB-2 protein in Paget's disease of the nipple.

Lammie GA, Barnes DM, Millis RR, Gullick WJ.

Imperial Cancer Research Fund ClinicalOncology Unit, Guy's Hospital, London, UK.

Histopathology 1989 Nov;15(5):505-14 Abstract quote

Tumours from 45 patients with Paget's disease of the nipple have been stained with antibody 21N which was raised against a peptide from the C-terminus of the predicted c-erbB-2 protein.

Positive staining was observed in 41 cases (91%). In 42 cases the underlying mammary carcinoma was also available for study. In all but two cases staining was similar in the Paget's cells and the underlying carcinoma whether the latter was purely in situ ductal (35%) or in situ associated with infiltrating carcinoma (65%); the malignant cells in both components were large and pleomorphic and the in situ ductal carcinoma was of the comedo type. In the two exceptions the underlying carcinoma showed different histological features.

The significance of the high levels of c-erbB-2 protein in this pattern of mammary carcinoma is considered.

Routine diagnosis of mammary Paget's disease. A modern approach.

Hitchcock A, Topham S, Bell J, Gullick W, Elston CW, Ellis IO.

Department of Histopathology, City Hospital, Nottingham, England.

Am J Surg Pathol 1992 Jan;16(1):58-61 Abstract quote

This study compares the diagnostic reliability of conventional mucin histochemistry and immunocytochemical techniques in distinguishing mammary Paget's disease from superficial spreading malignant melanoma and primary intraepidermal carcinoma.

Formalin-fixed, paraffin-embedded archival tissue was used and comprised 13 cases of mammary Paget's disease, five cases of superficial spreading melanoma, and six cases of intraepidermal carcinoma. Sections from each case were stained for the presence of mucin using diastase periodic-acid-Schiff (d-PAS) with and without an alcian blue counterstain as well as immunocytochemistry for cytokeratin (CAM 5.2), epithelial membrane antigen (NCRC-11) and c-erb B-2 (21N).

Mucin staining in intraepidermal carcinoma and malignant melanoma was consistently negative. Diastase-resistant PAS positivity was seen in six of 13 cases of mammary Paget's disease and eight of 13 cases using an alcian blue counterstain. NCRC-11 showed positive immunoreactivity in four of six cases of intraepidermal carcinoma, one in five cases of melanoma, and five of 13 cases of mammary Paget's disease. Positive immunoreactivity using CAM 5.2 and 21N was seen in all cases of mammary Paget's disease, with consistent negative immunoreactivity in the other tumor types.

We conclude that CAM 5.2 and 21N should be used in the investigation of mammary Paget's disease in preference to conventional mucin stains.


Immunocytochemical detection of estrogen receptors in mammary Paget cells.

Tani EM, Skoog L.

Department of Pathology, Karolinska Hospital, Stockholm, Sweden.

Acta Cytol 1988 Nov-Dec;32(6):825-8 Abstract quote

Immunocytochemistry was used to analyze the estrogen receptor (ER) content in mammary Paget cells obtained by scraping the nipples of six patients.

The Paget cells in the smears were ER positive in four cases and ER negative in two cases. Five of the patients underwent a modified radical mastectomy; histologic study of the excision specimens showed three invasive ductal carcinomas and two intraductal carcinomas. Analysis of the ER status of the three invasive tumors, analyzed both by immunohistochemistry and by the radioligand technique, showed that the ER content in the Paget cells reflected that in the tumor in the breast parenchyma.

This finding lends support to the hypothesis that Paget cells originate from an epidermotropic cancer in the parenchyma of the breast.


Immunolabeling pattern of syndecan-1 expression may distinguish pagetoid Bowen's disease, extramammary Paget's disease, and pagetoid malignant melanoma in situ.

Bayer-Garner IB, Reed JA.

Marshfield Clinic, Marshfield, WI, and Baylor College of Medicine, Houston, TX, USA.

J Cutan Pathol. 2004 Feb;31(2):169-73. Abstract quote  

The differential diagnosis of pagetoid cells within the epidermis rests primarily between pagetoid Bowen's disease (PBD), extramammary Paget's disease (EPD), and pagetoid malignant melanoma (MIS) in situ. Although morphologic clues are often helpful in differentiating these lesions, the use of immunohistochemistry is often necessary to arrive at the correct diagnosis.

Syndecan-1 is a cell-surface proteoglycan that mediates adhesion between cells and the extracellular matrix, and between cells themselves. Twenty-two cases of PBD, four cases of intraepidermal EPD, and 13 cases of MIS were examined for syndecan-1 immunoreactivity. Cell-membrane syndecan-1 immunoreactivity was evident in PBD, cytoplasmic syndecan-1 immunoreactivity was evident in EPD, whereas immunoreactivity for syndecan-1 was not present in MIS.

