Mammary and extramammary Paget’s disease are uncommon intraepithelial ad- enocarcinomas. Both conditions have similar clinical features, which mimic inflammatory and infective diseases. His- tological diagnostic confusion can arise between Paget’s disease and other neo- plastic conditions aVecting the skin, with the most common diVerential diagnoses being malignant melanoma and atypical squamous disease. The glandular diVer- entiation of both mammary Paget’s dis- ease and extramammary Paget’s disease is indicated by morphological appear- ances, the presence of intracellular mucin in many cases, and positive immunohisto- chemical staining for glandular cytokerat- ins, epithelial membrane antigen, and carcinoembryonic antigen. This article provides an overview of mammary and extramammary Paget’s disease and dis- cusses recent evidence regarding the cell of origin. The concepts of primary and secondary Paget’s disease are presented and the diVerential diagnosis is discussed with reference to immunohistochemical markers that might be of diagnostic value. 

Mammary Paget’s disease was first described by James Paget in 1874.1 He stated that the malignancy originated in large lactiferous ducts from where it extended into the overlying epidermis. He considered that the changes in the skin preceded and induced malignant change in the underlying breast tissue. Ex- tramammary Paget’s disease was originally described in 1889 by Crocker,2 who reported lesions on the scrotum and penis, with histological features similar to those described by Paget. Crocker believed the tumour to be derived from sweat and sebaceous glands or hair follicles. Dubreuilh described the first case of vulval extramammary Paget’s disease in 1901. Mammary and extramammary Paget’s disease have many similar features, in particu- lar their gross and histological resemblance to a variety of other skin conditions. This article provides an overview of both diseases and the likely cell of origin. The diVerential diagnosis is discussed with reference to immunohisto- chemical markers that might be of diagnostic value. 

Cell of origin in mammary and extramammary Paget’s disease
Mammary Paget’s disease and extramammary Paget’s disease are neoplastic conditions, in which there is intraepithelial (usually intraepi- dermal) infiltration by neoplastic cells showing glandular diVerentiation. In recent years, there has been controversy as to the cell of origin in Paget’s disease, particularly in the extramam- mary form.

The prevailing view is that most, if not all, cases of mammary Paget’s disease originate from in situ or invasive ductal carcinoma in the underlying breast tissue. The origin of ex- tramammary Paget’s disease is less well de- fined, and the findings in mammary Paget’s disease were initially extrapolated in an attempt to explain the development of the extramam- mary form. It was therefore proposed that all cases of extramammary Paget’s disease arose as epidermotropic spread from an in situ or inva- sive neoplasm arising in an adnexal gland within the dermis, analogous to mammary Paget’s disease arising from ductal carcinoma in situ.

However, unlike mammary Paget’s disease, where the proportion of cases in which an associated neoplasm can be demonstrated is high, the extramammary form is associated with an underlying in situ or invasive neoplasm in a much smaller proportion of cases (9–32% in several small studies).3–11 On average, 25% of cases of extramammary Paget’s disease are said to have associated neoplastic disease (in adnexal structures or in organs with a contigu- ous epithelial lining), although the frequency varies with the site of the disease (see below). Many workers, having assumed that ex- tramammary Paget’s disease must, like the mammary form, be associated with an underly- ing neoplasm in most cases, proposed reasons for the low rate of detection of associated neo- plastic disease in extramammary Paget’s dis- ease that include: (1) in situ disease of apocrine glands may manifest only as microscopic foci, confined to sweat gland ducts, and might be overlooked in histological examination9 10; (2) failure to detect a small, in situ or invasive neo- plasm in an adnexal gland, the result of inadequate histological sampling.

Conversely, it was argued that the reason a neoplasm could not be demonstrated in many cases of extramammary Paget’s disease was that, unlike mammary Paget’s disease, most cases arise primarily within the epidermis. Hence, many cases of extramammary Paget’s disease, purporting to demonstrate associated neoplastic disease in the skin, were said to be misdiagnoses based on the following: (1) Paget’s cells from the epidermis may infiltrate and colonise sweat gland ducts and hair follicle epithelium. This colonisation was then indis- tinguishable from primary intraductal carci- noma of the sweat gland. (2) Paget’s disease arising primarily within the epidermis may, with time, progress from intraepidermal neo- plasia (in situ disease) to dermally invasive adenocarcinoma (in a fashion analogous to invasive malignant melanoma arising from superficial spreading malignant mela- noma).12 13 This might subsequently metasta- sise to local lymph nodes and distant sites. Therefore, invasive carcinoma resulting from dermal invasion of epidermal Paget’s cells might be misinterpreted as a primary adnexal carcinoma, which had given rise secondarily to extramammary Paget’s disease.9 In cases with extensive dermal invasion, it may be impossible to prove whether the tumour originated within the epidermis or within an adnexal structure. 

The current theory is that extramammary Paget’s disease arises as a primary intraepider- mal neoplasm in most cases. The tumour cells are proposed to originate either from the intraepidermal cells of apocrine gland ducts or from pluripotent keratinocyte stem cells. The few cases of mammary Paget’s disease in which a breast neoplasm cannot be detected are felt to have a similar explanation.14 Such cases are sometimes referred to as “primary Paget’s dis- ease” to distinguish them from the small number of cases that arise as “secondary” spread from an underlying neoplasm in a dermal adnexal gland or a local organ with contiguous epithelium.9

The immunohistochemical profile of Paget’s cells is well characterised (see below), and indicates that they show definitive glandular diVerentiation. It has become clear that the immunohistochemical profiles of mammary and extramammary Paget’s disease are similar, but subtle diVerences exist that might reflect the diVerent cell of origin in each case. Cases remain, mainly of extramammary Paget’s disease, where the site of origin is still in ques- tion, but regardless of location, Paget’s cells are always adenocarcinoma cells.