The patterns of syndecan-1 immunoreactivity in these lesions may be a useful adjunct in the differentiation of PBD, EPD, and MIS.

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

Jahn H, Osther PJ, Nielsen EH, Rasmussen G, Andersen J.

Department of Surgery, Odense University Hospital, Denmark.

APMIS 1995 Sep;103(9):628-34 Abstract quote

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.



Cancer 1970;25:601

Found in about 10% of normal nipples by H and E staining
May be normal component of the epidermis along milk lines


Am J Dermatopathol 1995;17:487

Rare case of multifocal disease in association with a primary intraepidermal mammary Paget's disease


J Cutan Pathol 1998;25:568

Case report of CEA positive clear cells in normal appearing axillary skin from a patient with genital Paget's disease

Paget's disease versus Toker cell hyperplasia in a supernumerary nipple.

Decaussin M, Laville M, Mathevet P, Frappart L.

Department of Pathology, Edouard Herriot Hospital, Lyon, France.

Virchows Arch 1998 Mar;432(3):289-91 Abstract quote

We report the second case of mammary Paget's disease arising in a supernumerary nipple of a 29-year-old woman. The epithelium of the nipple was infiltrated by large cells with abundant and pale-staining cytoplasm. The nuclei had a vesicular chromatin pattern and identifiable nucleoli. The cells were strongly immunoreactive with KL1, CEA and EMA, but did not show reactivity with PS100, HMB45, or erb-B2.

The pathogenesis of Paget cells is unclear. In our case, the lesion showed nearly all the clinical, histological and histochemical characteristics of Paget's disease, though without involvement of mammary gland epithelium and underlying carcinoma.

The possibility of an intraepidermal origin, either by transformation from epidermal keratinocytes or by derivation from intraepidermal precursor cells, has to be considered. The differential diagnosis against Toker cell hyperplasia is also discussed.

Intraepidermal cytokeratin 7 immunoreactive cells in the non-neoplastic nipple may represent interepithelial extension of lactiferous duct cells.

Yao DX, Hoda SA, Chiu A, Ying L, Rosen PP.

Department of Pathology, New York Presbyterian Hospital, Weill Cornell Center, New York, NY, USA.


Histopathology 2002 Mar;40(3):230-6 Abstract quote

Intraepidermal cytokeratin 7 immunoreactive cells in the non-neoplastic nipple may represent interepithelial extension of lactiferous duct cellsAims: The interpretation of cytokeratin 7 (CK7)-positive cells in the epidermis of the nipple has been controversial. These cells have been described in Paget's disease of the nipple, and they have also been cited as benign 'Toker' cells or as Merkel cells.

Having observed CK7+ cells in histologically unremarkable nipple biopsies, we sought to assess the distribution of CK7+ cells in Paget's disease of the nipple and in histologically unremarkable nipple.

Methods and results: Representative sections from 37 cases of Paget's disease of the nipple and 32 cases of histologically unremarkable nipple were obtained. The histologically unremarkable nipple sections were taken from prophylactic mastectomies (n=17) and from autopsies of patients who did not have breast cancer (n=15). CK7 immunostaining was performed on sections from formalin-fixed paraffin blocks. Sequential sections were immunostained with antibodies to low-molecular weight cytokeratin-CAM 5.2 and HER-2/neu. CK7+ cells were present in the epidermis around the opening of the lactiferous ducts in Paget's disease (95%) and in histologically unremarkable nipple (45%) cases. CK7+ cells diminished in number with increasing distance from the orifice of the lactiferous ducts. The lactiferous duct epithelium in Paget's disease and in histologically unremarkable nipple was CK7+ in all specimens when this element was present. CAM5.2 immunostaining had a similar but weaker pattern of reactivity. HER-2/neu reactivity was seen in 68% cases of Paget's disease and was negative in all cases of histologically unremarkable nipple. Tumour cells in two cases of Paget's disease were CK7-. In one of these, the underlying breast carcinoma was also CK7-, the only CK7- tumour in this series. In the other case, the normal lactiferous duct was CK7+ and no underlying carcinomatous tissue was available to study.

Conclusions: The presence of CK7+ cells does not equate to Paget's disease of the nipple. Intraepidermal CK7+ cells in the non-neoplastic nipple can be a manifestation of interepithelial extension of benign lactiferous duct cells. The increased presence of CK7+ cells in Paget's disease probably results either from neoplastic transformation of native intraepithelial lactiferous duct cells or form direct extension/migration of neoplastic cells into the nipple. The distribution of CK7 immunoreactive cells in the nipple epidermis can be helpful in the diagnosis of Paget's disease of the nipple.



Paget disease of the breast: analysis of 41 patients.

Fu W, Mittel VK, Young SC.

Department of General Surgery, Providence Hospital & Medical Centers, Southfield, Michigan 48075, USA.

Am J Clin Oncol 2001 Aug;24(4):397-400 Abstract quote

The treatment for the patients with Paget disease of the breast is controversial. This review of its natural history, treatment approach, and clinical outcome will help to formulate treatment. Forty-one patients with a diagnosis of Paget disease of the breast were retrospectively reviewed at Providence Hospital & Medical Centers from 1980 to 1999. Ninety-eight percent of patients had underlying carcinoma (ductal carcinoma in situ and/or invasive ductal cancer).

Patients with a palpable mass have a much higher incidence of invasive ductal cancer, positive lymph node, and a worse survival rate. The median length of follow-up was 42 months (range: 6--200 months). Twenty-seven percent of patients (11/41) had conservative operations, including 1 patient with a palpable mass; 10 patients with no palpable mass; and 3 patients with recurrence after conservative operation. Thirty-seven percent of patients received adjuvant therapy. Paget disease of the breast has very high incidence of underlying carcinoma (100% in a palpable mass, 96% in nonpalpable mass).

Patients with a palpable mass have a worse survival than do patients with nonpalpable mass. Conservative operation should cautiously be selected even for patients with no palpable mass because of a higher recurrence rate.


Paget's disease of the nipple: a ten year review including clinical, pathological, and immunohistochemical findings.

Chaudary MA, Millis RR, Lane EB, Miller NA.

Breast Cancer Res Treat 1986;8(2):139-46 Abstract quote

Thirty-five women with biopsy-proven Paget's disease of the nipple were treated over a 10 year period at the Breast Cancer Unit, Guy's Hospital. Twenty-four (69%) patients had Paget's disease without a palpable mass in the breast; eleven (31%) presented with a palpable mass and Paget's disease of the nipple. Definitive treatment consisted of modified radical mastectomy in 32 patients, radiotherapy only in 2, and one patient had no definitive treatment.

All 11 patients with Paget's disease and an associated lump proved to have invasive ductal carcinoma; five also had associated positive axillary nodes. Nine of the 23 patients with nipple changes only, treated by mastectomy, also had invasive carcinoma; three of these had positive axillary nodes. The remaining 14 patients with nipple changes only were found to have in situ ductal carcinoma, which was extensive in the majority of cases. In 13 cases, histological sections of the nipple were examined by immunohistochemical staining which showed that the Paget's cells expressed a keratin phenotype that was specifically characteristic of simple epithelial cells as seen in glandular epithelium. This was quite unrelated to the normal keratin phenotype of the surrounding skin keratinocytes.

Clinical, pathological, and immunohistochemical data suggest a mammary origin of the abnormal cells in Paget's disease of the nipple. Mastectomy appears to be the treatment of choice.

Paget's disease of the breast: a 33-year experience.

Kollmorgen DR, Varanasi JS, Edge SB, Carson WE

3rd. Division of Surgical Oncology, Roswell Park Cancer Institute, State University of New York at Buffalo, USA.

J Am Coll Surg 1998 Aug;187(2):171-7 Abstract quote

BACKGROUND: Paget's disease (PD) of the breast is an uncommon condition traditionally treated with mastectomy. To assess the natural history and treatment options in PD we have reviewed the experience at the Roswell Park Cancer Institute (RPCI).

STUDY DESIGN: The medical records of patients treated for PD at RPCI between 1963 and 1996 were reviewed.

RESULTS: Eighty patients were treated in the period reviewed. The median follow up was 61 months. Sixty-eight of 80 patients had nipple changes consistent with PD including 30 who had an associated breast mass (group 1), and 38 who had no associated mass (group 2). Of the 68 patients with clinical PD, 58 (85%) were treated with mastectomy while the remainder were treated with some form of breast conserving therapy. Breast cancer (BC) was found in 56 of 68 patients (82%) with clinical PD, including 28 of 30 patients (93%) in group 1 and 28 of 38 patients (74%) in group 2. Breast cancer was centrally located (within 2 cm of the areolar margin) in 61% of patients, including 71% in group 1 and 50% in group 2. Of the 28 patients with an associated BC in group 1, 21 (75%) had invasive cancer, 6 (21%) had ductal carcinoma in situ (DCIS), and 16 (57%) had pathologic axillary nodes. Of the 28 patients with an associated BC in group 2, 10 (36%) had invasive cancer, 18 (64%) had DCIS, and 6 (21%) had positive axillary nodes. The median survival was significantly shorter for group 1 (42 months) than for group 2 (126 months; p = 0.007).

CONCLUSION: Most patients with PD have an associated BC (82%) that was centrally located (61%). In those patients without an associated mass, a significant number (26% in this series) may not have an underlying BC and may be overtreated with mastectomy. On the other hand, a significant number of patients with PD and no associated breast mass will be found to have a peripherally located tumor (29% in this series). These non-central BC masses could potentially be missed by a wide local excision that includes the areolar complex.

Paget's disease of the breast.

Sakorafas GH, Blanchard K, Sarr MG, Farley DR.

Department of Surgery, 251 Hellenic Air Force General Hospital, GR--115 25 Athens, Greece.

Cancer Treat Rev 2001 Feb;27(1):9-18 Abstract quote

Paget's disease of the breast is a rare disorder of the nipple-areola complex that is often associated with an underlying in situ or invasive carcinoma. A change in sensation of the nipple-areola, such as itching and burning, is a common presenting symptom. Objectively, eczematoid changes of the nipple-areola complex are common. The later stages of Paget's disease of the breast are characterized by ulceration and destruction of the nipple-areola complex. Eczematoid changes of the nipple-areola complex and persisting soreness or itching, without obvious reason, is a suspicious symptom for Paget's disease of the breast and calls for thorough evaluation, including mammography. Exfoliative cytology with demonstration of Paget's cells may be useful, but a negative finding does not exclude Paget's disease of the breast. Surgical biopsy is the diagnostic standard and therefore the diagnosis should always be confirmed by open (surgical) biopsy.

The histogenesis of Paget's disease of the breast continues to be debated. The epidermotropic theory holds that Paget's cells are ductal carcinoma cells that have migrated from the underlying breast parenchyma to the nipple epidermis. According to the in situ transformation theory, the Paget's cells arise as malignant cells in the nipple epidermis independent from any other pathologic process within the breast parenchyma. This theory has been proposed to explain those cases in which there is no underlying mammary carcinoma or when there is a carcinoma remote from the nipple-areola complex. Each of these theories is plausible; however, treatment approaches differ markedly depending on the theory of histogenesis.

Mastectomy has been considered the standard of care in the management of patients with Paget's disease of the breast. Nowadays, however, some patients with Paget's disease of the breast are candidates for breast-conserving therapy. Patients must be selected carefully on an individual basis. Until there is a better understanding of the relationship of Paget's disease of the breast to the underlying cancer the surgeon should understand the natural history and behaviour of this lesion and be aware of both the risks of under- and over-treating patients with Paget's disease of the breast.

Breast-conserving therapy for Paget disease of the nipple: a prospective European Organization for Research and Treatment of Cancer study of 61 patients.

Bijker N, Rutgers EJ, Duchateau L, Peterse JL, Julien JP, Cataliotti L;

The EORTC Breast Cancer Cooperative Group. Department of Radiation Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.

Cancer 2001 Feb 1;91(3):472-7 Abstract quote

BACKGROUND: The purpose of the current study was to assess the outcome of breast-conserving therapy by means of a cone excision and radiotherapy in patients with Paget disease of the nipple without associated invasive breast carcinoma.

METHODS: Between 1987 and 1998, 61 eligible patients were registered in the European Organization for Research and Treatment of Cancer Study 10873. The majority of patients (97%) presented without an associated palpable mass. At histologic examination, the majority (93%%) of patients had an underlying ductal carcinoma in situ (DCIS); in the remaining 7%, only Paget disease was found. Treatment was comprised of a complete excision of the nipple-areolar complex including the underlying breast tissue with tumor free margins, followed by external irradiation to the whole breast (50 gray in 25 fractions). The primary endpoint was local recurrence.

RESULTS: At a median follow-up of 6.4 years, 4 of the 61 patients developed a recurrence in the treated breast (1 patient with DCIS and 3 patients with invasive disease). One patient with an invasive local recurrence died of disseminated breast carcinoma. The 5-year local recurrence rate was 5.2% (95% confidence interval, 1.8-14.1%).

CONCLUSIONS: Breast-conserving therapy is a feasible alternative for patients with Paget disease and a limited extent of underlying DCIS. To achieve good local control, treatment should be comprised of a complete excision of the nipple-areolar complex including the underlying disease, followed by irradiation to the whole breast.

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